excitotoxic

Excitotoxicity is a pathological process in which neurons are damaged and killed due to excessive stimulation by excitatory neurotransmitters, particularly glutamate. The term arose from observations of injury after stroke and other energy-depriving insults, where glutamate accumulation leads to neuron death.

Mechanism: Under energy failure, glutamate release increases and uptake by astrocytes and neurons becomes impaired. Overactivation of ionotropic receptors—NMDA, AMPA, and kainate—permits excessive calcium influx. The resulting rise in intracellular calcium triggers enzymatic pathways (proteases, lipases, endonucleases), mitochondrial dysfunction, reactive oxygen species production, and inflammatory cascades, culminating in necrotic and/or apoptotic cell death.

Role in disease: Excitotoxicity contributes to tissue damage in acute central nervous system injuries such as ischemic stroke and traumatic brain injury, and is implicated in chronic neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. It can also occur in epilepsy and hepatic encephalopathy.

Mitigation and research: Approaches aim to limit glutamate release, boost its uptake, or block ionotropic receptors. NMDA receptor antagonists have shown neuroprotective effects in experimental models but clinical use is limited by side effects; memantine is an approved NMDA antagonist for Alzheimer's disease that exhibits relatively low affinity. Other strategies include enhancing astrocytic glutamate transport, antioxidant therapies, and anti-inflammatory interventions. The effectiveness of excitotoxicity-targeted therapies in humans remains an area of active investigation.