Current evidence does not establish statins or nitric oxide donors as acute cytoprotective therapiesNew insights into brain protection methods for patients with acute stroke

Intravenous thrombolysis and mechanical thrombectomy have transformed acute ischemic stroke (AIS) care, yet angiographic recanalization does not guarantee adequate tissue reperfusion or long-term functional independence. Brain cytoprotection has therefore expanded from neuron-centered rescue to preservation of the ischemic penumbra, neurovascular unit, blood-brain barrier (BBB), and microcirculation. Using a systems-immunology perspective, this clinically oriented narrative review examines ischemia-reperfusion injury as a dynamic network linking danger-associated molecular pattern sensing, microglia and astrocytes, circulating leukocytes, platelets and complement, endothelium and pericytes, cytokine signaling, edema, no-reflow, and regulated cell-death programs. We integrate classic and recent evidence for excitotoxic, redox and mitochondrial, inflammatory, barrier, microvascular, and cell-death targets; evaluate representative pharmacologic and nonpharmacologic interventions; and distinguish negative primary endpoints from exploratory subgroup or surrogate signals. Confirmatory excitotoxicity trials have remained negative overall. Selected multitarget agents have shown benefit in specific Chinese populations, whereas immune-, edema-, and no-reflow-directed approaches have yielded stage-specific but inconsistent safety, imaging, and functional results. Statins, nitric oxide donors, and phosphodiesterase inhibition have plausible vascular or immunomodulatory actions, but available trials do not establish them as acute cytoprotective therapies. Future development should align the right mechanism, tissue phenotype, treatment time, exposure, target-engagement measure, and patient-centered endpoint, followed by multicenter preclinical testing and independent cross-regional clinical replication. This end-to-end framework reframes brain cytoprotection as precision modulation of a spatially and temporally evolving neuroimmune-vascular system rather than a single undifferentiated treatment class.