title: Acidotoxicity in brain ischaemia.
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.
authors.affiliation: Legacy Clinical Research and Technology Center, 1225 NE 2nd Avenue, Portland, OR 97232, USA. rsimon@downeurobiology.org
authors.forename: R
authors.initials: R
authors.lastname: Simon
authors.forename: Z
authors.initials: Z
authors.lastname: Xiong
mesh_terms: D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D019556:COS Cells; D002118:Calcium / Q000502:physiology / Q000633:toxicity*; D016923:Cell Death; D002522:Chlorocebus aethiops; D005727:Ganglia, Spinal / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D015222:Sodium Channels / Q000502:physiology*; D014162:Transfection
chemical_list: D062565:Acid Sensing Ion Channels; D007473:Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D002118:Calcium