Conceptual review reveals astrocytic dysfunction as the primary driver of neuronal death in ischemic injury, highlighting glial failure as the upstream trigger of metabolic collapse.
Key Points
To revisit the glial failure hypothesis thirty years after its proposal and evaluate astrocytes as central homeostatic regulators that unify mechanisms of ischemic neuronal death.
Synthesized physiological and pathological evidence detailing astrocytic regulation of metabolic, ionic, and vascular homeostasis in cerebral ischemia.
Evaluated the mechanistic continuum from early protective glial adaptations to progressive dysfunction and terminal tissue failure.
Early astrocytic responses promote transient tissue survival through adenosine-mediated synaptic suppression that reduces cellular energetic demand.
Progressive glial failure drives spontaneous spreading depolarizations and impairs their termination, dictating immediate or delayed neuronal terminal depolarization based on local energetic capacity.
Astrocytic homeostatic breakdown represents the primary upstream disturbance that directly links cellular metabolic failure to irreversible ischemic injury.