Mitochondrial reactive oxygen species (mROS) play a crucial physiological role in intracellular signalling. However, high levels of ROS can overwhelm antioxidant defences and lead to detrimental modifications in protein, lipid and DNA structure and function. Ischaemia-reperfusion injury is a multifaceted pathological state characterised by excessive production of mROS. There is a significant clinical need for therapies mitigating mitochondrial oxidative stress. To date, a variety of strategies have been investigated, ranging from enhancing antioxidant reserve capacity to metabolism reduction. While success has been achieved in non-clinical models, no intervention has yet successfully transitioned into routine clinical practice. In this article, we explore the different strategies investigated and discuss the possible reasons for the lack of translation.

The optimal therapeutic intervention for salvaging ischaemic tissue entails the timely restoration of blood flow – ‘reperfusion’. However, reperfusion itself induces paradoxical damage, resulting in the condition termed ischaemia-reperfusion injury (IRI)’. The concept originated nearly six decades ago when Jennings et al. reported an increase in myocardial infarct size upon reperfusion [1]. In the 1970s, Hearse et al. observed that the reintroduction of oxygen to deprived tissues caused a distinct injury, separate from the initial ischaemic insult [2].

Since the inception of the IRI concept, a rapidly growing body of literature has investigated this pathological phenomenon and its association with various medical procedures including, but not limited to, cardiopulmonary resuscitation (CPR), revascularisation of blocked arteries (e.g. stroke and myocardial infarction) and organ transplantation (Figure 1). In the early 1980s, the concept of ‘oxygen-derived free radicals’ – now termed reactive oxygen species (ROS) – was proposed as a major driving force behind the damage caused by IRI [3]. This premise was rapidly embraced, as the damage induced by IRI was clearly apparent when molecular oxygen was introduced [3]. Reintroduction of oxygen to oxygen-starved tissues created a mismatch between the rate of ROS production and removal [4]. As ROS are formed predominantly within mitochondria, many subsequent studies have targeted mitochondrial pathology and protection strategies.

Publications by year related to ischaemia-reperfusion injury.

Figure 1:
Publications by year related to ischaemia-reperfusion injury.

The search on this database (with data extraction) was conducted on December 22, 2024. IRI, ischaemia-reperfusion injury,; ROS:, reactive oxygen species.

Figure 1:
Publications by year related to ischaemia-reperfusion injury.

The search on this database (with data extraction) was conducted on December 22, 2024. IRI, ischaemia-reperfusion injury,; ROS:, reactive oxygen species.

Close modal

This article considers the physiological significance of mitochondrial reactive oxygen species (mROS) in health and their contribution to IRI. The diverse therapeutic approaches aimed at ameliorating mitochondrial oxidative stress in the context of IRI are subsequently examined.

Mitochondria are the predominant source of ROS, with multiple pathways identified for ROS production [5,6]. Production primarily occurs during oxidative phosphorylation (OXPHOS) at complexes I and III of the electron transport chain (ETC) [6,7]. This occurs in both health and disease states, predominating in the latter in which endogenous antioxidant defences are frequently overwhelmed.

OXPHOS involves a series of oxidation and reduction reactions resulting in the generation of adenosine triphosphate (ATP). These reactions are catalysed by a series of mitochondrial enzymes (complexes I–IV), collectively forming the ETC [8]. Briefly, NADH and FADH2, generated predominantly by the citric acid (Krebs’) cycle, donate electrons to complexes I and II, respectively. Ubiquinone receives electrons predominantly from complexes I and II and transfers them to complex III [8]. Complex III contains two ubiquinone sites (Qo, Qi). At the Qo site, ubiquinol (the reduced form of ubiquinone) passes a single electron to cytochrome c (Cyt c) and the other to the Qi site [7,8]. Reduced Cyt c then shuttles electrons to complex IV, which consists of four metal-based groups facilitating electron transfer to oxygen, the terminal electron acceptor [7,9,10].

As electrons flow through the respiratory chain, complexes I, III and IV induce reactions leading to proton movement from the mitochondrial matrix to the intermembrane space, thereby creating an electrochemical gradient [7,11]. This gradient drives a conformational rotation of complex V (ATP synthase), enabling phosphorylation of adenosine diphosphate (ADP) to ATP [12]. However, as electrons are carried through the ETC, they may prematurely bind to oxygen, forming superoxide (O2•-) [7,13]. While several sites within mitochondria produce ROS in health, complexes I and III are the primary sources [14-17]. Figure 2 depicts mechanisms of ROS formation within the ETC in health.

Mitochondrial physiology and mechanisms of mROS production in health.

Figure 2:
Mitochondrial physiology and mechanisms of mROS production in health.

During normal electron transport chain (ETC) flow, NADH and FADH2 donate electrons to complexes I and II, respectively. Electrons pass down the chain with oxygen being the terminal electron acceptor at complex IV. In doing so, protons are pumped into the intermembrane space via complexes I, III and IV creating an electrochemical gradient. This energy gradient is used by complex V (ATP synthase) to phosphorylate adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which is then used to fuel cellular metabolism. As electrons are carried through the ETC, a small fraction prematurely binds to oxygen, forming superoxide (O2•-). Red stars indicate the most common sources of mROS in health. Mitochondria have strong antioxidant systems that rapidly scavenge mROS to less potent ROS and then to water.

CAT, catalase; e-, electron; FMN, flavin mononucleotide; GPx, glutathione peroxidase; H2O, water; H2O2, hydrogen peroxide; O2, oxygen; Prx, peroxiredoxin; ROS, reactive oxygen species; SOD-2, superoxide dismutase-2; TRx, thioredoxin; TRxR, thioredoxin reductase; UQ, ubiquinone.

Figure 2:
Mitochondrial physiology and mechanisms of mROS production in health.

During normal electron transport chain (ETC) flow, NADH and FADH2 donate electrons to complexes I and II, respectively. Electrons pass down the chain with oxygen being the terminal electron acceptor at complex IV. In doing so, protons are pumped into the intermembrane space via complexes I, III and IV creating an electrochemical gradient. This energy gradient is used by complex V (ATP synthase) to phosphorylate adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which is then used to fuel cellular metabolism. As electrons are carried through the ETC, a small fraction prematurely binds to oxygen, forming superoxide (O2•-). Red stars indicate the most common sources of mROS in health. Mitochondria have strong antioxidant systems that rapidly scavenge mROS to less potent ROS and then to water.

CAT, catalase; e-, electron; FMN, flavin mononucleotide; GPx, glutathione peroxidase; H2O, water; H2O2, hydrogen peroxide; O2, oxygen; Prx, peroxiredoxin; ROS, reactive oxygen species; SOD-2, superoxide dismutase-2; TRx, thioredoxin; TRxR, thioredoxin reductase; UQ, ubiquinone.

Close modal

Physiological mROS production accounts for approximately 1–2% of oxygen consumed by mitochondria in health. mROS play an integral role in intracellular signalling. They are critical mediators within cell differentiation pathways [18-21] and play a role in autophagy and mitophagy [22,23]. mROS play a significant role in adaptation pathways to hypoxia [24,25] and are also required for various functional responses in immune cells including inflammasome activation and phagocytic killing of pathogenic bacteria [26-28].

Antioxidants

Mitochondria are equipped with powerful antioxidant systems that rapidly scavenge mROS. Superoxide dismutase (SOD)-2 is exclusively localised within the mitochondrial matrix where it catalyses dismutation of O2•- to hydrogen peroxide (H2O2) [29]. H2O2 is relatively stable and less harmful compared with O2•-, but it too is an oxidant. Numerous mitochondrial antioxidant systems actively contribute to the conversion of H2O2 into water and oxygen, including catalase (CAT) and the thioredoxin system (thioredoxin reductase (TRxR), thioredoxin (TRx) and peroxiredoxin (Prx)) [30,31] (Figure 2).

Uncoupling proteins

Uncoupling proteins (UCPs) are a five-member family (UCP1-5) of mitochondrial carrier proteins. UCP-1, located within brown adipose tissue, enables a regulated leak of protons across the inner mitochondrial membrane, thereby diverting energy from ATP synthesis to thermogenesis [32]. UCP-2 and UCP-3 are present at much lower abundances than UCP1 [33]. UCP-2, present in multiple tissues, is up-regulated by an increase in H2O2, while UCP-3 is overexpressed in skeletal muscle triggered by an increase in H2O2 and circulating free fatty acids [32,34,35]. UCPs inhibit mROS production via a reduction in the mitochondrial membrane potential [36,37]. UCP-4 and UCP-5 may be involved in thermoregulation within the brain and also protect against oxidative stress [38].

The pathophysiology of IRI can be broadly divided into ischaemic and reperfusion phases [39]. During the ischaemic phase, oxygen depletion results in the slowing of electron flow through the ECT, a fall in mitochondrial membrane potential and a reduction in ATP production [40,41]. The cell reacts by increasing glycolytic (anaerobic) respiration to partially compensate for the decrease in ATP generated by OXPHOS. However, with ischaemia, the rate of ATP production remains insufficient to meet cellular metabolic demands. The decreased flow through the ECT facilitates mROS formation at complex III within the Q cycle and the accumulation of metabolites including succinate, resulting in reverse electron flow from complex II to complex I with increased mROS production at the flavin mononucleotide site ( Figure 3-A) [42,43].

Mechanisms of mROS formation during ischaemia and reperfusion phases.

Figure 3:
Mechanisms of mROS formation during ischaemia and reperfusion phases.

(A) Ischaemia phase. During hypoxia (ischaemia), electron flow down the electron transport chain (ETC) falls. Electrons accumulating at complex II lead to reverse electron flow towards complex I (indicated by red-dotted arrows) with increased ROS production and decreased ATP synthesis. Reduced electron flow also promotes ROS generation at complex III, particularly at the Qi and Qo sites within the Q cycle. These events cause the accumulation of mitochondrial metabolites, setting the stage for an ‘oxidative burst’ upon reperfusion/reoxygenation. (B) Reperfusion phase. Upon reoxygenation, the substrate-driven ETC resumes operation at high capacity, generating more ATP as well as more mitochondrial ROS (mROS). This also forces electrons to flow in reverse from complex II to complex I (again indicated by red-dotted arrows). Red stars mark common sources (complexes I and III) of mROS during reperfusion. The increase in mitochondrial oxidative stress triggers the opening of the mitochondrial permeability transition pore (mPTP) and release of cytochrome Cc (Cyt c), trigerring cell death pathways.

e, electron; H2O, water; O2, oxygen; ROS, reactive oxygen species; UQ, ubiquinone.

Figure 3:
Mechanisms of mROS formation during ischaemia and reperfusion phases.

(A) Ischaemia phase. During hypoxia (ischaemia), electron flow down the electron transport chain (ETC) falls. Electrons accumulating at complex II lead to reverse electron flow towards complex I (indicated by red-dotted arrows) with increased ROS production and decreased ATP synthesis. Reduced electron flow also promotes ROS generation at complex III, particularly at the Qi and Qo sites within the Q cycle. These events cause the accumulation of mitochondrial metabolites, setting the stage for an ‘oxidative burst’ upon reperfusion/reoxygenation. (B) Reperfusion phase. Upon reoxygenation, the substrate-driven ETC resumes operation at high capacity, generating more ATP as well as more mitochondrial ROS (mROS). This also forces electrons to flow in reverse from complex II to complex I (again indicated by red-dotted arrows). Red stars mark common sources (complexes I and III) of mROS during reperfusion. The increase in mitochondrial oxidative stress triggers the opening of the mitochondrial permeability transition pore (mPTP) and release of cytochrome Cc (Cyt c), trigerring cell death pathways.

e, electron; H2O, water; O2, oxygen; ROS, reactive oxygen species; UQ, ubiquinone.

Close modal

Tissue hypoxia sets the scene for excessive mROS formation on reoxygenation [44-46]. The more the mitochondrial metabolites that accumulate during the ischaemic phase, the greater the mROS formation that occurs at reperfusion [42,46,47]. While the extent of pathological damage during the ischaemic interval varies among tissues, it correlates with the duration of ischaemia [48]. At reperfusion, with restoration of oxygen, electron flow through the ETC is significantly accelerated. Mitochondrial membrane potential increases above normal, driving both ATP and mROS production [46]. Succinate accumulated during ischaemia is restored to pre-ischaemic levels within 5 minutes [42]. There is an increased counter-directional movement of electrons from complex II to complex I, resulting in greatly increased ROS production (Figure 3B). Antioxidant defences are overwhelmed, allowing excess mROS to cause damage to its mitochondrial host, other cellular organelles and the plasma membrane. Mitochondrial oxidative stress also opens the mitochondrial permeability transition pore (mPTP) with the release of mitochondrial molecules (e.g. Cyt c and mitochondrial DNA) into the cytosol that, in turn, triggers various cell death pathways [49,50]. Released mitochondrial molecules also act as damage-associated molecular patterns, triggering a systemic inflammatory response [51]. mROS also directly induces the assembly and activation of the NLRP3 inflammasome complex [52,53] that further amplifies the inflammatory response and the pathological progression of IRI. However, as a protective mechanism to mitigate oxidative stress, mitophagy is thereby, activated to selectively degrade damaged mitochondria [54,55].

A significant surge in mROS production initially occurs within minutes of reoxygenation, marking the hyperacute phase [56-59]. This temporal window presents a crucial opportunity for targeted interventions. While enhancing mitochondrial antioxidants is generally considered a protective strategy, incomplete downstream scavenging may still permit some mROS-mediated damage. In contrast, directly modulating metabolism to reduce mROS production is more likely to mitigate upstream effects by lowering mROS formation, thereby preventing secondary damage such as the activation of apoptotic or inflammatory pathways. Figure 4 illustrates cellular pathways activated by mROS elevation during IRI and highlights the therapeutic window for intervention.

Mitochondrial reactive oxygen species (mROS) production pathways during IRI and associated damage mechanisms.

Figure 4:
Mitochondrial reactive oxygen species (mROS) production pathways during IRI and associated damage mechanisms.

ATP: adenosine triphosphate, Cyt c: cytochrome c, DAMPs: damage-associated molecular patterns, O2: oxygen.

Figure 4:
Mitochondrial reactive oxygen species (mROS) production pathways during IRI and associated damage mechanisms.

ATP: adenosine triphosphate, Cyt c: cytochrome c, DAMPs: damage-associated molecular patterns, O2: oxygen.

Close modal

Other mechanisms underlying IRI – calcium overload

During the ischaemic phase, anaerobic respiration increases. Intracellular H+ accumulation leads to decreased intracellular pH and increased sodium influx through the sodium/hydrogen exchanger (NHE) [60]. Excessive intracellular sodium promotes sodium excretion and calcium uptake via the sodium/calcium exchanger (NCE), resulting in significant intracellular calcium accumulation and subsequent calcium overload. Upon re-oxygenation, extracellular pH increases while intracellular pH remains acidic [60]. This pH gradient facilitates the extrusion of H+ from the cell in exchange for sodium [61]. The increased cytosolic sodium can be extruded by Na+-K+ -ATPase or the NCE in exchange for potassium and calcium, respectively, thereby raising intracellular calcium levels [61]. Direct H+/Ca2+ exchange also contributes to calcium overload [60]. Elevated intracellular calcium activates further calcium-induced calcium release from the sarcoplasmic/endoplasmic reticulum into the cytosol [62-64]. In addition, excess mROS can damage cell membrane integrity, increasing permeability and extracellular Ca2+ influx leading to hypercontracture [60,65]. mROS also damage the sarcoplasmic/endoplasmic reticulum membrane, further exacerbating intracellular calcium overload [60,62]. Excessive intracellular calcium enters mitochondria impairing ATP production, activating caspases and calpains, and triggering apoptotic cell death pathways [66].

Inducing mild-to-moderate oxidative stress

mROS at supraphysiological, but non-toxic, concentrations participate in signalling processes that play a protective role [67-69]. This has been applied therapeutically by inducing mild-to-moderate oxidative stress using approaches such as ischaemic pre-conditioning (IPC) and MitoParaquat.

Direct and remote ischaemic pre-conditioning

IPC involves cycles of transient occlusion of blood flow before reperfusion [70]. This strategy was first conceived by Mutty et al. in 1986, who demonstrated its cardioprotective effects [71]. Various techniques have been employed, including proximal or distal methods. Proximal IPC typically involves local occlusion–reperfusion of the affected organ, while distal IPC often uses an inflated blood pressure cuff applied to a limb. Clinical studies have, however, yielded variable results [72], and the optimal technique for IPC remains to be definitively established.

IPC was proposed to enhance resilience of ischaemic tissues to the deleterious effects of ‘second hit’ reperfusion [73]. By inducing mild oxidative stress during the ischaemic phase, IPC initiates signalling pathways to up-regulate the production of mitochondrial antioxidant enzymes [73-77]. Animal models demonstrate increased antioxidant activity in myocardial and cerebral tissues following IPC [74-76]. Of note, administration of antioxidants attenuated the protective effects of IPC [78-80].

Remote ischaemic pre-conditioning (RIPC) utilises transient episodes of ischaemia and reperfusion usually induced by intermittent inflation of an arm blood pressure cuff to protect a distant organ [81]. Previous studies in cardiac surgery suggested cardioprotective effects, including reduced postoperative troponin-I levels [82,83]. However, three large randomised controlled trials (RCTs) investigating RIPC in elective cardiac surgery and before primary percutaneous coronary intervention (PCI) failed to demonstrate clinical benefit [84-86]. Large RCTs investigating the impact of RIPC prior to revascularisation of acute ischaemic stroke have also revealed conflicting results [87-89].

