Brain Advance Access originally published online on November 17, 2006
Brain 2007 130(1):151-158; doi:10.1093/brain/awl325
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Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia
Robert S. Dow Neurobiology Laboratories, Legacy Research Portland, OR, USA
Correspondence to: Zhi-Gang Xiong, Robert S. Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Avenue, 97232, Portland, OR, USA E-mail: zxiong{at}downeurobiology.org
Acid-sensing ion channels (ASICs), newly discovered members of epithelial Na+ channels/degenirin superfamily, are widely distributed throughout the mammalian peripheral and central nervous system and have been implicated in many physiological and pathophysiological processes. We have recently shown that activation of calcium-permeable ASIC1a is involved in acidosis-mediated, glutamate independent, ischaemic brain injury. In this study the neuroprotective time window for ASIC1a blockade in a mouse model of focal ischaemia is examined and the role of acidosis per se addressed by continuous pH measurements in penumbral cortex and post-ischaemic alkalization of brain. The effects of NMDA receptor blockade and ASIC1a blockade were compared. Specific ASIC1a blockade by the tarantula toxin psalmotoxin, PcTX, administered intracerebroventricularly as late as 5 h after 60 min of transient middle cerebral artery occlusion (MCAO) reduced infarct volume by >50%; the protection persisted for at least 7 days. Protection was also demonstrated after permanent MCAO. In penumbral cortex alkaline pH preceded acid pH and infarction. Attenuating brain acidosis by NaHCO3 or blocking ASIC1a with PcTX were both protective. NMDA blockade produced additive neuroprotection and the presence of PcTX prolonged the time window of effectiveness of NMDA blockade. Neuroprotection by PcTX was also achievable by intranasal administration. These findings further suggest that ASIC1a is a novel molecular target involved in ischaemic brain injury. Post-ischaemic administration of an ASIC1a blocker may prove to be an effective neuroprotective strategy for stroke patients.
Key Words: acidosis; acid-sensing ion channels; ischaemia; neuroprotection
Abbreviations: ASIC, acid-sensing ionic channels; CBF, cerebral blood flow; i.c.v., intracerebroventricularly; i.n., intranasal; MCAO, middle cerebral artery occlusion
Received June 6, 2006. Revised October 11, 2006. Accepted October 19, 2006.
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