Mild Hypothermia Attenuates Mitochondrial Oxidative Stress by Protecting Respiratory Enzymes and Upregulating MnSOD in a Pig Model of Cardiac Arrest

Abstract

Mild hypothermia is the only effective treatment confirmed clinically to improve neurological outcomes for comatose patients with cardiac arrest. However, the underlying mechanism is not fully elucidated. In this study, our aim was to determine the effect of mild hypothermia on mitochondrial oxidative stress in the cerebral cortex. We intravascularly induced mild hypothermia (33°C), maintained this temperature for 12 h, and actively rewarmed in the inbred Chinese Wuzhishan minipigs successfully resuscitated after 8 min of untreated ventricular fibrillation. Cerebral samples were collected at 24 and 72 h following return of spontaneous circulation (ROSC). We found that mitochondrial malondialdehyde and protein carbonyl levels were significantly increased in the cerebral cortex in normothermic pigs even at 24 h after ROSC, whereas mild hypothermia attenuated this increase. Moreover, mild hypothermia attenuated the decrease in Complex I and Complex III (i.e., major sites of reactive oxygen species production) activities of the mitochondrial respiratory chain and increased antioxidant enzyme manganese superoxide dismutase (MnSOD) activity. This increase in MnSOD activity was consistent with the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and protein expressions, and with the increase of Nrf2 nuclear translocation in normothermic pigs at 24 and 72 h following ROSC, whereas mild hypothermia enhanced these tendencies. Thus, our findings indicate that mild hypothermia attenuates mitochondrial oxidative stress in the cerebral cortex, which may be associated with reduced impairment of mitochondrial respiratory chain enzymes, and enhancement of MnSOD activity and expression via Nrf2 activation.

Evidence for the Therapeutic Efficacy of Either Mild Hypothermia or Oxygen Radical Scavengers after Repetitive Mild Traumatic Brain Injury

“…Though the possible mechanisms associated with this mild hypothermiainduced axonal and vascular protection remain unclear, it is most likely that its benefits derive from subtle reductions in brain metabolism and/or oxygen radical production capable of evoking both axonal and microvascular change. [35][36][37][38][39] Some previous articles that demonstrated reduction of neuronal oxidative damage by induction of mild hypothermia (33-35°C) in TBI, intracerebral hemorrhage, and hypoxic ischemia support our opinion. [40][41][42] Whereas it is relatively remarkable that a 2°C temperature drop, which would result in a 14% reduction in brain metabolism, 38 could be capable of effecting such protection, our observation suggests that this is the case and, as such, that the use of mild hypothermia may ultimately prove a rational choice in patients showing adverse consequences of secondary or repetitive injury, particularly those patients manifesting rapid deterioration in second impact syndrome.…”

Hypothermia-Induced Neuroprotection is Associated with Reduced Mitochondrial Membrane Permeability in a Swine Model of Cardiac Arrest

“…3 Cardiopulmonary resuscitation time was similar in NT and HT pigs (3.3±1.2 versus 3.4±1.3 minutes, respectively, P40.05).…”

“…18,19 Isolation of Mitochondria Mitochondria were isolated according to a protocol that has been described in detail in our earlier paper. 3 The final pellet was resuspended in 300 mL of ice-cold isolation medium (20 mg protein/mL) and kept on ice for further assays. The isolation of mitochondria was validated by western blotting ( Figure 4C).…”

Hypothermia-induced ischemic tolerance is associated with Drp1 inhibition in cerebral ischemia-reperfusion injury of mice

“…It was reported that hypothermia could attenuate mitochondrial oxidative stress and reduce mitochondrial membrane permeability (Gong et al, 2012(Gong et al, , 2013. Furthermore, hypothermia could attenuate Cyto C release and decrease caspase-3 expression (Zhao et al, 2005).…”