Ischaemic post-conditioning

Ischaemic post-conditioning (IPostC) involves brief ischaemic episodes during early reperfusion. It has been applied both proximally and distally to IRI sites [70]. In dogs, cycles of coronary occlusion–reperfusion during early myocardial reperfusion reduced infarct size similar to IPC [56]. Small proof-of-concept clinical trials suggested that combining PCI with IPostC may reduce infarct size [90-93]; however, magnetic resonance imaging-based studies yielded mixed results [94-96]. The largest RCT, involving 1234 patients with ST-elevation myocardial infarction (STEMI) undergoing conventional PCI with or without IPostC (four cycles of 30 second balloon occlusions and reperfusion), found no effect on either all-cause mortality or hospitalisation for heart failure [97]. Studies utilising both RIPC and IPostC in elective cardiac surgery and during PCI for acute myocardial infarction also found no impact on clinical outcomes [98,99].

MitoParaquat

MitoParaquat is a selective mitochondrial superoxide generator that moderately elevates mROS in anoxia/reoxygenation and cardiac IRI models [100]. Lower doses were protective, while higher doses disrupted Ca2+ homeostasis and mitochondrial function, leading to cell dysfunction and death. The suggested mechanism is the preservation of mPTP integrity [100].

Metabolism reduction

Targeted Temperature Control

Targeted temperature control (TTC), also known as therapeutic hypothermia or targeted temperature management, aims to reduce metabolism by lowering core temperature to between 32°C and 34°C. In animal models, TTC decreases cerebral oxygen consumption, and mROS production, andleading to improved clinical outcomes in the models of circulatory arrest [101-105].

TTC has been investigated clinically in numerous IRI conditions including comatose patients surviving cardiac arrest, MI, stroke, and neonates born with hypoxic-ischaemic encephalopathy (HIE). However, as described below, these clinical trials have been disappointing and have not translated into routine clinical practice in most IRI conditions. Optimal duration [106] and depth of cooling remain uncertain [107,108].

Targeted Temperature Control in cardiac arrest

In 2002, two small RCTs found long-term neurofunctional benefits from TTC in out-of-hospital cardiac arrest (OHCA) patients [109,110]. Consequently, TTC was widely adopted,; however, two subsequent large RCTs failed to show any difference, either for survival or neurological outcomes [111,112]. Of note, the target temperature was only reached at around approximately 8 hours after the initial insult (Table 1,1 ); this delay may explain the negative results. Experimental data suggest a therapeutic window of up to 4 hours for TTC [113]. A recent study did show improved neurological outcomes, but not survival, in patients with non-shockable rhythms undergoing TTC [114].

Table 1:
Summary of the major RCTs testing Targeted Temperature Control in ischaemia-reperfusion injury conditions.
StudyDesignSample sizeConditionTemperatures(°C)Duration (hours)Time to TT (hours)Improved survivalImproved neurological function
Hachimi-Idrissi et al. 2001 [115P-RCT 30 OHCA 34 vs. N No No 
Bernard et al. 2002 [110Qm-rct 77 OHCA 33 vs. N 12 Yes Yes 
HACA 2002 [109M-RCT 275 OHCA 33 ± 1vs. N 24 No Yes 
Hachimi-Idrissi et al. 2005 [116S-RCT 33 OHCA 33 vs. N NR No No 
Hachimi-Idrissi et al. 2005 [116S-RCT 28 OHCA 33 vs. N 24 NR No No 
TTM-1 Trial 2013 [111M-RCT 950 OHCA 33 vs 36 28 No No 
Lascarrou et al. 2019 [114M-RCT 584 CA 33 vs. < 37.8 24 No Yes 
TTM-2 Trial 2021 [112M-RCT 1851 OHCA 33 ± 0.5 vs 37 ± 0.5 28 No No 
Dixon et al. 2002[117M-RCT 42 MI 33 vs. N 0.5 No NA 
Götberg et al. 2010 [118S-RCT 20 MI 33 vs. N 0.5 No NA 
Erlinge et al. 2014 [119M-RCT 120 MI 33 vs. N 0.5 No NA 
Nichol et al. 2015 [120M-RCT 54 MI 32.5–34.9 vs. N 0.3 No NA 
Noc et al. 2021 [121M-RCT 111 MI 32 vs. N No NA 
Els et al. 2006 [122S-RCT 25 MCAO 35 vs. N 48 No No 
Neugebauer et al. 2019 [123M-RCT 50 MCAO 33 ± 1 vs N 72 24 No No 
Gluckman et al. 2005 [124M-RCT 218 Hi.e. 34–35 vs. 37 ± 0.2 72 6 > No Yes1 
Shankaran et al. 2005 [125M-RCT 205 Hi.e. 33.5 vs 36.5-37 72 6 > No Yes1 
Azzopardi et al. 2009 [126M-RCT 325 Hi.e. 33–34 vs. 37 ± 0.2 72 6 > No Yes 
Simbruner et al. 2010 [127M-RCT 129 Hi.e. 33–34 vs. 37 ± 0.5 72 6.2 Yes Yes 
Azzopardi et al. 2014 [128M-RCT 325 Hi.e. 33–34 vs. N 72 NR No Yes 
StudyDesignSample sizeConditionTemperatures(°C)Duration (hours)Time to TT (hours)Improved survivalImproved neurological function
Hachimi-Idrissi et al. 2001 [115P-RCT 30 OHCA 34 vs. N No No 
Bernard et al. 2002 [110Qm-rct 77 OHCA 33 vs. N 12 Yes Yes 
HACA 2002 [109M-RCT 275 OHCA 33 ± 1vs. N 24 No Yes 
Hachimi-Idrissi et al. 2005 [116S-RCT 33 OHCA 33 vs. N NR No No 
Hachimi-Idrissi et al. 2005 [116S-RCT 28 OHCA 33 vs. N 24 NR No No 
TTM-1 Trial 2013 [111M-RCT 950 OHCA 33 vs 36 28 No No 
Lascarrou et al. 2019 [114M-RCT 584 CA 33 vs. < 37.8 24 No Yes 
TTM-2 Trial 2021 [112M-RCT 1851 OHCA 33 ± 0.5 vs 37 ± 0.5 28 No No 
Dixon et al. 2002[117M-RCT 42 MI 33 vs. N 0.5 No NA 
Götberg et al. 2010 [118S-RCT 20 MI 33 vs. N 0.5 No NA 
Erlinge et al. 2014 [119M-RCT 120 MI 33 vs. N 0.5 No NA 
Nichol et al. 2015 [120M-RCT 54 MI 32.5–34.9 vs. N 0.3 No NA 
Noc et al. 2021 [121M-RCT 111 MI 32 vs. N No NA 
Els et al. 2006 [122S-RCT 25 MCAO 35 vs. N 48 No No 
Neugebauer et al. 2019 [123M-RCT 50 MCAO 33 ± 1 vs N 72 24 No No 
Gluckman et al. 2005 [124M-RCT 218 Hi.e. 34–35 vs. 37 ± 0.2 72 6 > No Yes1 
Shankaran et al. 2005 [125M-RCT 205 Hi.e. 33.5 vs 36.5-37 72 6 > No Yes1 
Azzopardi et al. 2009 [126M-RCT 325 Hi.e. 33–34 vs. 37 ± 0.2 72 6 > No Yes 
Simbruner et al. 2010 [127M-RCT 129 Hi.e. 33–34 vs. 37 ± 0.5 72 6.2 Yes Yes 
Azzopardi et al. 2014 [128M-RCT 325 Hi.e. 33–34 vs. N 72 NR No Yes 

1infants with moderate HIE

CA, cardiac arrest (in-hospital and out-of-hospital). HIE, hypoxic-ischaemic encephalopathy. MCAO, middle cerebral artery occlusion. MI, myocardial infarction. M-RCT, multi-centre randomised controlled trial. N, normothermia. NA, not applicable. NR, not reported. OHCA, out-of-hospital cardiac arrest. P-RCT, pilot randomised controlled trial. QM-RCT, quasi-multi-centre randomised controlled trial. S-RCT, single-centre randomised controlled trial.

Targeted Temperature Control in myocardial infarction

TTC in animal models resulted in reduced infarct size and coronary microvascular injury if the target temperature was achieved before reperfusion [129-131]. Small RCTs in STEMI patients, however, failed to demonstrate significant infarct size reduction [117,119-121]. Again, this may be due to technical challenges in achieving rapid, effective cooling in clinical settings. Both cold saline infusion (0.6–2 litres) [118,120] and endovascular cooling [117] were both able to reduce core temperature to aroundapproximately 34.5°C at the time of PCI, but failed to reach the target of 32-33°C. Moreover, these procedures increased door-to-balloon time, potentially causing detriment through a prolonged ischaemia time [120,121].

Targeted Temperature Control in ischaemic stroke

Non-clinical data suggest that TTC is most effective when initiated early after vessel occlusion, at a moderate cooling level (32-34°C) and maintained for over 48 hours [132-134]. TTC combined with hemicraniectomy has been studied in patients with malignant ischaemic stroke. A pilot study using an intravascular cooling catheter was able to safely maintain core temperature at 35°C for 48 hours [122]. A later study induced TTC using cooled saline and maintained a core temperature of 33 ± 1.0°C for three days with intravascular or surface cooling [123]. Patients remained intubated and sedated throughout the induction, maintenance, and rewarming phases. However, severe adverse events, including bradycardia, tachyarrhythmias, deep vein thrombosis, pulmonary oedema and cardiac arrest, resulted in premature trial termination [123].

Targeted Temperature Control in neonatal hypoxic-ischaemic encephalopathy (HIE)

TTC is associated with significant neurological benefits when initiated shortly after birth in neonates with HIE [124-128]. Only one study reported survival benefit from TTC [127], although it does appear to improve long-term neurocognitive function (assessed by IQ scoring at age 6–7 years) in comparison with a normothermic control group [128]. A systematic review and meta-analysis that included 11 RCTs of 1505 subjects with moderate and severe HIE showed consistently superior results with TTC in terms of mortality and neurological disability [135].

Pharmacological modulation of metabolism

Hydrogen sulfphide

Hydrogen sulfphide (herein sulfphide) is a colourless gas with a rotten egg odour, historically identified as a ‘“sewer gas’” and respiratory toxicant. More recently, sulfphide was identified as an important signalling molecule with pleiotropic effects across numerous physiological systems, warranting its inclusion as the third member of the endogenous gasotransmitter class alongside nitric oxide (NO) and carbon monoxide (CO) [136,137]. In a landmark publication in 2005, Blackstone et al.. showed that exogenous sulfphide (administered as inhaled H2S gas) induced a “‘suspended animation-like state”’ in mice [138]. Global metabolism fell rapidly and profoundly, with a 90% fall recorded at 6 hours, as measured by whole-body calorimetry. Importantly, on cessation of the gas, animals showed no adverse effects, with neurological function similar to controls [138]. The mechanism of action is through reversible inhibition of complex IV in the mitochondrial ETC [139]. The rationale for he use of sulfphides in IRI is the decrease in mROS production generated on reperfusion by reducing mitochondrial membrane potential. As sulfphide gas would be difficult, not to mention unpleasant, to administer in a clinical environment, with potential toxicity risks to staff, attention switched to injectable sulfphide generators and donors.

Sulfphide generators

Sulfphide generators (e.g. sodium sulfphide and sodium hydrosulfphide; Na2S and NaHS, respectively) are simple salts that, upon dissolution, near-instantaneously release all of their sulfphur as sulfphide. As such, they facilitate rapid, unregulated sulfphide release, potentially causing off-target effects and compromising its putative efficacy [140]. Notwithstanding this, sulfphide generators have shown promise in various IRI animal models, including cerebral, myocardial, renal, hepatic, and global IRI [141-148]. However, on translation to patients, an RCT (NCT00858936) [149] using Na2S in coronary artery bypass surgery was terminated early, with results unpublished.

Sulfphide donors

Sulfphide donors release sulfphide in a slower, more controlled manner, influenced by several environmental factors (e.g. acidity, pH, temperature, light, and sound) and/or activation mechanisms (e.g. thiols, and enzymes) [140]. The most extensively trialled sulfphide donor in non-clinical studies, GYY4137, showed therapeutic efficacy in a model of myocardial infarction [150]. More, recently, ammonium tetrathiomolybdate (ATTM), a member of the thiometallate drug class, was identified by ourselves [140] and others [151] as a slow-release sulfphide donor. ATTM releases sulfphide in a controlled manner over time and is activated by both acidity and thiols; this dictates that more sulfphide should be released in more ischaemic, more acidic cells that would have a greater need for treatment, and, intracellularly, where higher concentrations of thiols are present [152]. Furthermore, ATTM gains intracellular access through the use of anion exchanger (AE-1) proteins that promote intracellular delivery and limit extracellular, off-target effects [152]. Administration of ATTM in animal models at the point of reperfusion conferred organ protection following myocardial infarction and stroke, and survival benefit following severe haemorrhage/resuscitation [140]. Follow-up studies in rats showed both histological and functional outcome benefits in a regional stroke model [153], and in pigs following myocardial infarction [154].

Sodium thiosulfphate (STS) had cardioprotective effects in isolated rat hearts using the Langendorff model, where it was shown to induce mitochondrial hypometabolism and enhance mROS scavenging [155,156]. Although these effects were not tested in myocardial IRI models in vivo, STS therapy advanced to phase II clinical trials. While a dose-–escalation study in patients with acute coronary syndrome found STS to be safe and well- tolerated [157], a subsequent phase II RCT in patients undergoing PCI for STEMI, with dosing given both pre- and 6 -hours’ post-reperfusion, found STS was well- tolerated but ineffective in reducing infarct size [158].

For more detail, readers are directed to reviews on the therapeutic effects of H2S and sulfphide donors in myocardial and cerebral IRI [159,160].

Nitric oxide

Despite being a reactive species itself, nitric oxide (NO) functions as a gaseous transmitter produced by three isoforms of nitric oxide synthase (NOS): endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). iNOS is produced in response to stimuli such as inflammation and ischaemia. NO inhibits the ETC, particularly complexes I, III, and IV [69,139,161,162]. NO reversibly inhibits complex I through selective S-nitrosation of Cys39, a subunit of NADH dehydrogenase 3, a constituent protein of complex I [162]. Mechanisms underlying complex III inhibition remain unclear, while inhibition of complex IV occurs via competitive binding at the oxygen site [163].

The effects of NO on mitochondria may be pathological or beneficial, or transient or permanent, based on concentration and context. For example, the reaction of NO with superoxide generates a highly potent radical, peroxynitrite (ONOO) which may lead to irreversible inhibition of the ETC [164-166]. However, NO may offer protection against IRI by activating soluble guanylate cyclase to increase the production of cyclic guanylate monophosphate and, thus, increase protein kinase. G (PKG) activity. This pathway, in turn, delays the opening of the mPTP, blocking the release of Cyt c and preventing the activation of the apoptosis [167]. NO may also delay mPTP opening through S-nitrosylation of cyclophilin, a critical mPTP mediator [168]. NO has also been shown to be an important mediator in simulating mitochondrial biogenesis [169]. Clinical trials using NO have been disappointing. In patients presenting with STEMI, inhalation of NO at 80 ppm for 4 -hours post-PCI was safe but, compared towith controls, did not impact onaffect infarct size up to 3 days post-treatment, or on left ventricular ejection fraction at 4 months [170].

Carbon monoxide

Carbon monoxide (CO) is a potent toxicant that impairs oxygen delivery due to its high affinity for haemoglobin, forming carboxyhaemoglobin [171], and oxygen consumption by inhibiting the ETC particularly at complex IV [139,172]. CO is, however, endogenously produced at low levels, functioning as a signalling molecule with anti-inflammatory, anti-apoptotic, and antioxidant properties [173-177]. Clinical application of CO inhalation is, however, restricted due to its potential toxicity and challenges in gas safety regulations [178,179]. Nonetheless, human safety assessments have included exposing healthy volunteers to 500 ppm CO inhalation for one1 hour, with no toxic effects reported [180]. Despite its therapeutic potential, high-dose administration of CO does remain a possible concern due to elevation of carboxyhaemoglobin levels and thus reduction in the oxygen-carrying capacity of haemoglobin [181].

To address this clinical use challenge, CO-releasing molecules (CORMs) were developed to enable safer, and better -targeted CO delivery [182-184]. In rodent models of cardiac arrest, CORMs demonstrated neuroprotective effects and improved survival [185,186]. In large animal models using extracorporeal resuscitation, CORMs producing carboxyhaemoglobin levels of 7–14% were neuroprotective [187]. In a porcine myocardial infarction model, pre-reperfusion CORM administration reduced infarct size and improved left ventricular function [188].

Enhancing the mitochondrial antioxidant system

Coenzyme Q10

Ubiquinone, also known as Coenzyme Q10 (CoQ10), is both a fat-soluble electron carrier in the etc.ETcC and an exogenous mitochondrial antioxidant [189]. Its antioxidant properties arise from its redox forms (ubiquinone, semi-ubiquinone, and ubiquinol) that mitigate mROS generation by preventing premature electron interactions with oxygen. This dual role highlights the importance of CoQ10 in regulating oxidative processes, contributing to both cellular homeostasis and mitochondrial function. In acute MI models, exogenous CoQ10 regulated mitochondrial oxidative stress [190,191]. Small clinical trials have been performed in various IRI conditions, primarily elective cardiac surgery. Patients typically received CoQ10 doses for 3–5 days before surgery, a regimen not applicable to most IRI conditions,; however, the outcomes of these trials were inconsistent ( Table 2,2 ).

