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Excitotoxicity is a cellular phenomenon in which neurons undergo injury or death due to excessive activation of excitatory amino acid receptors, predominantly by glutamate. This occurs when glutamate concentrations in the synaptic cleft rise to pathological levels, either through increased release, impaired uptake by astrocytic transporters, or direct trauma. The result is overactivation of postsynaptic NMDA and AMPA receptors, leading to sustained calcium influx. Elevated intracellular calcium triggers a cascade that includes mitochondrial dysfunction, energy failure, overproduction of reactive oxygen and nitrogen species, activation of destructive enzymes such as calpain, and the initiation of cell death pathways including apoptosis and necrosis. Excitotoxicity is strongly implicated in a wide spectrum of acute and chronic CNS diseases, including trauma, ischemic stroke, epilepsy, and major neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and ALS. Therapeutic approaches target the process indirectly, by blocking glutamate receptors, enhancing glutamate uptake, or modulating downstream pathways involved in calcium and oxidative stress responses. Excitotoxicity is a pathological process, not a canonical molecular target. It should not be listed as a therapeutic target molecule/receptor according to standard conventions; instead, the targets within this process (such as NMDA receptors or glutamate transporters) are druggable entities.

Other names

Excitotoxic neuronal deathglutamate-induced excitotoxicityneuronal excitotoxicity

NMDA receptor antagonism (reduces pathological calcium influx); AMPA/kainate receptor antagonism; Enhanced glutamate clearance via transporter upregulation (EAAT2/GLT-1); Inhibition of downstream calcium-dependent enzymes (calpain inhibition)