Affiliation:
1. Legacy Clinical Research and Technology Center, 1225 NE 2nd Avenue, Portland, OR 97232, U.S.A.
Abstract
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.
Cited by
25 articles.
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