The NP must understand the ischemic stroke cascade to appreciate the rationale for time-critical reperfusion therapy. When a cerebral artery is occluded (by cardioembolism from atrial fibrillation in approximately 20-30%, large vessel atherothrombosis in 15-25%, or small vessel lacunar disease in 20-25%), the downstream territory is divided into two zones based on the severity of blood flow reduction. The ISCHEMIC CORE receives less than 10-12 mL/100g/min blood flow (normal is 50-55 mL/100g/min) and undergoes rapid irreversible neuronal death within minutes through energy failure, loss of ion homeostasis, cytotoxic edema, and necrosis. The ISCHEMIC PENUMBRA surrounds the core and receives 12-22 mL/100g/min blood flow from collateral circulation -- this tissue is functionally impaired (contributing to the neurological deficit) but structurally viable and represents the target for salvage through reperfusion. The penumbra undergoes a time-dependent cascade of injury: ATP depletion leads to failure of Na+/K+-ATPase pumps, causing depolarization and release of excitatory glutamate; glutamate activates NMDA and AMPA receptors, triggering massive calcium influx (excitotoxicity); intracellular calcium overload activates proteases, lipases, and endonucleases while also generating reactive oxygen species through mitochondrial dysfunction and...