The good, the bad and the ugly of nitric oxide, superoxide and peroxynitrite signaling during oxygen‐glucose deprivation in rat and arctic ground squirrel

• Published in: The FASEB Journal
• Main Authors: Bhowmick, Saurav, Drew, Kelly
• Other Authors: Medical Research and Materiel Command, National Institute of General Medical Sciences, National Institutes of Health
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2017
• Subjects: Arctic; Arctic ground squirrel; Urocitellus parryii
• Online Access: http://dx.doi.org/10.1096/fasebj.31.1_supplement.lb213

Cerebral ischemia‐reperfusion (I/R) injury initiates a complex cascade of events, several of which involve the generation of nitic oxide (NO) and oxygen (O 2 •− ) free radicals. NO and O 2 •− rapidly combine to form peroxynitrite (ONOO − ) a potent oxidant and nitrating agent. Previous studies have revealed that the arctic ground squirrel (AGS; Urocitellus parryii ) is a natural model of high tolerance to I/R injury, however, the mechanisms that contribute to the ability to tolerate this pathological scenario is still elusive. Here, we tested the hypothesis that tolerance to I/R injury modeled in an acute hippocampal slice preparation in AGS is modulated by reduced oxidative and nitrosative stress associated with oxygen glucose deprivation (OGD). Hippocampal slices (400 micron) from rat and AGS were subjected to oxygen glucose deprivation (OGD) to mimic I/R in vivo using a novel microperfusion technique. Injury consisted of exposing the brain slices to: 1) NO and O 2 •− donors with and without OGD; and 2) pretreatment of slices with inhibitors of NO, O 2 •− and ONOO − followed by OGD. In control slices, treatment was administered by switching to standard aCSF. Perfusates were collected every 15 min and analyzed for LDH release, an indicator of cell death; slices were analyzed for nitrosative and oxidative damage using the markers 3‐nitrotyrosine (3NT) and 4‐hydroxynonenal (4HNE). Results show the effect of NO, O 2 •− and ONOO − mediated injury in ischemic tolerant AGS and ischemic susceptible rat. 1) Effect of NO mediated Injury : An NO donor alone is not sufficient to cause cell death, but with OGD enhances cell death more in rat than in AGS; an inhibitor of nNOS attenuates OGD‐induced injury in rat but has no effect in AGS. 2) Effect of O 2 •− mediated injury : A O 2 •− donor alone causes slight injury in rat and even less injury in AGS. Combining the O 2 •− donor with OGD aggravates the injury in rat; a SOD mimetic attenuates OGD injury in rat but has no effect in AGS. 3) Effect of ONOO − mediated injury: A ...