Pathophysiology of Ischemic Cell Death in the Central Nervous System

The high metabolic demand and complex blood supply of the central nervous system (CNS) render it susceptible to both global and focal ischemic insults, which represent a leading cause of morbidity and mortality in humans. The effects of ischemia in the CNS are determined by duration, severity, and neuroanatomical location of the insult. The pathophysiology of ischemic cell death represents a dynamic process in which necrosis, apoptosis, and other forms of regulated cell death (i.e., necroptosis, pyroptosis, ferroptosis, and autophagic cell death) can be involved. Multiple molecular signaling pathways are implicated in ischemic cell death associated with ATP depletion, excitotoxicity, calcium overload, oxidative stress, mitochondrial dysfunction, and rough endoplasmic reticulum dysfunction. Multiple animal models have been developed to advance knowledge in the field, though translational gaps remain. Therapeutic approaches focus on timely reperfusion and emerging cytoprotective strategies. Toxicologic pathologists play a pivotal role in expanding translational research and supporting the development of emerging therapies.