Intracellular calcium toxicity remains the central feature in the pathophysiology of ischaemic cell death in brain. Glutamate-gated channels have been thought to be the major sites of ischaemia-induced toxic calcium entry, but the failure of glutamate antagonists in clinical trials has suggested that glutamate-independent mechanisms of calcium entry during ischaemia must exist and may prove central to ischaemic injury. We have shown that ASICs (acid-sensing ion channels) in brain are glutamate-independent vehicles of calcium flux and transport calcium in greater measure in the setting of the two major neurochemical components of ischaemia: acidosis and substrate depletion. Pharmacological blockade of ASICs markedly attenuates stroke injury with a robust therapeutic time window of 5 h following stroke onset. Here, we describe this new mechanism of calcium toxicity in brain ischaemia and offer a potential new therapy for stroke.
Conference Article| October 25 2006
Acidotoxicity in brain ischaemia
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R. Simon, Z. Xiong; Acidotoxicity in brain ischaemia. Biochem Soc Trans 1 December 2006; 34 (6): 1356–1361. doi: https://doi.org/10.1042/BST0341356
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