Recent studies have uncovered that accumulation of glutamate after ischaemic stroke is closely associated with the down-regulation of glutamate transporter-1 (GLT-1) expression, suggesting that GLT-1 expression critically controls glutamate accumulation and the abnormal glutamate transport-elicited neuronal cell excitotoxicity in patients with ischaemic stroke. However, it remains unknown how GLT-1 expression is regulated under ischaemic stroke conditions. In the present study, we screened the expression of nine brain-specific or brain-enriched miRNAs in a focal cerebral ischaemia/reperfusion (I/R) injury rat model, which showed glutamate accumulation and down-regulated GLT-1 expression as expected, and revealed that the miR-107 level was elevated in both brain tissue and plasma in the model. Next, we examined the functional relationship of miR-107 with GLT-1 expression in a nerve cell hypoxia/reoxygenation (H/R) injury model. H/R treatment increased apoptosis of the nerve cells concomitant with glutamate accumulation, miR-107 elevation and suppressed GLT-1 expression, mimicking our in vivo findings in the cerebral I/R injury rat model in vitro. Co-treating the cells with an miR-107 inhibitor blocked all of the effects, demonstrating that miR-107 functions to inhibit GLT-1 expression and elevate glutamate accumulation. To extend these animal and cell-based studies to clinical patients, we measured the plasma levels of miR-107 and glutamate, and observed that both miR-107 and glutamate were elevated in patients with ischaemic stroke. On the basis of these observations, we conclude that elevated miR-107 expression after ischaemic stroke accounts, at least partially, for glutamate accumulation through suppression of GLT-1 expression. Our findings also highlight that the plasma level of miR-107 may serve as a novel biomarker for monitoring excitotoxicity in patients with ischaemic stroke.
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Research Article|
August 08 2014
Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke
Zhong-Bao Yang;
Zhong-Bao Yang
1
*Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
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Zhen Zhang;
Zhen Zhang
1
†Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
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Ting-Bo Li;
Ting-Bo Li
*Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
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Zheng Lou;
Zheng Lou
*Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
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Shu-Yu Li;
Shu-Yu Li
†Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
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Huan Yang;
Huan Yang
†Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
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Jie Yang;
Jie Yang
†Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
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Xiu-Ju Luo;
*Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
‡Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha 410013 China
Correspondence: Dr Jun Peng (email [email protected]) or Dr Xiu-Ju Luo (email [email protected]).
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Jun Peng
*Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
†Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
§Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
Correspondence: Dr Jun Peng (email [email protected]) or Dr Xiu-Ju Luo (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 30 2014
Revision Received:
May 15 2014
Accepted:
June 19 2014
Accepted Manuscript online:
June 19 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 127 (12): 679–689.
Article history
Received:
January 30 2014
Revision Received:
May 15 2014
Accepted:
June 19 2014
Accepted Manuscript online:
June 19 2014
Citation
Zhong-Bao Yang, Zhen Zhang, Ting-Bo Li, Zheng Lou, Shu-Yu Li, Huan Yang, Jie Yang, Xiu-Ju Luo, Jun Peng; Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke. Clin Sci (Lond) 1 December 2014; 127 (12): 679–689. doi: https://doi.org/10.1042/CS20140084
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