Table 2:
Summary of randomised controlled clinical trials employing a pharmacological approach to enhance the mitochondrial antioxidant system during ischaemia-reperfusion injury.
StudySample sizeConditionTreatmentPrimary outcomesResults
Tanaka et al 1982 [21150 Cardiac valve replacement CoQ10 Cardiac output Positive 
Judy et al. 1993 [21220 CABG CoQ10 Speed of recovery, cardiac function, ejection fraction, CoQ10 serum level Positive 
Chello et al. 1994 [21340 CABG CoQ10 Arrhythmias, CoQ10 serum level, MDA, CK-MB Positive 
Taggart et al. 1996 [21420 CABG CoQ10 CoQ10 serum level, troponin T, myoglobin, CK-MB Negative 
Zhou et al. 1999 [21524 Cardiac valve replacement CoQ10 MDA, SOD, CK-MB Positive 
Rosenfeldt et al. 2005 [216121 CABG CoQ10 CoQ10 serum level, troponin I,MDA, hospital stay, quality of life Variable 
Makhija et al. 2008 [21730 CABG CoQ10 Arrhythmias, antioxidant level, inotropic need, length of stay Variable 
Mohseni et al. 2015 [21852 AMI CoQ10 IL-6 level, ICAM1 level Positive 
Ramezani et al. 2020 [21960 AIS CoQ10 Neurological outcomes, SOD, MDA Negative 
Dwaich et al. 2016 [22045 CABG Melatonin Troponin I, IL-1ß, Caspase-3, Positive 
Ekeloef et al. 2017 [20948 MI Melatonin Myocardial salvage index,troponin I, CK-MB, MDA, MPO Negative 
Rodrigues et al. 2016 [208146 MI Melatonin Infarct size, death, CHF Negative 
Shafiei et al. 2018 [20660 CABG Melatonin Troponin I, lactate, MDA, TNF-α Positive 
Zhao et al. 2018 [20460 Carotid stenosis Melatonin SOD, GPx, CAT, TNF-alpha, IL-6, Positive 
Panah et al. 2019 [21040 Renal transplant Melatonin Renal function, MDA, TNF-α Positive 
Nasseh et al. 2022 [207100 CABG Melatonin Troponin 1, CRP, CK-MB,length of stay Variable 
Gibson et al. 2016 [221118 MI MTP131 Safety, myocardial infarct size Safe, Negative 
Saad et al. 2017 [22214 Renal IRI MTP131 Renal function, BP, GFR Positive 
StudySample sizeConditionTreatmentPrimary outcomesResults
Tanaka et al 1982 [21150 Cardiac valve replacement CoQ10 Cardiac output Positive 
Judy et al. 1993 [21220 CABG CoQ10 Speed of recovery, cardiac function, ejection fraction, CoQ10 serum level Positive 
Chello et al. 1994 [21340 CABG CoQ10 Arrhythmias, CoQ10 serum level, MDA, CK-MB Positive 
Taggart et al. 1996 [21420 CABG CoQ10 CoQ10 serum level, troponin T, myoglobin, CK-MB Negative 
Zhou et al. 1999 [21524 Cardiac valve replacement CoQ10 MDA, SOD, CK-MB Positive 
Rosenfeldt et al. 2005 [216121 CABG CoQ10 CoQ10 serum level, troponin I,MDA, hospital stay, quality of life Variable 
Makhija et al. 2008 [21730 CABG CoQ10 Arrhythmias, antioxidant level, inotropic need, length of stay Variable 
Mohseni et al. 2015 [21852 AMI CoQ10 IL-6 level, ICAM1 level Positive 
Ramezani et al. 2020 [21960 AIS CoQ10 Neurological outcomes, SOD, MDA Negative 
Dwaich et al. 2016 [22045 CABG Melatonin Troponin I, IL-1ß, Caspase-3, Positive 
Ekeloef et al. 2017 [20948 MI Melatonin Myocardial salvage index,troponin I, CK-MB, MDA, MPO Negative 
Rodrigues et al. 2016 [208146 MI Melatonin Infarct size, death, CHF Negative 
Shafiei et al. 2018 [20660 CABG Melatonin Troponin I, lactate, MDA, TNF-α Positive 
Zhao et al. 2018 [20460 Carotid stenosis Melatonin SOD, GPx, CAT, TNF-alpha, IL-6, Positive 
Panah et al. 2019 [21040 Renal transplant Melatonin Renal function, MDA, TNF-α Positive 
Nasseh et al. 2022 [207100 CABG Melatonin Troponin 1, CRP, CK-MB,length of stay Variable 
Gibson et al. 2016 [221118 MI MTP131 Safety, myocardial infarct size Safe, Negative 
Saad et al. 2017 [22214 Renal IRI MTP131 Renal function, BP, GFR Positive 

AIS, acute ischaemic stroke. AMI, acute myocardial infarction. BP, blood pressure. CABG, coronary artery bypass graft. CAT, catalase. CHF, congestive heart failure. CK-MB, creatine kinase myocardial band. CoQ10, coenzyme Q10. GFR, glomerular filtration rate. GPx, glutathione peroxidase. ICAM-1, intercellular adhesion molecule-1. IL-1ß, interleukin-1 beta. IL-6, interleukin-6. MDA, malondialdehyde. MI, myocardial infarction. MPO, myeloperoxidase. SOD, superoxide dismutase. TNF-α, tumor necrosis factor-alpha.

MitoQ (mitoquinol)

MitoQ is a modified form of CoQ10. It acts as a mitochondrial-targeted antioxidant that enters mitochondria more readily due to its positive charge. It comprises the antioxidant quinone moiety covalently attached to a lipophilic triphenylphosphonium cation [192]. Once inside the mitochondria, MitoQ accumulates on the matrix surface of the inner membrane, where it is continually recycled to the active quinol antioxidant form by complex II in the ETC [192].

MitoQ has been tested in various IRI models [193-196] but not yet in humans. Given the evidence suggesting that mitochondrial oxidative stress is a pathogenic factor in Parkinson’s disease [197,198], MitoQ has been tested in this patient group but failed to impact on disease progression [199].

Melatonin

Melatonin is an endogenous mitochondrial-targeted antioxidant that directly detoxifies mROS produced during IRI [200]. Experimental evidence supports its efficacy across various IRI models [201-204]. Melatonin transforms mROS into less toxic reactive species and generatinges by-products (melatonin metabolites) that also have ROS scavenging effects [205].

Two small trials found that melatonin significantly reduced myocardial damage when given for 1–5 days preoperatively in patients undergoing coronary artery bypass graft surgery [206]. In a more recent study involving 100 patients, melatonin was administered twice before reperfusion [207]. While CK-MB levels were lower in the melatonin group compared towith placebo, neither troponin nor inflammatory markers were affected. In acute STEMI patients, melatonin was given both pre- and post-reperfusion yetbut failed to show superior clinical outcomes [208,209]. Melatonin did show benefits in patients undergoing carotid endarterectomy and renal transplantation [204,210] (please refer to Table 2 for additional details). While small trials do indicate potential, the overall clinical evidence for melatonin use remains uncertain.

Bendavia

Bendavia, also known as MTP-131 or elamipretide, is a targeted mitochondrial antioxidant that penetrates cell membranes and selectively binds to cardiolipin in the inner mitochondrial membrane [223-225]. MTP-131 may also work by promoting mitochondrial supercomplex formation, which improves electron transfer efficiency and reduces mROS production [225,226]. MTP-131 scavenges mROS in various IRI models, including cardiac, hepatic, kidney, and cerebral [227-231]. A phase II trial in STEMI patients undergoing PCI found that MTP-131 was safe but ineffective in reducing cardiac infarct size, as measured by CK-MB [221]. In a small study of patients with renal artery stenosis undergoing revascularizsation, MTP-131 improved renal blood flow, renal function, and blood pressure stability [222]. Larger RCTs are needed for a conclusive assessment of the utility of this approach.

Other mitochondrial-directed strategies

Various other pharmacological strategies have been tested to mitigate the damage caused by IRI through varying effects on mitochondria, though clinical data have been largely disappointing. Cyclosporine A has been investigated for its potential to prevent the opening of the mPTP, thereby blocking apoptosis and reducing mitochondrial calcium influx. While it showed promising effects in multiple experimental IRI models [232-236], these results could not be replicated in clinical trials involving patients with acute anterior ST-elevation myocardial infarction or out-of-hospital cardiac arrest [237,238].

Accumulation of the Krebs’ cycle intermediate, succinate, during ischaemia results in mROS production during reperfusion and injury. This could be blocked by dimethyl malonate, a membrane-permeable precursor of the succinate dehydrogenase competitive inhibitor, malonate [42,239-241]. A subsequent study using diacetoxymethyl malonate diester (MAM), which rapidly delivers malonate to cells, reported cardioprotectivity [242]. However, the optimal dose of dimethyl malonate remains to be defined before progression to “‘proof of concept”’ clinical studies to enhance its translational potential [242].

Several therapies have been trialled in large RCTs that sought to reduce calcium overload and, thus, the extent of reperfusion injury. The EXPEDITION study assessed cariporide, a sodium hydrogen exchanger isoform-1 (NHE-1) inhibitor in 5761 high-risk patients undergoing coronary artery bypass graft surgery which, by limiting intracellular sodium accumulation, also limits Na/Ca-exchanger-mediated calcium overload [243]. While there was a highly significant short-term reduction in myocardial infarction with cariporide, there was, however, an increase in mortality related to an increase in cerebrovascular events, albeit significance was lost by 6 months. Another strategy trialled in 3023 intermediate- to high-risk patients undergoing cardiac bypass graft surgery was the use of MC-1, a purinergic receptor antagonist, which prevents cellular calcium overload by antagonizsing the positive inotropic effect of extracellular ATP [244]. Unfortunately, no impact was seen on the composite outcome of cardiovascular death or nonfatal myocardial infarction.

Enthusiasm has also been shown for pre- or post-conditioning with volatile anaesthetics such as isoflurane and sevoflurane for cardio- or neuro-protection. Multiple mechanisms of action have been proposed, including impacts on adenosine signalling, activation of sarcolemmal or mitochondrial ATP-sensitive potassium channels, G protein-coupled receptor activation, and small-burst ROS production, and suppressionng of apoptosis through inhibiting the release of Ca2+ and phospholipase C or through activationng of Akt [245-247]. While some laboratory models, small clinical trials, and early RCTs did show benefits [245-248], these have not been reproduced in more recent large RCTs., e.g. [249,250].

IRI creates a state of oxidative stress responsible for organ dysfunction and activation of multiple cell death pathways. Various mechanisms are implicated, including excess mitochondrial ROS production, calcium overload, and other inflammatory processes. These are magnified during the reperfusion phase, which, thus, represents an important window for treatment. This review has focussed primarily on interventions that aim to decrease mitochondria-generated oxidative stress with a brief mention of other non-mitochondrial-targeted approaches. Unfortunately, all strategies aimed at attenuating these mechanisms have so far failed to translate to routine clinical practice, despite often promising non-clinical results and positive outcomes from small clinical cohorts, yet failure at the level of the large multi-centre randomised trial. Some reasons for these repeated failures can be identified. For example, the targeted temperature control trials did not attain target temperatures for at least 4–6 hours, by which time much of the reperfusion injury has likely occurred. Indeed, mitochondrial ROS production peaks within the first minutes of reperfusion, highlighting this period as the optimal therapeutic window for intervention [56-59]. Pre-conditioning and post-conditioning studies have adopted a wide variety of direct and remote techniques, and few, if any, head-to-head comparisons have been performed to identify an optimal strategy. Even the same concept, IPC induced by intermittent limb ischaemia, has been applied in a diverse manner. To our knowledge, no clear attempt has been made to determine the best approach. Similarly, with the pharmacological approaches, optimal dosing and duration regimens have not often not been characterised before embarking on large Phase III studies, while the Phase II studies have usually focussed on a clinical signal suggesting benefit rather than confirming a clear biological effect such as a reduction in oxidative damage. The non-clinical model designs should also come under scrutiny. These usually utilise young, healthy animals without comorbidities, and the results may not be generalisable to older, comorbid patient populations. Species differences in terms of responsible pathways and drug dosing may also be relevant.

Because of the imperative for early intervention to ameliorative oxidative stress, pharmacological approaches most likely offer the greatest chance of success, particularly for acute ischaemic conditions such as stroke, haemorrhagic shock and myocardial infarction. The main mitochondrial strategies are either to boost antioxidant defences, to prevent downstream processes such as the opening of the mPTP which can lead to cell death, or to attenuate the degree of ROS production. Our personal bias is towards the latter strategy, as this tackles the problem at the source.

A final consideration is a multi-modal approach, for example, targeting both calcium overload and mitochondrial ROS production. WhileAs an attractive proposition, this runs counter to standard approaches that rely on first demonstrating efficacy with one agent and then seeking incremental benefit from the addition of another. Until a first agent success can be clearly demonstrated, this is unlikely to happen.

IRI is a complex pathological condition associated with the excess production of mROS that overwhelms endogenous antioxidant defences. The consequence is structural and functional modifications in proteins, lipids and DNA, withleading to cell death. There remains an unmet clinical need to ameliorate oxidative stress, though promising non-clinical findings have yet to translate into routine clinical practice.

A.D. and M.S. are developing thiometallates for the treatment of ischaemia-reperfusion injury.

Khalid Alotaibi: Writing – original draft, review and editing. Nishkantha Arulkumaran: Writing – review and editing. Alex Dyson: Writing – review and editing. Mervyn Singer: Writing – review and editing.

We thank Drs Pietro Arina and Naveed Saleem for providing insights and discussion. BioRender was used to generate Figures 2 and 3.

ADP

adenosine diphosphate

AIS

acute ischaemic stroke

AMI

acute myocardial infarction

ATP

adenosine triphosphate

ATTM

ammonium tetrathiomolybdate

BP

blood pressure

CA

cardiac arrest (in-hospital and out-of-hospital)

