title: Acidotoxicity via ASIC1a Mediates Cell Death during Oxygen Glucose Deprivation and Abolishes Excitotoxicity.
abstract: Ischemic reperfusion (I/R) injury is associated with a complex and multifactorial cascade of events involving excitotoxicity, acidotoxicity, and ionic imbalance. While it is known that acidosis occurs concomitantly with glutamate-mediated excitotoxicity during brain ischemia, it remains elusive how acidosis-mediated acidotoxicity interacts with glutamate-mediated excitotoxicity. Here, we investigated the effect of acidosis on glutamate-mediated excitotoxicity in acute hippocampal slices. We tested the hypothesis that mild acidosis protects against I/R injury via modulation of NMDAR, but produces injury via activation of acid sensing ion channels (ASIC1a). Using a novel microperfusion approach, we monitored time course of injury in acutely prepared, adult hippocampal slices. We varied the duration of insult to delay the return to preinsult conditions to determine if injury was caused by the primary insult or by the modeled reperfusion phase. We also manipulated pH in presence and absence of oxygen glucose deprivation (OGD). The role of ASIC1a and NMDAR was deciphered by treating the slices with and without an ASIC or NMDAR antagonist. Our results show that injury due to OGD or low pH occurs during the insult rather than the modeled reperfusion phase. Injury mediated by low pH or low pH OGD requires ASIC1a and is independent of NMDAR activation. These findings point to ASIC1a as a mediator of ischemic cell death caused by stroke and cardiac arrest.
authors.affiliation: Department of Chemistry and Biochemistry and ‡Institute of Arctic Biology, University of Alaska Fairbanks , Fairbanks, Alaska 99775, United States.
authors.forename: Saurav
authors.identifier: 0000-0001-9069-4728
authors.initials: S
authors.lastname: Bhowmick
authors.affiliation: Department of Chemistry and Biochemistry and ‡Institute of Arctic Biology, University of Alaska Fairbanks , Fairbanks, Alaska 99775, United States.
authors.forename: Jeanette T
authors.initials: JT
authors.lastname: Moore
authors.affiliation: Department of Chemistry and Biochemistry and ‡Institute of Arctic Biology, University of Alaska Fairbanks , Fairbanks, Alaska 99775, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kirschner
authors.affiliation: Department of Chemistry and Biochemistry and ‡Institute of Arctic Biology, University of Alaska Fairbanks , Fairbanks, Alaska 99775, United States.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Curry
authors.affiliation: Department of Chemistry and Biochemistry and ‡Institute of Arctic Biology, University of Alaska Fairbanks , Fairbanks, Alaska 99775, United States.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Westbrook
authors.affiliation: Department of Chemistry and Biochemistry and ‡Institute of Arctic Biology, University of Alaska Fairbanks , Fairbanks, Alaska 99775, United States.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Rasley
authors.affiliation: Department of Chemistry and Biochemistry and ‡Institute of Arctic Biology, University of Alaska Fairbanks , Fairbanks, Alaska 99775, United States.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Drew
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000138:Acidosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D016923:Cell Death / Q000502:physiology; D005947:Glucose; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009924:Organ Culture Techniques; D010100:Oxygen; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D062565:Acid Sensing Ion Channels; C568268:Asic1 protein, rat; D005947:Glucose; D010100:Oxygen
keywords: Brain Ischemia; acute hippocampal slice; excitotoxicity; glutamate; oxygen-glucose deprivation and reperfusion; pH