Candidate Mechanisms of Cerebral Ischemia/Hypoxia Tolerance: Insights from Hibernating Rodents

Cerebral ischemia/hypoxia constitutes a central pathological process in ischemic stroke and a range of neurological disorders, yet effective and safe neuroprotective strategies remain scarce in clinical practice. Hibernating rodents repeatedly undergo extreme physiological fluctuations, including marked reductions in cerebral blood flow and subsequent reperfusion, during torpor-arousal cycles, yet they do not exhibit overt neurological deficits upon emergence from hibernation. This unique phenotype renders them a valuable natural model for investigating endogenous tolerance to cerebral ischemia/hypoxia. In this narrative review, we systematically summarize the physiological characteristics of hibernating rodents and their differential tolerance to cerebral ischemia/hypoxia under euthermic versus hibernating conditions. We further focus on several candidate mechanisms, including suppression of excitotoxicity, regulation of sulfide metabolism, global inhibition of protein synthesis, and enhanced SUMOylation. Current evidence suggests that these mechanisms may contribute to hibernation-associated tolerance; however, the quality of evidence and the strength of causal inferences remain inconsistent or limited. Overall, hibernating rodents provide a novel perspective for understanding tolerance to cerebral ischemia/hypoxia, and the underlying mechanisms may offer valuable insights for future basic research and potential translational applications.