Arctic ground squirrel resist peroxynitrite-mediated cell death in response to oxygen glucose deprivation

Abstract

Cerebral ischemia-reperfusion (I/R) injury initiate a cascade of events, generating nitric oxide (NO) and superoxide(O2•−) to form peroxynitrite (ONOO−), a potent oxidant. Arctic ground squirrel (AGS; Urocitellus parryii) show high tolerance to I/R injury. However, the underlying mechanism remains elusive. We hypothesize that tolerance to I/R modeled in an acute hippocampal slice preparation in AGS is modulated by reduced oxidative and nitrative stress. Hippocampal slices (400 microns) from rat and AGS were subjected to oxygen glucose deprivation (OGD) using a novel microperfusion technique. Slices were exposed to NO, O2·− donors with and without OGD; pretreatment with inhibitors of NO, O2·− and ONOO− followed by OGD. Perfusates collected every 15 min were analyzed for LDH release, a marker of cell death. 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE) were measured to assess oxidative and nitrative stress. Results show that NO/O2·− alone is not sufficient to cause ischemic-like cell death, but with OGD enhances cell death more in rat than AGS. NOS inhibitor, SOD mimetic and ONOO− inhibitor attenuates OGD injury in rat but has no effect in AGS. Rats also show a higher level of 3NT and 4HNE with OGD than AGS suggesting a greater level of injury is via formation of ONOO−.

Role of HMGB1/TLR4 Axis in Ischemia/Reperfusion-Impaired Extracellular Glutamate Clearance in Primary Astrocytes

“…An in vitro model of OGD/reperfusion has been used for studying the mechanisms of neuron death after ischemic stroke. NMDA (N-methyl-d-aspartic acid) mediated excitotoxicity, and oxidative stress were reported to be involved in neuron death [28][29][30]. However, the roles of astrocytes in ischemic brain injury-induced excitotoxicity have been seldom investigated before.…”

Naked mole‐rat brain mitochondria tolerate in vitro ischaemia

“…3D), which is likely an indicator not only of outer mitochondrial membrane (OMM) but also IMM damage following ischaemia. Importantly, others have directly correlated this cytochrome c response to the degree of membrane damage using LDH leakage assays in Sprague Dawley rat brain (Fernández-López et al 2005;Bhowmick & Drew, 2017). Thus, in NMRs, a stable cytochrome c-induced O 2 consumption response across treatment groups indicates that the IMM integrity is well-maintained, whereas the decreased capacity of complex II-linked OXPHOS might be due to slight damage to the OMM (Fig.…”

Resilience to Injury: A New Approach to Neuroprotection?

“…Interestingly, this study demonstrated that tolerance to oxygen glucose deprivation in AGS occurs independent of hibernation season and persists in conditions mimicking ischemia-reperfusion such as following depletion of ATP, glutamate excitotoxicity, and acidosis. As in hypoxia preconditioning, reduced release of ROS and reactive nitrogen species in response to oxygen glucose deprivation are key factors underlying reduced cell death in AGS [54]. While the bioenergetic feats of AGS hibernation are notable, perhaps even more astounding is the rapid dendritic regrowth and synaptic rebuilding accompanying each IBA [55].…”