CAT

catalase

CHF

congestive heart failure

CK-MB

creatine kinase myocardial band

CO

carbon monoxide

CORMs

CO-releasing molecules

CPR

cardiopulmonary resuscitation

CoQ10

coenzyme Q10

Cyt c

cytochrome c

ETC

electron transport chain

FMN

flavin mononucleotide

GFR

glomerular filtration rate

GPx

glutathione peroxidase

HIE

hypoxic-ischaemic encephalopathy

ICAM-1

intercellular adhesion molecule-1

IL-1ß

interleukin-1 beta

IL-6

interleukin-6

IPC

ischaemic pre-conditioning

IPostC

ischaemic post-conditioning

IRI

ischaemia-reperfusion injury

MAM

diacetoxymethyl malonate diester

MCAO

middle cerebral artery occlusion

MI

myocardial infarction

MPO

myeloperoxidase

M-RCT

multi-centre randomised controlled trial

NA

not applicable

NCE

sodium/calcium exchanger

NHE-1

sodium hydrogen exchanger isoform-1

NHE

sodium/hydrogen exchanger

NO

nitric oxide

NOS

nitric oxide synthase

NR

not reported

OHCA

out-of-hospital cardiac arrest

Prx

peroxiredoxin

RIPC

remote ischaemic pre-conditioning

ROS

reactive oxygen species

SOD-2

superoxide dismutase-2

SOD

superoxide dismutase

S-RCT

single-centre randomised controlled trial

STEMI

ST-elevation myocardial infarction

TNF-α

tumor necrosis factor-alpha

TRx

thioredoxin

TRxR

thioredoxin reductase

UCPs

uncoupling proteins

UQ

ubiquinone

eNOS

endothelial nitric oxide synthase

iNOS

inducible nitric oxide synthase

mPTP

mitochondrial permeability transition pore

mROS

mitochondrial reactive oxygen species

nNOS

neuronal nitric oxide synthase

1
Jennings
,
R.B.
,
Sommers
,
H.M.
,
Smyth
,
G.A.
,
Flack
,
H.A.
and
Linn
,
H
. (
1960
)
Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog
.
Arch. Pathol.
70
,
68
78
2
Hearse
,
D.J.
,
Humphrey
,
S.M.
and
Chain
,
E.B
. (
1973
)
Abrupt reoxygenation of the anoxic potassium-arrested perfused rat heart: a study of myocardial enzyme release
.
J. Mol. Cell. Cardiol.
5
,
395
407
https://doi.org/10.1016/0022-2828(73)90030-8
3
Guarnieri
,
C.
,
Flamigni
,
F.
and
Caldarera
,
C.M
. (
1980
)
Role of oxygen in the cellular damage induced by re-oxygenation of hypoxic heart
.
J. Mol. Cell. Cardiol.
12
,
797
808
https://doi.org/10.1016/0022-2828(80)90081-4
4
Granger
,
D.N.
,
Rutili
,
G.
and
McCord
,
J.M
. (
1981
)
Superoxide radicals in feline intestinal ischemia
.
Gastroenterology
81
,
22
29
https://doi.org/10.1016/0016-5085(81)90648-X
5
Mailloux
,
R.J
. (
2020
)
An update on mitochondrial reactive oxygen species production
.
Antioxidants (Basel).
9
,
472
https://doi.org/10.3390/antiox9060472
6
Brand
,
M.D
. (
2016
)
Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling
.
Free Radic. Biol. Med.
100
,
14
31
https://doi.org/10.1016/j.freeradbiomed.2016.04.001
7
Wang
,
Y.
and
Hekimi
,
S
. (
2016
)
Understanding ubiquinone
.
Trends Cell Biol.
26
,
367
378
https://doi.org/10.1016/j.tcb.2015.12.007
8
Lenaz
,
G.
and
Genova
,
M.L
. (
2010
)
Structure and organization of mitochondrial respiratory complexes: a new understanding of an old subject
.
Antioxid. Redox Signal.
12
,
961
1008
https://doi.org/10.1089/ars.2009.2704
9
Pierron
,
D.
,
Wildman
,
D.E.
,
Hüttemann
,
M.
,
Markondapatnaikuni
,
G.C.
,
Aras
,
S.
and
Grossman
,
L.I
. (
2012
)
Cytochrome c oxidase: evolution of control via nuclear subunit addition
.
Biochim. Biophys. Acta
1817
,
590
597
https://doi.org/10.1016/j.bbabio.2011.07.007
10
Kadenbach
,
B
. (
2021
)
Complex IV - The regulatory center of mitochondrial oxidative phosphorylation
.
Mitochondrion
58
,
296
302
https://doi.org/10.1016/j.mito.2020.10.004
11
Nunnari
,
J.
and
Suomalainen
,
A
. (
2012
)
Mitochondria: in sickness and in health
.
Cell
148
,
1145
1159
https://doi.org/10.1016/j.cell.2012.02.035
12
Okuno
,
D.
,
Iino
,
R.
and
Noji
,
H
. (
2011
)
Rotation and structure of FoF1-ATP synthase
.
J. Biochem.
149
,
655
664
https://doi.org/10.1093/jb/mvr049
13
Hernansanz-Agustín
,
P.
and
Enríquez
,
J.A
. (
2021
)
Generation of reactive oxygen species by mitochondria
.
Antioxidants (Basel).
10
,
415
https://doi.org/10.3390/antiox10030415
14
Saggau
,
W.W.
,
Baća
,
I.
,
Fey
,
K.
,
Metzker
,
M.
and
Mittmann
,
U
. (
1979
)
Regional myocardial blood flow and ventricle function following hypothermic ischemia and cardioplegia
.
Chir. Forum Exp. Klin. Forsch.
33
38
15
Pryde
,
K.R.
and
Hirst
,
J
. (
2011
)
Superoxide is produced by the reduced flavin in mitochondrial complex I: a single, unified mechanism that applies during both forward and reverse electron transfer
.
J. Biol. Chem.
286
,
18056
18065
https://doi.org/10.1074/jbc.M110.186841
16
Muller
,
F.L.
,
Roberts
,
A.G.
,
Bowman
,
M.K.
and
Kramer
,
D.M
. (
2003
)
Architecture of the Qo site of the cytochrome bc1 complex probed by superoxide production
.
Biochemistry
42
,
6493
6499
https://doi.org/10.1021/bi0342160
17
Cape
,
J.L.
,
Bowman
,
M.K.
and
Kramer
,
D.M
. (
2007
)
A semiquinone intermediate generated at the Qo site of the cytochrome bc1 complex: importance for the Q-cycle and superoxide production
.
Proc. Natl. Acad. Sci. U.S.A.
104
,
7887
7892
https://doi.org/10.1073/pnas.0702621104
18
Owusu-Ansah
,
E.
and
Banerjee
,
U
. (
2009
)
Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation
.
Nature New Biol.
461
,
537
541
https://doi.org/10.1038/nature08313
19
Tormos
,
K.V.
,
Anso
,
E.
,
Hamanaka
,
R.B.
,
Eisenbart
,
J.
,
Joseph
,
J.
,
Kalyanaraman
,
B.
et al.
(
2011
)
Mitochondrial complex III ROS regulate adipocyte differentiation
.
Cell Metab.
14
,
537
544
https://doi.org/10.1016/j.cmet.2011.08.007
20
Hamanaka
,
R.B.
,
Glasauer
,
A.
,
Hoover
,
P.
,
Yang
,
S.
,
Blatt
,
H.
,
Mullen
,
A.R.
et al.
(
2013
)
Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development
.
Sci. Signal.
6
, ra8 https://doi.org/10.1126/scisignal.2003638
21
Zhang
,
H.
,
Menzies
,
K.J.
and
Auwerx
,
J
. (
2018
)
The role of mitochondria in stem cell fate and aging
.
Development (Rome)
145
, dev143420 https://doi.org/10.1242/dev.143420
22
Roca-Agujetas
,
V.
de Dios
,
C.
Lestón
,
L.
,
Marí
,
M.
,
Morales
,
A.
and
Colell
,
A
. (
2019
)
Recent insights into the mitochondrial role in autophagy and its regulation by oxidative stress
.
Oxid. Med. Cell. Longev.
2019
, 3809308 https://doi.org/10.1155/2019/3809308
23
Sena
,
L.A.
and
Chandel
,
N.S
. (
2012
)
Physiological roles of mitochondrial reactive oxygen species
.
Mol. Cell
48
,
158
167
https://doi.org/10.1016/j.molcel.2012.09.025
24
Viollet
,
B.
,
Athea
,
Y.
,
Mounier
,
R.
,
Guigas
,
B.
,
Zarrinpashneh
,
E.
,
Horman
,
S.
et al.
(
2009
)
AMPK: Lessons from transgenic and knockout animals
.
Front Biosci (Landmark Ed)
14
,
19
44
https://doi.org/10.2741/3229
25
Gonzalez
,
F.J.
,
Xie
,
C.
and
Jiang
,
C
. (
2018
)
The role of hypoxia-inducible factors in metabolic diseases
.
Nat. Rev. Endocrinol.
15
,
21
32
https://doi.org/10.1038/s41574-018-0096-z
26
Garaude
,
J.
,
Acín-Pérez
,
R.
,
Martínez-Cano
,
S.
,
Enamorado
,
M.
,
Ugolini
,
M.
,
Nistal-Villán
,
E.
et al.
(
2016
)
Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense
.
Nat. Immunol.
17
,
1037
1045
https://doi.org/10.1038/ni.3509
27
West
,
A.P.
,
Shadel
,
G.S.
and
Ghosh
,
S
. (
2011
)
Mitochondria in innate immune responses
.
Nat. Rev. Immunol.
11
,
389
402
https://doi.org/10.1038/nri2975
28
West
,
A.P.
,
Brodsky
,
I.E.
,
Rahner
,
C.
,
Woo
,
D.K.
,
Erdjument-Bromage
,
H.
,
Tempst
,
P.
et al.
(
2011
)
TLR signalling augments macrophage bactericidal activity through mitochondrial ROS
.
Nature New Biol.
472
,
476
480
https://doi.org/10.1038/nature09973
29
Murphy
,
M.P
. (
2009
)
How mitochondria produce reactive oxygen species
.
Biochem. J.
417
,
1
13
https://doi.org/10.1042/BJ20081386
30
Napolitano
,
G.
,
Fasciolo
,
G.
and
Venditti
,
P
. (
2021
)
Mitochondrial management of reactive oxygen species
.
Antioxidants (Basel).
10
,
1824
https://doi.org/10.3390/antiox10111824
31
Holmgren
,
A.
and
Lu
,
J
. (
2010
)
Thioredoxin and thioredoxin reductase: current research with special reference to human disease
.
Biochem. Biophys. Res. Commun.
396
,
120
124
https://doi.org/10.1016/j.bbrc.2010.03.083
32
Echtay
,
K.S.
,
Roussel
,
D.
,
St-Pierre
,
J.
,
Jekabsons
,
M.B.
,
Cadenas
,
S.
,
Stuart
,
J.A.
et al.
(
2002
)
Superoxide activates mitochondrial uncoupling proteins
.
Nature New Biol.
415
,
96
99
https://doi.org/10.1038/415096a
33
Brand
,
M.D.
and
Esteves
,
T.C
. (
2005
)
Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3
.
Cell Metab.
2
,
85
93
https://doi.org/10.1016/j.cmet.2005.06.002
34
Anedda
,
A.
,
López-Bernardo
,
E.
,
Acosta-Iborra
,
B.
,
Saadeh Suleiman
,
M.
,
Landázuri
,
M.O.
and
Cadenas
,
S
. (
2013
)
The transcription factor Nrf2 promotes survival by enhancing the expression of uncoupling protein 3 under conditions of oxidative stress
.
Free Radic. Biol. Med.
61
,
395
407
https://doi.org/10.1016/j.freeradbiomed.2013.04.007
35
Murray
,
A.J.
,
Panagia
,
M.
,
Hauton
,
D.
,
Gibbons
,
G.F.
and
Clarke
,
K
. (
2005
)
Plasma free fatty acids and peroxisome proliferator-activated receptor alpha in the control of myocardial uncoupling protein levels
.
Diabetes
54
,
3496
3502
https://doi.org/10.2337/diabetes.54.12.3496
36
Nègre-Salvayre
,
A.
,
Hirtz
,
C.
,
Carrera
,
G.
,
Cazenave
,
R.
,
Troly
,
M.
,
Salvayre
,
R.
et al.
(
1997
)
A role for uncoupling protein-2 as A regulator of mitochondrial hydrogen peroxide generation
.
Faseb J.
11
,
809
815
https://doi.org/10.1096/fasebj.11.10.9271366
37
Zhao
,
R.Z.
,
Jiang
,
S.
,
Zhang
,
L.
and
Yu
,
Z.B
. (
2019
)
Mitochondrial electron transport chain, ROS generation and uncoupling (Review)
.
Int. J. Mol. Med.
44
,
3
15
https://doi.org/10.3892/ijmm.2019.4188
38
Hass
,
D.T.
and
Barnstable
,
C.J
. (
2021
)
Uncoupling proteins in the mitochondrial defense against oxidative stress
.
Prog. Retin. Eye Res.
83
, 100941 https://doi.org/10.1016/j.preteyeres.2021.100941
39
Nastos
,
C.
,
Kalimeris
,
K.
,
Papoutsidakis
,
N.
,
Tasoulis
,
M.-K.
,
Lykoudis
,
P.M.
,
Theodoraki
,
K.
et al.
(
2014
)
Global consequences of liver ischemia/reperfusion injury
.
Oxid. Med. Cell. Longev.
2014
, 906965 https://doi.org/10.1155/2014/906965
40
Ansari
,
F.
,
Yoval-Sánchez
,
B.
,
Niatsetskaya
,
Z.
,
Sosunov
,
S.
,
Stepanova
,
A.
,
Garcia
,
C.
et al.
(
2021
)
Quantification of NADH:ubiquinone oxidoreductase (complex I) content in biological samples
.
J. Biol. Chem.
297
, 101204 https://doi.org/10.1016/j.jbc.2021.101204
41
Galkin
,
A.
,
Abramov
,
A.Y.
,
Frakich
,
N.
,
Duchen
,
M.R.
and
Moncada
,
S
. (
2009
)
Lack of oxygen deactivates mitochondrial complex I: implications for ischemic injury?
J. Biol. Chem.
284
,
36055
36061
https://doi.org/10.1074/jbc.M109.054346
42
Chouchani
,
E.T.
,
Pell
,
V.R.
,
Gaude
,
E.
,
Aksentijević
,
D.
,
Sundier
,
S.Y.
,
Robb
,
E.L.
et al.
(
2014
)
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
.
Nature New Biol.
515
,
431
435
https://doi.org/10.1038/nature13909
43
Robb
,
E.L.
,
Hall
,
A.R.
,
Prime
,
T.A.
,
Eaton
,
S.
,
Szibor
,
M.
,
Viscomi
,
C.
et al.
(
2018
)
Control of mitochondrial superoxide production by reverse electron transport at complex I
.
J. Biol. Chem.
293
,
9869
9879
https://doi.org/10.1074/jbc.RA118.003647
44
Stepanova
,
A.
,
Shurubor
,
Y.
,
Valsecchi
,
F.
,
Manfredi
,
G.
and
Galkin
,
A
. (
2016
)
Differential susceptibility of mitochondrial complex II to inhibition by oxaloacetate in brain and heart
.
Biochim. Biophys. Acta
1857
,
1561
1568
https://doi.org/10.1016/j.bbabio.2016.06.002
45
Schlegel
,
A.
,
Muller
,
X.
,
Mueller
,
M.
,
Stepanova
,
A.
,
Kron
,
P.
de Rougemont
,
O
et al.
(
2020
)
Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation
.
EBioMedicine
60
, 103014 https://doi.org/10.1016/j.ebiom.2020.103014
46
Panconesi
,
R.
,
Widmer
,
J.
,
Carvalho
,
M.F.
,
Eden
,
J.
,
Dondossola
,
D.
,
Dutkowski
,
P.
et al.
(
2022
)
Mitochondria and ischemia reperfusion injury
.
Curr. Opin. Organ Transplant.
27
,
434
445
https://doi.org/10.1097/MOT.0000000000001015
47
Kussmaul
,
L.
and
Hirst
,
J
. (
2006
)
The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria
.
Proc. Natl. Acad. Sci. U.S.A.
103
,
7607
7612
https://doi.org/10.1073/pnas.0510977103
48
Soares
,
R.O.S.
,
Losada
,
D.M.
,
Jordani
,
M.C.
,
Évora
,
P.
and
Castro-E-Silva
,
O
. (
2019
)
Ischemia/Reperfusion injury revisited: an overview of the latest pharmacological strategies
.
Int. J. Mol. Sci.
20
,
5034
https://doi.org/10.3390/ijms20205034
49
Minutoli
,
L.
,
Puzzolo
,
D.
,
Rinaldi
,
M.
,
Irrera
,
N.
,
Marini
,
H.
,
Arcoraci
,
V.
et al.
(
2016
)
ROS-Mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury
.
Oxid. Med. Cell. Longev.
2016
, 2183026 https://doi.org/10.1155/2016/2183026
50
Li
,
H.
,
Xia
,
Z.
,
Chen
,
Y.
,
Qi
,
D.
and
Zheng
,
H
. (
2018
)
Mechanism and therapies of oxidative stress-mediated cell death in ischemia reperfusion injury
.
Oxid. Med. Cell. Longev.
2018
, 2910643 https://doi.org/10.1155/2018/2910643
51
Zhang
,
Q.
,
Raoof
,
M.
,
Chen
,
Y.
,
Sumi
,
Y.
,
Sursal
,
T.
,
Junger
,
W.
et al.
(
2010
)
Circulating mitochondrial DAMPs cause inflammatory responses to injury
.
Nature New Biol.
464
,
104
107
https://doi.org/10.1038/nature08780
52
Schroder
,
K.
and
Tschopp
,
J
. (
2010
)
The inflammasomes
.
Cell
140
,
821
832
