Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia.
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.
Pignataro
Giuseppe
G
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA.
Simon
Roger P
RP
Xiong
Zhi-Gang
ZG
D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D002552:Cerebral Ventricles; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D017693:Sodium Bicarbonate / Q000008:administration & dosage; D015222:Sodium Channels / Q000378:metabolism*; D013111:Spider Venoms / Q000008:administration & dosage; D013997:Time Factors
C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D015222:Sodium Channels; D013111:Spider Venoms; D016202:N-Methylaspartate; D017693:Sodium Bicarbonate