Ischemic Stroke Cascade: Energy Failure And

The ischemic stroke cascade is a sequence of molecular events that begins within seconds of cerebral blood flow interruption and progresses over hours to days, converting the potentially salvageable ischemic penumbra into irreversible infarction. The brain consumes 20% of total body oxygen despite representing only 2% of body weight, and neurons have virtually no energy reserves, making them exquisitely vulnerable to ischemia. Within seconds of arterial occlusion, ATP production via oxidative phosphorylation ceases in the ischemic core. ATP depletion causes failure of the Na+/K+-ATPase pump, leading to loss of ionic gradients: intracellular sodium accumulates (causing cytotoxic edema as water follows osmotically), and the resting membrane potential depolarizes, opening voltage-gated calcium channels and triggering massive release of the excitatory neurotransmitter glutamate into the synaptic cleft. This is excitotoxicity: excess glutamate overstimulates NMDA and AMPA receptors on postsynaptic neurons, causing pathological calcium influx. Intracellular calcium overload activates destructive enzymes — calpains (proteases that degrade cytoskeletal proteins), phospholipase A2 (which liberates arachidonic acid from membrane phospholipids, generating inflammatory eicosanoids and free radicals), and endonucleases (which fragment DNA). Mitochondrial calcium overload triggers the mitochondrial...