https://doi.org/10.1016/j.cell.2010.01.040
53
Zhou
,
R.
,
Yazdi
,
A.S.
,
Menu
,
P.
and
Tschopp
,
J
. (
2011
)
A role for mitochondria in NLRP3 inflammasome activation
.
Nature New Biol.
469
,
221
225
https://doi.org/10.1038/nature09663
54
Xiao
,
B.
,
Goh
,
J.Y.
,
Xiao
,
L.
,
Xian
,
H.
,
Lim
,
K.L.
and
Liou
,
Y.C
. (
2017
)
Reactive oxygen species trigger Parkin/PINK1 pathway-dependent mitophagy by inducing mitochondrial recruitment of Parkin
.
J. Biol. Chem.
292
,
16697
16708
https://doi.org/10.1074/jbc.M117.787739
55
Schofield
,
J.H.
and
Schafer
,
Z.T
. (
2021
)
Mitochondrial reactive oxygen species and mitophagy: a complex and nuanced relationship
.
Antioxid. Redox Signal.
34
,
517
530
https://doi.org/10.1089/ars.2020.8058
56
Zhao
,
Z.-Q.
,
Corvera
,
J.S.
,
Halkos
,
M.E.
,
Kerendi
,
F.
,
Wang
,
N.-P.
,
Guyton
,
R.A.
et al.
(
2003
)
Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning
.
Am. J. Physiol. Heart Circ. Physiol.
285
,
H579
H588
https://doi.org/10.1152/ajpheart.01064.2002
57
Zweier
,
J.L
. (
1988
)
Measurement of superoxide-derived free radicals in the reperfused heart. Evidence for a free radical mechanism of reperfusion injury
.
J. Biol. Chem.
263
,
1353
1357
https://doi.org/10.1016/S0021-9258(19)57309-4
58
Kevin
,
L.G.
,
Camara
,
A.K.S.
,
Riess
,
M.L.
,
Novalija
,
E.
and
Stowe
,
D.F
. (
2003
)
Ischemic preconditioning alters real-time measure of O2 radicals in intact hearts with ischemia and reperfusion
.
Am. J. Physiol. Heart Circ. Physiol.
284
,
H566
574
https://doi.org/10.1152/ajpheart.00711.2002
59
Granger
,
D.N.
and
Kvietys
,
P.R
. (
2015
)
Reperfusion injury and reactive oxygen species: The evolution of a concept
.
Redox Biol.
6
,
524
551
https://doi.org/10.1016/j.redox.2015.08.020
60
Wang
,
R.
,
Wang
,
M.
,
He
,
S.
,
Sun
,
G.
and
Sun
,
X
. (
2020
)
Targeting calcium homeostasis in myocardial ischemia/reperfusion injury: an overview of regulatory mechanisms and therapeutic reagents
.
Front. Pharmacol.
11
,
872
https://doi.org/10.3389/fphar.2020.00872
61
Murphy
,
E.
and
Steenbergen
,
C
. (
2008
)
Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury
.
Physiol. Rev.
88
,
581
609
https://doi.org/10.1152/physrev.00024.2007
62
Mozaffari
,
M.S.
,
Liu
,
J.Y.
,
Abebe
,
W.
and
Baban
,
B
. (
2013
)
Mechanisms of load dependency of myocardial ischemia reperfusion injury
.
Am. J. Cardiovasc. Dis.
3
,
180
196
63
Garcia-Dorado
,
D.
,
Ruiz-Meana
,
M.
,
Inserte
,
J.
,
Rodriguez-Sinovas
,
A.
and
Piper
,
H.M
. (
2012
)
Calcium-mediated cell death during myocardial reperfusion
.
Cardiovasc. Res.
94
,
168
180
https://doi.org/10.1093/cvr/cvs116
64
Trujillo-Rangel
,
W.Á.
,
García-Valdés
,
L.
,
Méndez-Del Villar
,
M.
,
Castañeda-Arellano
,
R.
,
Totsuka-Sutto
,
S.E.
and
García-Benavides
,
L
. (
2022
)
Therapeutic targets for regulating oxidative damage induced by ischemia-reperfusion injury: a study from a pharmacological perspective
.
Oxid. Med. Cell. Longev.
2022
, 8624318 https://doi.org/10.1155/2022/8624318
65
Fiolet
,
J.W.
and
Baartscheer
,
A
. (
2000
)
Cellular calcium homeostasis during ischemia; a thermodynamic approach
.
Cardiovasc. Res.
45
,
100
106
https://doi.org/10.1016/s0008-6363(99)00294-1
66
Dorn
,
G.W.
II
and
Maack
,
C
. (
2013
)
SR and mitochondria: calcium cross-talk between kissing cousins
.
J. Mol. Cell. Cardiol.
55
,
42
49
https://doi.org/10.1016/j.yjmcc.2012.07.015
67
Hegstad
,
A.C.
,
Antonsen
,
O.H.
and
Ytrehus
,
K
. (
1997
)
Low concentrations of hydrogen peroxide improve post-ischaemic metabolic and functional recovery in isolated perfused rat hearts
.
J. Mol. Cell. Cardiol.
29
,
2779
2787
https://doi.org/10.1006/jmcc.1997.0513
68
Sies
,
H
. (
2017
)
Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress
.
Redox Biol.
11
,
613
619
https://doi.org/10.1016/j.redox.2016.12.035
69
Andreadou
,
I.
,
Schulz
,
R.
,
Papapetropoulos
,
A.
,
Turan
,
B.
,
Ytrehus
,
K.
,
Ferdinandy
,
P.
et al.
(
2020
)
The role of mitochondrial reactive oxygen species, NO and H2 S in ischaemia/reperfusion injury and cardioprotection
.
J. Cell. Mol. Med.
24
,
6510
6522
https://doi.org/10.1111/jcmm.15279
70
Heusch
,
G
. (
2020
)
Myocardial ischaemia-reperfusion injury and cardioprotection in perspective
.
Nat. Rev. Cardiol.
17
,
773
789
https://doi.org/10.1038/s41569-020-0403-y
71
Murry
,
C.E.
,
Jennings
,
R.B.
and
Reimer
,
K.A
. (
1986
)
Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium
.
Circulation
74
,
1124
1136
https://doi.org/10.1161/01.cir.74.5.1124
72
Buske
,
M.
,
Desch
,
S.
,
Heusch
,
G.
,
Rassaf
,
T.
,
Eitel
,
I.
,
Thiele
,
H.
et al.
(
2023
)
Reperfusion injury: how can we reduce it by pre-, per-, and postconditioning
.
J. Clin. Med.
13
,
159
https://doi.org/10.3390/jcm13010159
73
Glantz
,
L.
,
Avramovich
,
A.
,
Trembovler
,
V.
,
Gurvitz
,
V.
,
Kohen
,
R.
,
Eidelman
,
L.A.
et al.
(
2005
)
Ischemic preconditioning increases antioxidants in the brain and peripheral organs after cerebral ischemia
.
Exp. Neurol.
192
,
117
124
https://doi.org/10.1016/j.expneurol.2004.11.012
74
Das
,
D.K.
,
Engelman
,
R.M.
and
Kimura
,
Y
. (
1993
)
Molecular adaptation of cellular defences following preconditioning of the heart by repeated ischaemia
.
Cardiovasc. Res.
27
,
578
584
https://doi.org/10.1093/cvr/27.4.578
75
Das
,
D.K.
,
Prasad
,
M.R.
,
Lu
,
D.
and
Jones
,
R.M
. (
1992
)
Preconditioning of heart by repeated stunning. Adaptive modification of antioxidative defense system
.
Cell. Mol. Biol. (Noisy-le-grand)
38
,
739
749
76
Lee
,
J.-C.
,
Park
,
J.H.
,
Kim
,
I.H.
,
Cho
,
G.-S.
,
Ahn
,
J.H.
,
Tae
,
H.-J.
et al.
(
2017
)
Neuroprotection of ischemic preconditioning is mediated by thioredoxin 2 in the hippocampal CA1 region following a subsequent transient cerebral ischemia
.
Brain Pathol.
27
,
276
291
https://doi.org/10.1111/bpa.12389
77
Crestanello
,
J.A.
,
Lingle
,
D.M.
,
Kamelgard
,
J.
,
Millili
,
J.
and
Whitman
,
G.J
. (
1996
)
Ischemic preconditioning decreases oxidative stress during reperfusion: a chemiluminescence study
.
J. Surg. Res.
65
,
53
58
https://doi.org/10.1006/jsre.1996.0342
78
Puisieux
,
F.
,
Deplanque
,
D.
,
Bulckaen
,
H.
,
Maboudou
,
P.
,
Gelé
,
P.
,
Lhermitte
,
M.
et al.
(
2004
)
Brain ischemic preconditioning is abolished by antioxidant drugs but does not up-regulate superoxide dismutase and glutathion peroxidase
.
Brain Res.
1027
,
30
37
https://doi.org/10.1016/j.brainres.2004.08.067
79
Tsovolas
,
K.
,
Iliodromitis
,
E.K.
,
Andreadou
,
I.
,
Zoga
,
A.
,
Demopoulou
,
M.
,
Iliodromitis
,
K.E.
et al.
(
2008
)
Acute administration of vitamin C abrogates protection from ischemic preconditioning in rabbits
.
Pharmacol. Res.
57
,
283
289
https://doi.org/10.1016/j.phrs.2008.02.003
80
Skyschally
,
A.
,
Schulz
,
R.
,
Gres
,
P.
,
Korth
,
H.G.
and
Heusch
,
G
. (
2003
)
Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid
.
Am. J. Physiol. Heart Circ. Physiol.
284
,
H698
703
https://doi.org/10.1152/ajpheart.00693.2002
81
Przyklenk
,
K.
,
Bauer
,
B.
,
Ovize
,
M.
,
Kloner
,
R.A.
and
Whittaker
,
P
. (
1993
)
Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion
.
Circulation
87
,
893
899
https://doi.org/10.1161/01.cir.87.3.893
82
Hausenloy
,
D.J.
,
Mwamure
,
P.K.
,
Venugopal
,
V.
,
Harris
,
J.
,
Barnard
,
M.
,
Grundy
,
E.
et al.
(
2007
)
Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial
.
Lancet
370
,
575
579
https://doi.org/10.1016/S0140-6736(07)61296-3
83
Cheung
,
M.M.H.
,
Kharbanda
,
R.K.
,
Konstantinov
,
I.E.
,
Shimizu
,
M.
,
Frndova
,
H.
,
Li
,
J.
et al.
(
2006
)
Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans
.
J. Am. Coll. Cardiol.
47
,
2277
2282
https://doi.org/10.1016/j.jacc.2006.01.066
84
Meybohm
,
P.
,
Bein
,
B.
,
Brosteanu
,
O.
,
Cremer
,
J.
,
Gruenewald
,
M.
,
Stoppe
,
C.
et al.
(
2015
)
A multicenter trial of remote ischemic preconditioning for heart surgery
.
N. Engl. J. Med.
373
,
1397
1407
https://doi.org/10.1056/NEJMoa1413579
85
Hausenloy
,
D.J.
,
Candilio
,
L.
,
Evans
,
R.
,
Ariti
,
C.
,
Jenkins
,
D.P.
,
Kolvekar
,
S.
et al.
(
2015
)
Remote ischemic preconditioning and outcomes of cardiac surgery
.
N. Engl. J. Med.
373
,
1408
1417
https://doi.org/10.1056/NEJMoa1413534
86
Hausenloy
,
D.J.
,
Kharbanda
,
R.K.
,
Møller
,
U.K.
,
Ramlall
,
M.
,
Aarøe
,
J.
,
Butler
,
R
, et al.
(
2019
)
Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial
.
Lancet
394
,
1415
1424
https://doi.org/10.1016/S0140-6736(19)32039-2
87
Pico
,
F.
,
Lapergue
,
B.
,
Ferrigno
,
M.
,
Rosso
,
C.
,
Meseguer
,
E.
,
Chadenat
,
M.-L.
et al.
(
2020
)
Effect of in-hospital remote ischemic perconditioning on BRAIN infarction growth and clinical outcomes in patients with acute ischemic stroke: the RESCUE BRAIN randomized clinical trial
.
JAMA Neurol.
77
,
725
734
https://doi.org/10.1001/jamaneurol.2020.0326
88
Chen
,
H.-S.
,
Cui
,
Y.
,
Li
,
X.-Q.
,
Wang
,
X.-H.
,
Ma
,
Y.-T.
,
Zhao
,
Y.
et al.
(
2022
)
Effect of remote ischemic conditioning vs usual care on neurologic function in patients with acute moderate ischemic stroke: the RICAMIS randomized clinical trial
.
JAMA
328
,
627
636
https://doi.org/10.1001/jama.2022.13123
89
Blauenfeldt
,
R.A.
,
Hjort
,
N.
,
Valentin
,
J.B.
,
Homburg
,
A.-M.
,
Modrau
,
B.
,
Sandal
,
B.F.
et al.
(
2023
)
Remote ischemic conditioning for acute stroke: the RESIST randomized clinical trial
.
JAMA
330
,
1236
1246
https://doi.org/10.1001/jama.2023.16893
90
Xue
,
F.
,
Yang
,
X.
,
Zhang
,
B.
,
Zhao
,
C.
,
Song
,
J.
,
Jiang
,
T.
et al.
(
2010
)
Postconditioning the human heart in percutaneous coronary intervention
.
Clin. Cardiol.
33
,
439
444
https://doi.org/10.1002/clc.20796
91
Liu
,
T.
,
Mishra
,
A.K.
and
Ding
,
F.X
. (
2011
)
Protective effect of ischemia postconditioning on reperfusion injury in patients with ST-segment elevation acute myocardial infarction
.
Zhonghua Xin Xue Guan Bing Za Zhi
39
,
35
39
92
Mewton
,
N.
,
Thibault
,
H.
,
Roubille
,
F.
,
Lairez
,
O.
,
Rioufol
,
G.
,
Sportouch
,
C.
et al.
(
2013
)
Postconditioning attenuates no-reflow in STEMI patients
.
Basic Res. Cardiol.
108
,
383
https://doi.org/10.1007/s00395-013-0383-8
93
Araszkiewicz
,
A.
,
Grygier
,
M.
,
Pyda
,
M.
,
Rajewska
,
J.
,
Michalak
,
M.
,
Lesiak
,
M.
et al.
(
2014
)
Postconditioning reduces enzymatic infarct size and improves microvascular reperfusion in patients with ST-segment elevation myocardial infarction
.
Cardiology
129
,
250
257
https://doi.org/10.1159/000367965
94
Sörensson
,
P.
,
Saleh
,
N.
,
Bouvier
,
F.
,
Böhm
,
F.
,
Settergren
,
M.
,
Caidahl
,
K.
et al.
(
2010
)
Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction
.
Heart
96
,
1710
1715
https://doi.org/10.1136/hrt.2010.199430
95
Lønborg
,
J.
,
Kelbaek
,
H.
,
Vejlstrup
,
N.
,
Jørgensen
,
E.
,
Helqvist
,
S.
,
Saunamäki
,
K.
et al.
(
2010
)
Cardioprotective effects of ischemic postconditioning in patients treated with primary percutaneous coronary intervention, evaluated by magnetic resonance
.
Circ. Cardiovasc. Interv.
3
,
34
41
https://doi.org/10.1161/CIRCINTERVENTIONS.109.905521
96
Tarantini
,
G.
,
Favaretto
,
E.
,
Marra
,
M.P.
,
Frigo
,
A.C.
,
Napodano
,
M.
,
Cacciavillani
,
L
, et al.
(
2012
)
Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial
.
Int. J. Cardiol.
162
,
33
38
https://doi.org/10.1016/j.ijcard.2012.03.136
97
Engstrøm
,
T.
,
Kelbæk
,
H.
,
Helqvist
,
S.
,
Høfsten
,
D.E.
,
Kløvgaard
,
L.
,
Clemmensen
,
P.
et al.
(
2017
)
Effect of ischemic postconditioning during primary percutaneous coronary intervention for patients with ST-segment elevation myocardial infarction: a randomized clinical trial
.
JAMA Cardiol.
2
,
490
497
https://doi.org/10.1001/jamacardio.2017.0022
98
Eitel
,
I.
,
Stiermaier
,
T.
,
Rommel
,
K.P.
,
Fuernau
,
G.
,
Sandri
,
M.
,
Mangner
,
N.
et al.
(
2015
)
Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial
.
Eur. Heart J.
36
,
3049
3057
https://doi.org/10.1093/eurheartj/ehv463
99
Hong
,
D.M.
,
Lee
,
E.H.
,
Kim
,
H.J.
,
Min
,
J.J.
,
Chin
,
J.H.
,
Choi
,
D.K
, et al.
(
2014
)
Does remote ischaemic preconditioning with postconditioning improve clinical outcomes of patients undergoing cardiac surgery?Remote Ischaemic Preconditioning with Postconditioning Outcome Trial
.
Eur Heart J
35
,
176
183
https://doi.org/10.1093/eurheartj/eht346
100
Antonucci
,
S.
,
Mulvey
,
J.F.
,
Burger
,
N.
,
Di Sante
,
M.
,
Hall
,
A.R.
,
Hinchy
,
E.C
, et al.
(
2019
)
Selective mitochondrial superoxide generation in vivo is cardioprotective through hormesis
.
Free Radic. Biol. Med.
134
,
678
687
https://doi.org/10.1016/j.freeradbiomed.2019.01.034
101
Rosomoff
,
H.L.
and
Holaday
,
D.A
. (
1954
)
Cerebral blood flow and cerebral oxygen consumption during hypothermia
.
Am. J. Physiol.
179
,
85
88
https://doi.org/10.1152/ajplegacy.1954.179.1.85
102
Mezrow
,
C.K.
,
Sadeghi
,
A.M.
,
Gandsas
,
A.
,
Shiang
,
H.H.
,
Levy
,
D.
,
Green
,
R.
et al.
(
1992
)
Cerebral blood flow and metabolism in hypothermic circulatory arrest
.
Ann. Thorac. Surg.
54
,
609
615
https://doi.org/10.1016/0003-4975(92)91002-q
103
Chopp
,
M.
,
Knight
,
R.
,
Tidwell
,
C.D.
,
Helpern
,
J.A.
,
Brown
,
E.
and
Welch
,
K.M
. (
1989
)
The metabolic effects of mild hypothermia on global cerebral ischemia and recirculation in the cat: comparison to normothermia and hyperthermia
