title: Neuroprotective effect of acid-sensing ion channel inhibitor psalmotoxin-1 after hypoxia-ischemia in newborn piglet striatum.
abstract: Na+,Ca2+-permeable acid-sensing ion channel 1a (ASIC1a) is involved in the pathophysiologic process of adult focal brain ischemia. However, little is known about its role in the pathogenesis of global cerebral ischemia or newborn hypoxia-ischemia (H-I). Here, using a newborn piglet model of asphyxia-induced cardiac arrest, we investigated the effect of ASIC1a-specific blocker psalmotoxin-1 on neuronal injury. During asphyxia and the first 30min of recovery, brain tissue pH fell below 7.0, the approximate activation pH of ASIC1a. Psalmotoxin-1 injection at 20min before hypoxia, but not at 20min of recovery, partially protected the striatonigral and striatopallidal neurons in putamen. Psalmotoxin-1 pretreatment largely attenuated the increased protein kinase A-dependent phosphorylation of DARPP-32 and N-methyl-d-aspartate (NMDA) receptor NR1 subunit and decreased nitrative and oxidative damage to proteins at 3h of recovery. Pretreatment with NMDA receptor antagonist MK-801 also provided partial neuroprotection in putamen, and combined pretreatment with psalmotoxin-1 and MK-801 yielded additive neuroprotection. These results indicate that ASIC1a activation contributes to neuronal death in newborn putamen after H-I through mechanisms that may involve protein kinase A-dependent phosphorylation of NMDA receptor and nitrative and oxidative stress.
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. zyang4@jhmi.edu
authors.forename: Zeng-Jin
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Xinli
authors.initials: X
authors.lastname: Ni
authors.forename: Erin L
authors.initials: EL
authors.lastname: Carter
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kibler
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000254:growth & development; D004195:Disease Models, Animal; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism; D007231:Infant, Newborn; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides; D015222:Sodium Channels / Q000502:physiology; D013111:Spider Venoms / Q000494:pharmacology* / Q000627:therapeutic use; D034421:Sus scrofa
chemical_list: C568266:ASIC1 protein, human; D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C413209:PcTX1 protein, Psalmopoeus cambridgei; D010455:Peptides; D015222:Sodium Channels; D013111:Spider Venoms