Ischemic stroke is a leading cause of global neurological mortality and disability, characterized by a complex pathogenesis wherein calcium overload constitutes a pivotal mechanism in neuronal and glial cell death. Following ischemia and reperfusion, excitotoxicity triggered by excessive glutamate release activates NMDA receptors and voltage-dependent calcium channels, leading to a large accumulation of intracellular Ca2+. This calcium dyshomeostasis subsequently initiates a cascade of detrimental events, including mitochondrial dysfunction, endoplasmic reticulum stress, reactive oxygen species generation, and the activation of calcium-dependent enzymes (such as calpain and phospholipase A2), ultimately culminating in cellular apoptosis or necrosis. In addition, calcium signaling imbalance is closely related to various forms of programmed cell death, such as ferroptosis and necroptosis. Research on calcium overload extends beyond neurons, with investigations in microglia and astrocytes yielding significant mechanistic insights. Although targeted interventions, encompassing calcium channel blockers, NMDA receptor antagonists, mitochondrial calcium homeostasis regulators, and calmodulin/calmodulin kinase (CaM/CaMK) inhibitors, have demonstrated preclinical progress, their clinical translation remains constrained. Future investigations should prioritize elucidating the nuanced regulatory mechanisms of calcium signaling pathways, developing highly selective and low-toxicity calcium intervention drugs, and combining multi-target treatment strategies such as neuroprotection, anti-inflammation, and tissue repair to provide theoretical basis and new solutions for the precise treatment of ischemic stroke.
Jiang et al. (Sat,) studied this question.