.
J. Cereb. Blood Flow Metab.
9
,
141
148
https://doi.org/10.1038/jcbfm.1989.21
104
Sterz
,
F.
,
Leonov
,
Y.
,
Safar
,
P.
,
Johnson
,
D.
,
Oku
,
K.
,
Tisherman
,
S.A.
et al.
(
1992
)
Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs. Reperfusion with open-chest CPR or cardiopulmonary bypass
.
Resuscitation
24
,
27
47
https://doi.org/10.1016/0300-9572(92)90171-8
105
Kramer
,
R.S.
,
Sanders
,
A.P.
,
Lesage
,
A.M.
,
Woodhall
,
B.
and
Sealy
,
W.C
. (
1968
)
The effect profound hypothermia on preservation of cerebral ATP content during circulatory arrest
.
J. Thorac. Cardiovasc. Surg.
56
,
699
709
106
Kirkegaard
,
H.
,
Søreide
,
E.
de Haas
,
I.
Pettilä
,
V.
,
Taccone
,
F.S.
,
Arus
,
U.
et al.
(
2017
)
Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial
.
JAMA
318
,
341
350
https://doi.org/10.1001/jama.2017.8978
107
Lopez-de-Sa
,
E.
,
Rey
,
J.R.
,
Armada
,
E.
,
Salinas
,
P.
,
Viana-Tejedor
,
A.
,
Espinosa-Garcia
,
S.
et al.
(
2012
)
Hypothermia in comatose survivors from out-of-hospital cardiac arrest: pilot trial comparing 2 levels of target temperature
.
Circulation
126
,
2826
2833
https://doi.org/10.1161/CIRCULATIONAHA.112.136408
108
Lopez-de-Sa
,
E.
,
Juarez
,
M.
,
Armada
,
E.
,
Sanchez-Salado
,
J.C.
,
Sanchez
,
P.L.
,
Loma-Osorio
,
P.
et al.
(
2018
)
A multicentre randomized pilot trial on the effectiveness of different levels of cooling in comatose survivors of out-of-hospital cardiac arrest: the FROST-I trial
.
Intensive Care Med.
44
,
1807
1815
https://doi.org/10.1007/s00134-018-5256-z
109
Martens
,
P.
,
Roine
,
R.
,
Sterz
,
F.
,
Eisenburger
,
P.
,
Havel
,
C.
and
Kofler
,
J
. (
2002
)
Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest
.
N. Engl. J. Med.
346
,
549
556
https://doi.org/10.1056/NEJMoa012689
110
Bernard
,
S.A.
,
Gray
,
T.W.
,
Buist
,
M.D.
,
Jones
,
B.M.
,
Silvester
,
W.
,
Gutteridge
,
G.
et al.
(
2002
)
Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia
.
N. Engl. J. Med.
346
,
557
563
https://doi.org/10.1056/NEJMoa003289
111
Nielsen
,
N.
,
Wetterslev
,
J.
,
Cronberg
,
T.
,
Erlinge
,
D.
,
Gasche
,
Y.
,
Hassager
,
C.
et al.
(
2013
)
Targeted temperature management at 33°C versus 36°C after cardiac arrest
.
N. Engl. J. Med.
369
,
2197
2206
https://doi.org/10.1056/NEJMoa1310519
112
Dankiewicz
,
J.
,
Cronberg
,
T.
,
Lilja
,
G.
,
Jakobsen
,
J.C.
,
Levin
,
H.
,
Ullén
,
S.
et al.
(
2021
)
Hypothermia versus normothermia after out-of-hospital cardiac arrest
.
N. Engl. J. Med.
384
,
2283
2294
https://doi.org/10.1056/NEJMoa2100591
113
Che
,
D.
,
Li
,
L.
,
Kopil
,
C.M.
,
Liu
,
Z.
,
Guo
,
W.
and
Neumar
,
R.W
. (
2011
)
Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest
.
Crit. Care Med.
39
,
1423
1430
https://doi.org/10.1097/CCM.0b013e318212020a
114
Lascarrou
,
J.-B.
,
Merdji
,
H.
,
Le Gouge
,
A.
,
Colin
,
G.
,
Grillet
,
G.
,
Girardie
,
P.
et al.
(
2019
)
Targeted temperature management for cardiac arrest with nonshockable rhythm
.
N. Engl. J. Med.
381
,
2327
2337
https://doi.org/10.1056/NEJMoa1906661
115
Hachimi-Idrissi
,
S.
,
Corne
,
L.
,
Ebinger
,
G.
,
Michotte
,
Y.
and
Huyghens
,
L
. (
2001
)
Mild hypothermia induced by a helmet device: a clinical feasibility study
.
Resuscitation
51
,
275
281
https://doi.org/10.1016/s0300-9572(01)00412-9
116
Hachimi-Idrissi
,
S.
,
Zizi
,
M.
,
Nguyen
,
D.N.
,
Schiettecate
,
J.
,
Ebinger
,
G.
,
Michotte
,
Y.
et al.
(
2005
)
The evolution of serum astroglial S-100 beta protein in patients with cardiac arrest treated with mild hypothermia
.
Resuscitation
64
,
187
192
https://doi.org/10.1016/j.resuscitation.2004.08.008
117
Dixon
,
S.R.
,
Whitbourn
,
R.J.
,
Dae
,
M.W.
,
Grube
,
E.
,
Sherman
,
W.
,
Schaer
,
G.L.
et al.
(
2002
)
Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction
.
J. Am. Coll. Cardiol.
40
,
1928
1934
https://doi.org/10.1016/s0735-1097(02)02567-6
118
Götberg
,
M.
,
Olivecrona
,
G.K.
,
Koul
,
S.
,
Carlsson
,
M.
,
Engblom
,
H.
,
Ugander
,
M.
et al.
(
2010
)
A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction
.
Circ. Cardiovasc. Interv.
3
,
400
407
https://doi.org/10.1161/CIRCINTERVENTIONS.110.957902
119
Erlinge
,
D.
,
Götberg
,
M.
,
Lang
,
I.
,
Holzer
,
M.
,
Noc
,
M.
,
Clemmensen
,
P
, et al.
(
2014
)
Rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. The CHILL-MI trial: a randomized controlled study of the use of central venous catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction.
.
J. Am. Coll. Cardiol.
63
,
1857
1865
https://doi.org/10.1016/j.jacc.2013.12.027
120
Nichol
,
G.
,
Strickland
,
W.
,
Shavelle
,
D.
,
Maehara
,
A.
,
Ben-Yehuda
,
O.
,
Genereux
,
P.
et al.
(
2015
)
Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction
.
Circ. Cardiovasc. Interv.
8
, e001965 https://doi.org/10.1161/CIRCINTERVENTIONS.114.001965
121
Noc
,
M.
,
Laanmets
,
P.
,
Neskovic
,
A.N.
,
Petrović
,
M.
,
Stanetic
,
B.
,
Aradi
,
D
, et al.
(
2021
)
A multicentre, prospective, randomised controlled trial to assess the safety and effectiveness of cooling as an adjunctive therapy to percutaneous intervention in patients with acute myocardial infarction: the COOL AMI EU Pivotal Trial
.
EuroIntervention
17
,
466
473
https://doi.org/10.4244/EIJ-D-21-00348
122
Els
,
T.
,
Oehm
,
E.
,
Voigt
,
S.
,
Klisch
,
J.
,
Hetzel
,
A.
and
Kassubek
,
J
. (
2006
)
Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke
.
Cerebrovasc. Dis.
21
,
79
85
https://doi.org/10.1159/000090007
123
Neugebauer
,
H.
,
Schneider
,
H.
,
Bösel
,
J.
,
Hobohm
,
C.
,
Poli
,
S.
,
Kollmar
,
R.
et al.
(
2019
)
Outcomes of hypothermia in addition to decompressive hemicraniectomy in treatment of malignant middle cerebral artery stroke: a randomized clinical trial
.
JAMA Neurol.
76
,
571
579
https://doi.org/10.1001/jamaneurol.2018.4822
124
Gluckman
,
P.D.
,
Wyatt
,
J.S.
,
Azzopardi
,
D.
,
Ballard
,
R.
,
Edwards
,
A.D.
,
Ferriero
,
D.M.
et al.
(
2005
)
Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial
.
Lancet
365
,
663
670
https://doi.org/10.1016/S0140-6736(05)17946-X
125
Shankaran
,
S.
,
Laptook
,
A.R.
,
Ehrenkranz
,
R.A.
,
Tyson
,
J.E.
,
McDonald
,
S.A.
,
Donovan
,
E.F.
et al.
(
2005
)
Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy
.
N. Engl. J. Med.
353
,
1574
1584
https://doi.org/10.1056/NEJMcps050929
126
Azzopardi
,
D.V.
,
Strohm
,
B.
,
Edwards
,
A.D.
,
Dyet
,
L.
,
Halliday
,
H.L.
,
Juszczak
,
E.
et al.
(
2009
)
Moderate hypothermia to treat perinatal asphyxial encephalopathy
.
N. Engl. J. Med.
361
,
1349
1358
https://doi.org/10.1056/NEJMoa0900854
127
Simbruner
,
G.
,
Mittal
,
R.A.
,
Rohlmann
,
F.
and
Muche
,
R
. (
2010
)
Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT
.
Pediatrics
126
,
e771
778
https://doi.org/10.1542/peds.2009-2441
128
Azzopardi
,
D.
,
Strohm
,
B.
,
Marlow
,
N.
,
Brocklehurst
,
P.
,
Deierl
,
A.
,
Eddama
,
O.
et al.
(
2014
)
Effects of hypothermia for perinatal asphyxia on childhood outcomes
.
N. Engl. J. Med.
371
,
140
149
https://doi.org/10.1056/NEJMoa1315788
129
Voorhees
,
W.D.
III
,
3rd Abendschein
,
D.R.
and
Tacker
,
W.A.
Jr
. (
1984
)
Effect of whole-body hypothermia on myocardial blood flow and infarct salvage during coronary artery occlusion in dogs
.
Am. Heart J.
107
,
945
949
https://doi.org/10.1016/0002-8703(84)90833-0
130
Dae
,
M.W.
,
Gao
,
D.W.
,
Sessler
,
D.I.
,
Chair
,
K.
and
Stillson
,
C.A
. (
2002
)
Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs
.
Am. J. Physiol. Heart Circ. Physiol.
282
,
H1584
1591
https://doi.org/10.1152/ajpheart.00980.2001
131
Götberg
,
M.
van der Pals
,
J.
Götberg
,
M.
,
Olivecrona
,
G.K.
,
Kanski
,
M.
,
Koul
,
S.
et al.
(
2011
)
Optimal timing of hypothermia in relation to myocardial reperfusion
.
Basic Res. Cardiol.
106
,
697
708
https://doi.org/10.1007/s00395-011-0195-7
132
Kollmar
,
R.
,
Blank
,
T.
,
Han
,
J.L.
,
Georgiadis
,
D.
and
Schwab
,
S
. (
2007
)
Different degrees of hypothermia after experimental stroke: short- and long-term outcome
.
Stroke
38
,
1585
1589
https://doi.org/10.1161/STROKEAHA.106.475897
133
Clark
,
D.L.
,
Penner
,
M.
,
Orellana-Jordan
,
I.M.
and
Colbourne
,
F
. (
2008
)
Comparison of 12, 24 and 48 h of systemic hypothermia on outcome after permanent focal ischemia in rat
.
Exp. Neurol.
212
,
386
392
https://doi.org/10.1016/j.expneurol.2008.04.016
134
van der Worp
,
H.B.
Sena
,
E.S.
,
Donnan
,
G.A.
,
Howells
,
D.W.
and
Macleod
,
M.R
. (
2007
)
Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis
.
Brain (Bacau)
130
,
3063
3074
https://doi.org/10.1093/brain/awm083
135
Jacobs
,
S.E.
,
Berg
,
M.
,
Hunt
,
R.
,
Tarnow-Mordi
,
W.O.
,
Inder
,
T.E.
and
Davis
,
P.G
. (
2013
)
Cooling for newborns with hypoxic ischaemic encephalopathy
.
Cochrane Database Syst. Rev.
2013
, CD003311 https://doi.org/10.1002/14651858.CD003311.pub3
136
Wang
,
R
. (
2002
)
Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter?
FASEB J.
16
,
1792
1798
https://doi.org/10.1096/fj.02-0211hyp
137
Wang
,
R
. (
2003
)
The gasotransmitter role of hydrogen sulfide
.
Antioxid. Redox Signal.
5
,
493
501
https://doi.org/10.1089/152308603768295249
138
Blackstone
,
E.
,
Morrison
,
M.
and
Roth
,
M.B
. (
2005
)
H2S induces a suspended animation-like state in mice
.
Science
308
,
518
https://doi.org/10.1126/science.1108581
139
Cooper
,
C.E.
and
Brown
,
G.C
. (
2008
)
The inhibition of mitochondrial cytochrome oxidase by the gases carbon monoxide, nitric oxide, hydrogen cyanide and hydrogen sulfide: chemical mechanism and physiological significance
.
J. Bioenerg. Biomembr.
40
,
533
539
https://doi.org/10.1007/s10863-008-9166-6
140
Dyson
,
A.
,
Dal-Pizzol
,
F.
,
Sabbatini
,
G.
,
Lach
,
A.B.
,
Galfo
,
F.
,
Dos Santos Cardoso
,
J.
et al.
(
2017
)
Ammonium tetrathiomolybdate following ischemia/reperfusion injury: Chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models
.
Plos med.
14
, e1002310 https://doi.org/10.1371/journal.pmed.1002310
141
Woo
,
C.-W.
,
Kwon
,
J.-I.
,
Kim
,
K.-W.
,
Kim
,
J.-K.
,
Jeon
,
S.-B.
,
Jung
,
S.-C.
et al.
(
2017
)
The administration of hydrogen sulphide prior to ischemic reperfusion has neuroprotective effects in an acute stroke model
.
Plos one
12
, e0187910 https://doi.org/10.1371/journal.pone.0187910
142
Elrod
,
J.W.
,
Calvert
,
J.W.
,
Morrison
,
J.
,
Doeller
,
J.E.
,
Kraus
,
D.W.
,
Tao
,
L.
et al.
(
2007
)
Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function
.
Proc. Natl. Acad. Sci. U.S.A.
104
,
15560
15565
https://doi.org/10.1073/pnas.0705891104
143
Azizi
,
F.
,
Seifi
,
B.
,
Kadkhodaee
,
M.
and
Ahghari
,
P
. (
2016
)
Administration of hydrogen sulfide protects ischemia reperfusion-induced acute kidney injury by reducing the oxidative stress
.
Ir. J. Med. Sci.
185
,
649
654
https://doi.org/10.1007/s11845-015-1328-z
144
Zhang
,
Q.
,
Fu
,
H.
,
Zhang
,
H.
,
Xu
,
F.
,
Zou
,
Z.
,
Liu
,
M.
et al.
(
2013
)
Hydrogen sulfide preconditioning protects rat liver against ischemia/reperfusion injury by activating Akt-GSK-3β signaling and inhibiting mitochondrial permeability transition
.
Plos one
8
, e74422 https://doi.org/10.1371/journal.pone.0074422
145
Minamishima
,
S.
,
Bougaki
,
M.
,
Sips
,
P.Y.
,
Yu
,
J.D.
,
Minamishima
,
Y.A.
,
Elrod
,
J.W.
et al.
(
2009
)
Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice
.
Circulation
120
,
888
896
https://doi.org/10.1161/CIRCULATIONAHA.108.833491
146
Pan
,
H.
,
Xie
,
X.
,
Chen
,
D.
,
Zhang
,
J.
,
Zhou
,
Y.
and
Yang
,
G
. (
2014
)
Protective and biogenesis effects of sodium hydrosulfide on brain mitochondria after cardiac arrest and resuscitation
.
Eur. J. Pharmacol.
741
,
74
82
https://doi.org/10.1016/j.ejphar.2014.07.037
147
Sodha
,
N.R.
,
Clements
,
R.T.
,
Feng
,
J.
,
Liu
,
Y.
,
Bianchi
,
C.
,
Horvath
,
E.M.
et al.
(
2008
)
The effects of therapeutic sulfide on myocardial apoptosis in response to ischemia-reperfusion injury
.
Eur. J. Cardiothorac. Surg.
33
,
906
913
https://doi.org/10.1016/j.ejcts.2008.01.047
148
Osipov
,
R.M.
,
Robich
,
M.P.
,
Feng
,
J.
,
Liu
,
Y.
,
Clements
,
R.T.
,
Glazer
,
H.P.
et al.
(
2009
)
Effect of hydrogen sulfide in a porcine model of myocardial ischemia-reperfusion: comparison of different administration regimens and characterization of the cellular mechanisms of protection
.
J. Cardiovasc. Pharmacol.
54
,
287
297
https://doi.org/10.1097/FJC.0b013e3181b2b72b
149
(
2016
)
Reduction of Ischemia-Reperfusion Mediated Cardiac Injury in Subjects Undergoing Coronary Artery Bypass Graft Surgery: ClinicalTrials.gov
. https://classic.clinicaltrials.gov/ct2/show/NCT00858936?term=IK-1001&rank=2
150
Meng
,
G.
,
Wang
,
J.
,
Xiao
,
Y.
,
Bai
,
W.
,
Xie
,
L.
,
Shan
,
L.
et al.
(
2015
)
GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis in rats
.
J. Biomed. Res.
29
,
203
213
https://doi.org/10.7555/JBR.28.20140037
151
Xu
,
S.
,
Yang
,
C.T.
,
Meng
,
F.H.
,
Pacheco
,
A.
,
Chen
,
L.
and
Xian
,
M
. (
2016
)
Ammonium tetrathiomolybdate as a water-soluble and slow-release hydrogen sulfide donor
.
Bioorg. Med. Chem. Lett.
26
,
1585
1588
https://doi.org/10.1016/j.bmcl.2016.02.005
152
Durham
,
T.
,
Zander
,
D.
,
Stomeo
,
N.
,
Minnion
,
M.
,
Hogarth
,
G.
,
Feelisch
,
M.
et al.
(
2020
)
Chemistry, pharmacology, and cellular uptake mechanisms of thiometallate sulfide donors
.
Br. J. Pharmacol.
177
,
745
756
https://doi.org/10.1111/bph.14670
153
Mendonça
,
B.P.
,
Cardoso
,
J.D.S.
,
Michels
,
M.
,
Vieira
,
A.C.
,
Wendhausen
,
D.
,
Manfredini
,
A.
et al.
(
2020
)
Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke
.
Intensive Care Med. Exp.
8
,
13
https://doi.org/10.1186/s40635-020-00300-8
154
Johnson
,
T.W.
,
Holt
,
J.
,
Kleyman
,
A.
,
Zhou
,
S.
,
Sammut
,
E.
,
Bruno
,
V.D.
et al.
(
2024
)
Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion
.
Redox Biol.
73
, 103167 https://doi.org/10.1016/j.redox.2024.103167
155
Ravindran
,
S.
,
Jahir Hussain
,
S.
,
Boovarahan
,
S.R.
and
Kurian
,
G.A
. (
2017
)
Sodium thiosulfate post-conditioning protects rat hearts against ischemia reperfusion injury via reduction of apoptosis and oxidative stress
.
Chem. Biol. Interact.
274
,
24
34
https://doi.org/10.1016/j.cbi.2017.07.002
156
Ravindran
,
S.
and
Kurian
,
G.A
. (
2019
)
Preconditioning the rat heart with sodium thiosulfate preserved the mitochondria in response to ischemia-reperfusion injury
.
J. Bioenerg. Biomembr.
51
,
189
201
https://doi.org/10.1007/s10863-019-09794-8
157
de Koning
,
M.L.Y.
Assa
,
S.
,
Maagdenberg
,
C.G.
van Veldhuisen
,
D.J.
Pasch
,
A.
van Goor
,
H.
et al.
(
2020
)
Safety and tolerability of sodium thiosulfate in patients with an acute coronary syndrome undergoing coronary angiography: a dose-escalation safety pilot study (SAFE-ACS)
.
J. Interv. Cardiol.
2020
, 6014915 https://doi.org/10.1155/2020/6014915
158
Assa
,
S.
,
Pundziute-Do Prado
,
G.
,
Voskuil
,
M.
,
Anthonio
,
R.L
, et al.
(
2023
)
Sodium thiosulfate in acute myocardial infarction: a randomized clinical trial
.
JACC Basic Transl. Sci.
8
,
1285
1294
https://doi.org/10.1016/j.jacbts.2023.06.001
159
Zhang
,
P.
,
Yu
,
Y.
,
Wang
,
P.
,
Shen
,
H.
,
Ling
,
X.
,
Xue
,
X.
et al.
(
2021
)
Role of hydrogen sulfide in myocardial ischemia-reperfusion injury
.
J. Cardiovasc. Pharmacol.
77
,
130
141
https://doi.org/10.1097/FJC.0000000000000943
160
Huang
,
Y.
,
Omorou
,
M.
,
Gao
,
M.
,
Mu
,
C.
,
Xu
,
W.
and
Xu
,
H
. (
2023
)
Hydrogen sulfide and its donors for the treatment of cerebral ischaemia-reperfusion injury: A comprehensive review
.
Biomedicine & Pharmacotherapy
161
,
114506
https://doi.org/10.1016/j.biopha.2023.114506
161
Radi
,
R.
,
Cassina
,
A.
,
Hodara
,
R.
,
Quijano
,
C.
and
Castro
,
L
. (
2002
)
Peroxynitrite reactions and formation in mitochondria
.
Free Radic. Biol. Med.
33
,
1451
1464
https://doi.org/10.1016/s0891-5849(02)01111-5
162
Chouchani
,
E.T.
,
Methner
,
C.
,
Nadtochiy
,
S.M.
,
Logan
,
A.
,
Pell
,
V.R.
,
Ding
,
S.
et al.
(
2013
)
Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I
.
Nat. Med.
19
,
753
759
https://doi.org/10.1038/nm.3212
163
Brown
,
G.C.
and
Cooper
,
C.E
. (
1994
)
Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase
.
FEBS Lett.
356
,
295
298
https://doi.org/10.1016/0014-5793(94)01290-3
164
Guzik
,
T.J.
,
West
,
N.E.J.
,
Pillai
,
R.
,
Taggart
,
D.P.
and
Channon
,
K.M
. (
2002
)
Nitric oxide modulates superoxide release and peroxynitrite formation in human blood vessels
.
Hypertension
39
,
1088
1094
https://doi.org/10.1161/01.hyp.0000018041.48432.b5
165
Radi
,
R.
,
Peluffo
,
G.
,
Alvarez
,
M.N.
,
Naviliat
,
M.
and
Cayota
,
A
. (
2001
)
Unraveling peroxynitrite formation in biological systems
.
Free Radic. Biol. Med.
30
,
463
488
https://doi.org/10.1016/s0891-5849(00)00373-7
166
Szabó
,
C.
,
Ischiropoulos
,
H.
and
Radi
,
R
. (
2007
)
Peroxynitrite: biochemistry, pathophysiology and development of therapeutics
.
Nat. Rev. Drug Discov.
6
,
662
680
https://doi.org/10.1038/nrd2222
167
Takuma
,
K.
,
Phuagphong
,
P.
,
Lee
,
E.
,
Mori
,
K.
,
Baba
,
A.
and
Matsuda
,
T
. (
2001
)
Anti-apoptotic effect of cGMP in cultured astrocytes: inhibition by cGMP-dependent protein kinase of mitochondrial permeable transition pore
.
J. Biol. Chem.
276
,
48093
48099
https://doi.org/10.1074/jbc.M108622200
168
Nguyen
,
T.T.
,
Stevens
,
M.V.
,
Kohr
,
M.
,
Steenbergen
,
C.
,
Sack
,
M.N.
and
Murphy
,
E
. (
2011
)
Cysteine 203 of cyclophilin D is critical for cyclophilin D activation of the mitochondrial permeability transition pore
.
J. Biol. Chem.
286
,
40184
40192
https://doi.org/10.1074/jbc.M111.243469
169
Nisoli
,
E.
,
Clementi
,
E.
,
Paolucci
,
C.
,
Cozzi
,
V.
,
Tonello
,
C.
,
Sciorati
,
C.
et al.
(
2003
)
Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide
.
Science
299
,
896
899
https://doi.org/10.1126/science.1079368
170
Janssens
,
S.P.
,
Bogaert
,
J.
,
Zalewski
,
J.
,
Toth
,
A.
,
Adriaenssens
,
T.
,
Belmans
,
A.
et al.
(
2018
)
Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind, randomized controlled trial
.
Eur. Heart J.
39
,
2717
2725
https://doi.org/10.1093/eurheartj/ehy232
171
Queiroga
,
C.S.F.
,
Vercelli
,
A.
and
Vieira
,
H.L.A
. (
2015
)
Carbon monoxide and the CNS: challenges and achievements
.
Br. J. Pharmacol.
172
,
1533
1545
https://doi.org/10.1111/bph.12729
172
Lo Iacono
,
L.
,
Boczkowski
,
J.
,
Zini
,
R.
,
Salouage
,
I.
,
Berdeaux
,
A.
,
Motterlini
,
R.
et al.
(
2011
)
A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species
.
Free Radic. Biol. Med.
50
,
1556
1564
https://doi.org/10.1016/j.freeradbiomed.2011.02.033
173
Zuckerbraun
,
B.S.
,
Chin
,
B.Y.
,
Bilban
,
M.
d’ Avila,
,
J.C.
Rao
,
J.
,
Billiar
,
T.R.
et al.
(
2007
)
Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species
.
Faseb J.
21
,
1099
1106
https://doi.org/10.1096/fj.06-6644com
174
Otterbein
,
L.E.
,
Bach
,
F.H.
,
Alam
,
J.
,
Soares
,
M.
,
Tao Lu
,
H.
,
Wysk
,
M.
et al.
(
2000
)
Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway
.
Nat. Med.
6
,
422
428
https://doi.org/10.1038/74680
175
Verma
,
A.
,
Hirsch
,
D.J.
,
Glatt
,
C.E.
,
Ronnett
,
G.V.
and
Snyder
,
S.H
. (
1993
)
Carbon monoxide: a putative neural messenger
.
Science
259
,
381
384
https://doi.org/10.1126/science.7678352
176
Brouard
,
S.
,
Otterbein
,
L.E.
,
Anrather
,
J.
,
Tobiasch
,
E.
,
Bach
,
F.H.
,
Choi
,
A.M.
et al.
(
2000
)
Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis
.
J. Exp. Med.
192
,
1015
1026
https://doi.org/10.1084/jem.192.7.1015
177
Nagao
,
S.
,
Taguchi
,
K.
,
Sakai
,
H.
,
Yamasaki
,
K.
,
Watanabe
,
H.
,
Otagiri
,
M.
et al.
(
2016
)
Carbon monoxide-bound hemoglobin vesicles ameliorate multiorgan injuries induced by severe acute pancreatitis in mice by their anti-inflammatory and antioxidant properties
.
Int. J. Nanomedicine
11
,
5611
5620
https://doi.org/10.2147/IJN.S118185
178
Ryter
,
S.W.
,
Alam
,
J.
and
Choi
,
A.M.K
. (
2006
)
Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications
.
Physiol. Rev.
86
,
583
650
https://doi.org/10.1152/physrev.00011.2005
179
Motterlini
,
R.
and
Otterbein
,
L.E
. (
2010
)
The therapeutic potential of carbon monoxide
.
Nat. Rev. Drug Discov.
9
,
728
743
https://doi.org/10.1038/nrd3228
180
Mayr
,
F.B.
,
Spiel
,
A.
,
Leitner
,
J.
,
Marsik
,
C.
,
Germann
,
P.
,
Ullrich
,
R.
et al.
(
2005
)
Effects of carbon monoxide inhalation during experimental endotoxemia in humans
.
Am. J. Respir. Crit. Care Med.
171
,
354
360
https://doi.org/10.1164/rccm.200404-446OC
181
Fredenburgh
,
L.E.
,
Perrella
,
M.A.
,
Barragan-Bradford
,
D.
,
Hess
,
D.R.
,
Peters
,
E.
,
Welty-Wolf
,
K.E.
et al.
(
2018
)
A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS
.
JCI Insight
3
, e124039 https://doi.org/10.1172/jci.insight.124039
182
Motterlini
,
R
. (
2007
)
Carbon monoxide-releasing molecules (CO-RMs): vasodilatory, anti-ischaemic and anti-inflammatory activities
.
Biochem. Soc. Trans.
35
,
1142
1146
https://doi.org/10.1042/BST0351142
183
Motterlini
,
R.
,
Clark
,
J.E.
,
Foresti
,
R.
,
Sarathchandra
,
P.
,
Mann
,
B.E.
and
Green
,
C.J
. (
2002
)
Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities
.
Circ. Res.
90
,
E17
24
https://doi.org/10.1161/hh0202.104530
184
Motterlini
,
R.
,
Sawle
,
P.
,
Hammad
,
J.
,
Bains
,
S.
,
Alberto
,
R.
,
Foresti
,
R.
et al.
(
2005
)
CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule
.
Faseb J.
19
,
284
286
https://doi.org/10.1096/fj.04-2169fje
185
Wu
,
J.
,
Li
,
Y.
,
Yang
,
P.
,
Huang
,
Y.
,
Lu
,
S.
and
Xu
,
F
. (
2019
)
Novel role of carbon monoxide in improving neurological outcome after cardiac arrest in aged rats: involvement of inducing mitochondrial autophagy
.
J. Am. Heart Assoc.
8
, e011851 https://doi.org/10.1161/JAHA.118.011851
186
Wang
,
P.
,
Yao
,
L.
,
Zhou
,
L.-L.
,
Liu
,
Y.-S.
,
Chen
,
M.
,
Wu
,
H.-D.
et al.
(
2016
)
Carbon monoxide improves neurologic outcomes by mitochondrial biogenesis after global cerebral ischemia induced by cardiac arrest in rats
.
Int. J. Biol. Sci.
12
,
1000
1009
https://doi.org/10.7150/ijbs.13222
187
Wollborn
,
J.
,
Steiger
,
C.
,
Doostkam
,
S.
,
Schallner
,
N.
,
Schroeter
,
N.
,
Kari
,
F.A.
et al.
(
2020
)
Carbon monoxide exerts functional neuroprotection after cardiac arrest using extracorporeal resuscitation in pigs
.
Crit. Care Med.
48
,
e299
e307
https://doi.org/10.1097/CCM.0000000000004242
188
Iqbal
,
J.
,
Chamberlain
,
J.
,
Alfaidi
,
M.
,
Hughes
,
M.
,
Alizadeh
,
T.
,
Casbolt
,
H.
et al.
(
2021
)
Carbon monoxide releasing molecule A1 reduces myocardial damage after acute myocardial infarction in a porcine model
.
J. Cardiovasc. Pharmacol.
78
,
e656
e661
https://doi.org/10.1097/FJC.0000000000001067
189
Gutierrez-Mariscal
,
F.M.
,
Torres-Peña
,
J.D.
,
Alcalá-Diaz
,
J.F.
,
Yubero-Serrano
,
E.M.
and
López-Miranda
,
J
. (
2021
)
Coenzyme Q(10) and cardiovascular diseases
.
Antioxidants (Basel)
10
,
906
https://doi.org/10.3390/antiox10060906
190
Liang
,
S.
,
Ping
,
Z.
and
Ge
,
J
. (
2017
)
Coenzyme Q10 regulates antioxidative stress and autophagy in acute myocardial ischemia-reperfusion injury
.
Oxid. Med. Cell. Longev.
2017
, 9863181 https://doi.org/10.1155/2017/9863181
191
Whitman
,
G.J.
,
Niibori
,
K.
,
Yokoyama
,
H.
,
Crestanello
,
J.A.
,
Lingle
,
D.M.
and
Momeni
,
R
. (
1997
)
The mechanisms of coenzyme Q10 as therapy for myocardial ischemia reperfusion injury
.
Mol. Aspects Med.
18 Suppl
,
S195
203
https://doi.org/10.1016/s0098-2997(97)00017-4
192
Smith
,
R.A.J.
and
Murphy
,
M.P
. (
2010
)
Animal and human studies with the mitochondria-targeted antioxidant MitoQ
.
Ann. N. Y. Acad. Sci.
1201
,
96
103
https://doi.org/10.1111/j.1749-6632.2010.05627.x
193
Adlam
,
V.J.
,
Harrison
,
J.C.
,
Porteous
,
C.M.
,
James
,
A.M.
,
Smith
,
R.A.J.
,
Murphy
,
M.P.
et al.
(
2005
)
Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury
.
Faseb J.
19
,
1088
1095
https://doi.org/10.1096/fj.05-3718com
194
Neuzil
,
J.
,
Widén
,
C.
,
Gellert
,
N.
,
Swettenham
,
E.
,
Zobalova
,
R.
,
Dong
,
L.-F.
et al.
(
2007
)
Mitochondria transmit apoptosis signalling in cardiomyocyte-like cells and isolated hearts exposed to experimental ischemia-reperfusion injury
.
Redox Rep.
12
,
148
162
https://doi.org/10.1179/135100007X200227
195
Dare
,
A.J.
,
Bolton
,
E.A.
,
Pettigrew
,
G.J.
,
Bradley
,
J.A.
,
Saeb-Parsy
,
K.
and
Murphy
,
M.P
. (
2015
)
Protection against renal ischemia-reperfusion injury in vivo by the mitochondria targeted antioxidant MitoQ
.
Redox Biol.
5
,
163
168
https://doi.org/10.1016/j.redox.2015.04.008
196
Dare
,
A.J.
,
Logan
,
A.
,
Prime
,
T.A.
,
Rogatti
,
S.
,
Goddard
,
M.
,
Bolton
,
E.M
, et al.
(
2015
)
The mitochondria-targeted anti-oxidant MitoQ decreases ischemia-reperfusion injury in a murine syngeneic heart transplant model
.
J. Heart Lung Transplant.
34
,
1471
1480
https://doi.org/10.1016/j.healun.2015.05.007
197
Greenamyre
,
J.T.
and
Hastings
,
T.G
. (
2004
)
Biomedicine. Parkinson’s--divergent causes, convergent mechanisms
.
Science
304
,
1120
1122
https://doi.org/10.1126/science.1098966
198
Abou-Sleiman
,
P.M.
,
Muqit
,
M.M.K.
and
Wood
,
N.W
. (
2006
)
Expanding insights of mitochondrial dysfunction in Parkinson’s disease
.
Nat. Rev. Neurosci.
7
,
207
219
https://doi.org/10.1038/nrn1868
199
Snow
,
B.J.
,
Rolfe
,
F.L.
,
Lockhart
,
M.M.
,
Frampton
,
C.M.
,
O’Sullivan
,
J.D.
,
Fung
,
V.
et al.
(
2010
)
A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as A disease-modifying therapy in Parkinson’s disease
.
Mov. Disord.
25
,
1670
1674
https://doi.org/10.1002/mds.23148
200
Reiter
,
R.J.
,
Mayo
,
J.C.
,
Tan
,
D.X.
,
Sainz
,
R.M.
,
Alatorre-Jimenez
,
M.
and
Qin
,
L
. (
2016
)
Melatonin as an antioxidant: under promises but over delivers
.
J. Pineal Res.
61
,
253
278
https://doi.org/10.1111/jpi.12360
201
Liu
,
L.-F.
,
Qin
,
Q.
,
Qian
,
Z.-H.
,
Shi
,
M.
,
Deng
,
Q.-C.
,
Zhu
,
W.-P
, et al.
(
2014
)
Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats
.
Eur. Rev. Med. Pharmacol. Sci.
18
,
3681
3686
202
Li
,
H.
,
Wang
,
Y.
,
Feng
,
D.
,
Liu
,
Y.
,
Xu
,
M.
,
Gao
,
A.
et al.
(
2014
)
Alterations in the time course of expression of the Nox family in the brain in a rat experimental cerebral ischemia and reperfusion model: effects of melatonin
.
J. Pineal Res.
57
,
110
119
https://doi.org/10.1111/jpi.12148
203
Cho
,
J.H.
,
Tae
,
H.-J.
,
Kim
,
I.-S.
,
Song
,
M.
,
Kim
,
H.
,
Lee
,
T.-K
, et al.
(
2019
)
Melatonin alleviates asphyxial cardiac arrest-induced cerebellar Purkinje cell death by attenuation of oxidative stress
.
Exp. Neurol.
320
, 112983 https://doi.org/10.1016/j.expneurol.2019.112983
204
Zhao
,
Z.
,
Lu
,
C.
,
Li
,
T.
,
Wang
,
W.
,
Ye
,
W.
,
Zeng
,
R.
et al.
(
2018
)
The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: In vivo assessment and a randomized controlled trial
.
J. Pineal Res.
65
, e12521 https://doi.org/10.1111/jpi.12521
205
Zhang
,
H.M.
and
Zhang
,
Y
. (
2014
)
Melatonin: a well-documented antioxidant with conditional pro-oxidant actions
.
J. Pineal Res.
57
,
131
146
https://doi.org/10.1111/jpi.12162
206
Shafiei
,
E.
,
Bahtoei
,
M.
,
Raj
,
P.
,
Ostovar
,
A.
,
Iranpour
,
D.
,
Akbarzadeh
,
S
, et al.
(
2018
)
Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting: A randomized open-labeled, placebo-controlled trial
.
Medicine (Baltimore)
97
, e11383 https://doi.org/10.1097/MD.0000000000011383
207
Nasseh
,
N.
,
Khezri
,
M.B.
,
Farzam
,
S.
,
Shiravandi
,
S.
and
Shafikhani
,
A.A
. (
2022
)
The effect of melatonin on cardiac biomarkers after coronary artery bypass graft surgery: A double-blind, randomized pilot study
.
J. Cardiothorac. Vasc. Anesth.
36
,
3800
3805
https://doi.org/10.1053/j.jvca.2022.06.003
208
Dominguez-Rodriguez
,
A.
,
Abreu-Gonzalez
,
P.
de la Torre-Hernandez
,
J.M.
Gonzalez-Gonzalez
,
J.
,
Garcia-Camarero
,
T.
,
Consuegra-Sanchez
,
L.
et al.
(
2017
)
Effect of intravenous and intracoronary melatonin as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: Results of the Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty trial
.
J. Pineal Res.
62
https://doi.org/10.1111/jpi.12374
209
Ekeloef
,
S.
,
Halladin
,
N.
,
Fonnes
,
S.
,
Jensen
,
S.E.
,
Zaremba
,
T.
,
Rosenberg
,
J.
et al.
(
2017
)
Effect of Intracoronary and Intravenous Melatonin on Myocardial Salvage Index in Patients with ST-Elevation Myocardial Infarction: a Randomized Placebo Controlled Trial
.
J. Cardiovasc. Transl. Res.
10
,
470
479
https://doi.org/10.1007/s12265-017-9768-7
210
Panah
,
F.
,
Ghorbanihaghjo
,
A.
,
Argani
,
H.
,
Haiaty
,
S.
,
Rashtchizadeh
,
N.
,
Hosseini
,
L
, et al.
(
2019
)
The effect of oral melatonin on renal ischemia-reperfusion injury in transplant patients: A double-blind, randomized controlled trial
.
Transpl. Immunol.
57
, 101241 https://doi.org/10.1016/j.trim.2019.101241
211
Tanaka
,
J.
,
Tominaga
,
R.
,
Yoshitoshi
,
M.
,
Matsui
,
K.
,
Komori
,
M.
,
Sese
,
A.
et al.
(
1982
)
Coenzyme Q10: the prophylactic effect on low cardiac output following cardiac valve replacement
.
Ann. Thorac. Surg.
33
,
145
151
https://doi.org/10.1016/s0003-4975(10)61900-5
212
Judy
,
W.V.
,
Stogsdill
,
W.W.
and
Folkers
,
K
. (
1993
)
Myocardial preservation by therapy with coenzyme Q10 during heart surgery
.
Clin. Investig.
71
,
S155
161
https://doi.org/10.1007/BF00226859
213
Chello
,
M.
,
Mastroroberto
,
P.
,
Romano
,
R.
,
Bevacqua
,
E.
,
Pantaleo
,
D.
,
Ascione
,
R.
et al.
(
1994
)
Protection by coenzyme Q10 from myocardial reperfusion injury during coronary artery bypass grafting
.
Ann. Thorac. Surg.
58
,
1427
1432
https://doi.org/10.1016/0003-4975(94)91928-3
214
Taggart
,
D.P.
,
Jenkins
,
M.
,
Hooper
,
J.
,
Hadjinikolas
,
L.
,
Kemp
,
M.
,
Hue
,
D.
et al.
(
1996
)
Effects of short-term supplementation with coenzyme Q10 on myocardial protection during cardiac operations
.
Ann. Thorac. Surg.
61
,
829
833
https://doi.org/10.1016/0003-4975(95)01120-X
215
Zhou
,
M.
,
Zhi
,
Q.
,
Tang
,
Y.
,
Yu
,
D.
and
Han
,
J
. (
1999
)
Effects of coenzyme Q10 on myocardial protection during cardiac valve replacement and scavenging free radical activity in vitro
.
J. Cardiovasc. Surg. (Torino)
40
,
355
361
216
Rosenfeldt
,
F.
,
Marasco
,
S.
,
Lyon
,
W.
,
Wowk
,
M.
,
Sheeran
,
F.
,
Bailey
,
M.
et al.
(
2005
)
Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue
.
J. Thorac. Cardiovasc. Surg.
129
,
25
32
https://doi.org/10.1016/j.jtcvs.2004.03.034
217
Makhija
,
N.
,
Sendasgupta
,
C.
,
Kiran
,
U.
,
Lakshmy
,
R.
,
Hote
,
M.P.
,
Choudhary
,
S.K.
et al.
(
2008
)
The role of oral coenzyme Q10 in patients undergoing coronary artery bypass graft surgery
.
J. Cardiothorac. Vasc. Anesth.
22
,
832
839
https://doi.org/10.1053/j.jvca.2008.03.007
218
Mohseni
,
M.
,
Vafa
,
M.
,
Zarrati
,
M.
,
Shidfar
,
F.
,
Hajimiresmail
,
S.J.
and
Rahimi Forushani
,
A
. (
2015
)
Beneficial effects of coenzyme Q10 supplementation on lipid profile and intereukin-6 and intercellular adhesion molecule-1 reduction, preliminary results of a double-blind trial in acute myocardial infarction
.
Int. J. Prev. Med.
6
,
73
https://doi.org/10.4103/2008-7802.162461
219
Ramezani
,
M.
,
Sahraei
,
Z.
,
Simani
,
L.
,
Heydari
,
K.
and
Shahidi
,
F
. (
2020
)
Coenzyme Q10 supplementation in acute ischemic stroke: Is it beneficial in short-term administration?
Nutr. Neurosci.
23
,
640
645
https://doi.org/10.1080/1028415X.2018.1541269
220
Dwaich
,
K.H.
,
Al-Amran
,
F.G.Y.
,
Al-Sheibani
,
B.I.M.
and
Al-Aubaidy
,
H.A
. (
2016
)
Melatonin effects on myocardial ischemia-reperfusion injury: Impact on the outcome in patients undergoing coronary artery bypass grafting surgery
.
Int. J. Cardiol.
221
,
977
986
https://doi.org/10.1016/j.ijcard.2016.07.108
221
Gibson
,
C.M.
,
Giugliano
,
R.P.
,
Kloner
,
R.A.
,
Bode
,
C.
,
Tendera
,
M.
,
Jánosi
,
A.
et al.
(
2016
)
EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention
.
Eur. Heart J.
37
,
1296
1303
https://doi.org/10.1093/eurheartj/ehv597
222
Saad
,
A.
,
Herrmann
,
S.M.S.
,
Eirin
,
A.
,
Ferguson
,
C.M.
,
Glockner
,
J.F.
,
Bjarnason
,
H.
et al.
(
2017
)
Phase 2a clinical trial of mitochondrial protection (Elamipretide) during stent revascularization in patients with atherosclerotic renal artery stenosis
.
Circ. Cardiovasc. Interv.
10
, e005487 https://doi.org/10.1161/CIRCINTERVENTIONS.117.005487
223
Zhao
,
K.
,
Zhao
,
G.-M.
,
Wu
,
D.
,
Soong
,
Y.
,
Birk
,
A.V.
,
Schiller
,
P.W.
et al.
(
2004
)
Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury
.
J. Biol. Chem.
279
,
34682
34690
https://doi.org/10.1074/jbc.M402999200
224
Birk
,
A.V.
,
Liu
,
S.
,
Soong
,
Y.
,
Mills
,
W.
,
Singh
,
P.
,
Warren
,
J.D.
et al.
(
2013
)
The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin
.
J. Am. Soc. Nephrol.
24
,
1250
1261
https://doi.org/10.1681/ASN.2012121216
225
Birk
,
A.V.
,
Chao
,
W.M.
,
Bracken
,
C.
,
Warren
,
J.D.
and
Szeto
,
H.H
. (
2014
)
Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis
.
Br. J. Pharmacol.
171
,
2017
2028
https://doi.org/10.1111/bph.12468
226
Chatfield
,
K.C.
,
Sparagna
,
G.C.
,
Chau
,
S.
,
Phillips
,
E.K.
,
Ambardekar
,
A.V.
,
Aftab
,
M.
et al.
(
2019
)
Elamipretide improves mitochondrial function in the failing human heart
.
JACC Basic Transl. Sci.
4
,
147
157
https://doi.org/10.1016/j.jacbts.2018.12.005
227
Shang
,
L.
,
Ren
,
H.
,
Wang
,
S.
,
Liu
,
H.
,
Hu
,
A.
,
Gou
,
P.
et al.
(
2021
)
SS-31 protects liver from ischemia-reperfusion injury via modulating macrophage polarization
.
Oxid. Med. Cell. Longev.
2021
, 6662156 https://doi.org/10.1155/2021/6662156
228
Cho
,
J.
,
Won
,
K.
,
Wu
,
D.
,
Soong
,
Y.
,
Liu
,
S.
,
Szeto
,
H.H.
et al.
(
2007
)
Potent mitochondria-targeted peptides reduce myocardial infarction in rats
.
Coron. Artery Dis.
18
,
215
220
https://doi.org/10.1097/01.mca.0000236285.71683.b6
229
Kloner
,
R.A.
,
Hale
,
S.L.
,
Dai
,
W.
,
Gorman
,
R.C.
,
Shuto
,
T.
,
Koomalsingh
,
K.J.
et al.
(
2012
)
Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective Peptide
.
J. Am. Heart Assoc.
1
, e001644 https://doi.org/10.1161/JAHA.112.001644
230
Szeto
,
H.H.
,
Liu
,
S.
,
Soong
,
Y.
,
Wu
,
D.
,
Darrah
,
S.F.
,
Cheng
,
F.-Y.
et al.
(
2011
)
Mitochondria-targeted peptide accelerates ATP recovery and reduces ischemic kidney injury
.
J. Am. Soc. Nephrol.
22
,
1041
1052
https://doi.org/10.1681/ASN.2010080808
231
Imai
,
T.
,
Matsubara
,
H.
,
Nakamura
,
S.
,
Hara
,
H.
and
Shimazawa
,
M
. (
2020
)
The Mitochondria-targeted peptide, bendavia, attenuated ischemia/reperfusion-induced stroke damage
.
Neuroscience
443
,
110
119
https://doi.org/10.1016/j.neuroscience.2020.07.044
232
Cour
,
M.
,
Loufouat
,
J.
,
Paillard
,
M.
,
Augeul
,
L.
,
Goudable
,
J.
,
Ovize
,
M.
et al.
(
2011
)
Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: a pre-clinical study
.
Eur. Heart J.
32
,
226
235
https://doi.org/10.1093/eurheartj/ehq112
233
Huang
,
C.-H.
,
Tsai
,
M.-S.
,
Hsu
,
C.-Y.
,
Su
,
Y.-J.
,
Wang
,
T.-D.
,
Chang
,
W.-T.
et al.
(
2011
)
Post-cardiac arrest myocardial dysfunction is improved with cyclosporine treatment at onset of resuscitation but not in the reperfusion phase
.
Resuscitation
82 Suppl 2
,
S41
47
https://doi.org/10.1016/S0300-9572(11)70150-2
234
Hausenloy
,
D.J.
,
Maddock
,
H.L.
,
Baxter
,
G.F.
and
Yellon
,
D.M
. (
2002
)
Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning?
Cardiovasc. Res.
55
,
534
543
https://doi.org/10.1016/s0008-6363(02)00455-8
235
Oka
,
N.
,
Wang
,
L.
,
Mi
,
W.
,
Zhu
,
W.
,
Honjo
,
O.
and
Caldarone
,
C.A
. (
2008
)
Cyclosporine A prevents apoptosis-related mitochondrial dysfunction after neonatal cardioplegic arrest
.
J. Thorac. Cardiovasc. Surg.
135
,
123
130
https://doi.org/10.1016/j.jtcvs.2007.05.009
236
Deng
,
H.
,
Zhang
,
S.
,
Ge
,
H.
,
Liu
,
L.
,
Liu
,
L.
,
Feng
,
H.
et al.
(
2020
)
The effect of cyclosporin a on ischemia-reperfusion damage in a mouse model of ischemic stroke
.
Neurol. Res.
42
,
721
729
https://doi.org/10.1080/01616412.2020.1762353
237
Cung
,
T.-T.
,
Morel
,
O.
,
Cayla
,
G.
,
Rioufol
,
G.
,
Garcia-Dorado
,
D.
,
Angoulvant
,
D.
et al.
(
2015
)
Cyclosporine before PCI in Patients with Acute Myocardial Infarction
.
N. Engl. J. Med.
373
,
1021
1031
https://doi.org/10.1056/NEJMoa1505489
238
Argaud
,
L.
,
Cour
,
M.
,
Dubien
,
P.-Y.
,
Giraud
,
F.
,
Jossan
,
C.
,
Riche
,
B.
et al.
(
2016
)
Effect of cyclosporine in nonshockable out-of-hospital cardiac arrest: the CYRUS randomized clinical trial
.
JAMA Cardiol.
1
,
557
565
https://doi.org/10.1001/jamacardio.2016.1701
239
Carlström
,
M.
,
Rannier Ribeiro Antonino Carvalho
,
L.
,
Guimaraes
,
D.
,
Boeder
,
A.
and
Schiffer
,
T.A
. (
2024
)
Dimethyl malonate preserves renal and mitochondrial functions following ischemia-reperfusion via inhibition of succinate dehydrogenase
.
Redox Biol.
69
, 102984 https://doi.org/10.1016/j.redox.2023.102984
240
Taghavi
,
S.
,
Abdullah
,
S.
,
Toraih
,
E.
,
Packer
,
J.
,
Drury
,
R.H.
,
Aras
,
O.A.Z.
et al.
(
2022
)
Dimethyl malonate slows succinate accumulation and preserves cardiac function in a swine model of hemorrhagic shock
.
J. Trauma Acute Care Surg.
93
,
13
20
https://doi.org/10.1097/TA.0000000000003593
241
Zhang
,
Z.
,
Lu
,
Z.
,
Liu
,
C.
,
Man
,
J.
,
Li
,
X.
,
Cui
,
K.
et al.
(
2021
)
Protective effects of Dimethyl malonate on neuroinflammation and blood-brain barrier after ischemic stroke
.
Neuroreport
32
,
1161
1169
https://doi.org/10.1097/WNR.0000000000001704
242
Prag
,
H.A.
,
Pala
,
L.
,
Kula-Alwar
,
D.
,
Mulvey
,
J.F.
,
Luping
,
D.
,
Beach
,
T.E.
et al.
(
2022
)
Ester prodrugs of malonate with enhanced intracellular delivery protect against cardiac ischemia-reperfusion injury in vivo
.
Cardiovasc. Drugs Ther.
36
,
1
13
https://doi.org/10.1007/s10557-020-07033-6
243
Mentzer
,
R.M.
Jr
,
Bartels
,
C.
,
Bolli
,
R.
,
Boyce
,
S.
,
Buckberg
,
G.D.
,
Chaitman
,
B.
et al.
(
2008
)
Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study
.
Ann. Thorac. Surg.
85
,
1261
1270
https://doi.org/10.1016/j.athoracsur.2007.10.054
244
Alexander
,
J.H.
,
Emery
,
R.W.
Jr
,
Carrier
,
M.
,
Ellis
,
S.J.
and
Mehta
,
R.H
. (
2008
)
Efficacy and safety of pyridoxal 5′-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: the MEND-CABG II randomized clinical trial
.
Jama
299
,
1777
1787
https://doi.org/10.1001/jama.299.15.joc80027
245
Bonney
,
S.
,
Hughes
,
K.
and
Eckle
,
T
. (
2014
)
Anesthetic cardioprotection: the role of adenosine : the role of adenosine.
.
Curr. Pharm. Des.
20
,
5690
5695
https://doi.org/10.2174/1381612820666140204102524
246
Swyers
,
T.
,
Redford
,
D.
and
Larson
,
D.F
. (
2014
)
Volatile anesthetic-induced preconditioning
.
Perfusion
29
,
10
15
https://doi.org/10.1177/0267659113503975
247
Jiang
,
M.
,
Sun
,
L.
,
Feng
,
D.-X.
,
Yu
,
Z.-Q.
,
Gao
,
R.
,
Sun
,
Y.-Z.
et al.
(
2017
)
Neuroprotection provided by isoflurane pre-conditioning and post-conditioning
.
Med. Gas Res.
7
,
48
55
https://doi.org/10.4103/2045-9912.202910
248
De Hert
,
S.
,
Vlasselaers
,
D.
,
Barbé
,
R.
,
Ory
,
J.-P.
,
Dekegel
,
D.
,
Donnadonni
,
R.
et al.
(
2009
)
A comparison of volatile and non volatile agents for cardioprotection during on-pump coronary surgery
.
Anaesthesia
64
,
953
960
https://doi.org/10.1111/j.1365-2044.2009.06008.x
249
Lurati Buse
,
G.A.L.
,
Schumacher
,
P.
,
Seeberger
,
E.
,
Studer
,
W.
,
Schuman
,
R.M.
,
Fassl
,
J.
et al.
(
2012
)
Randomized comparison of sevoflurane versus propofol to reduce perioperative myocardial ischemia in patients undergoing noncardiac surgery
.
Circulation
126
,
2696
2704
https://doi.org/10.1161/CIRCULATIONAHA.112.126144
250
Júnior
,
R.R.
,
Nigro
,
C.
,
Braga
,
S.N.
,
Sousa
,
A.G.
,
Feres
,
F.
and
Costa
,
J. de R
. (
2023
)
Effect of sevoflurane on serum CK-MB levels after percutaneous coronary stent placement: A prospective randomized clinical trial
.
J. Invasive Cardiol.
35
https://doi.org/10.25270/jic/23.00167
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).