excitotoxicity

Excitotoxicity is a pathological process in which neurons are damaged or killed by excessive stimulation from excitatory amino acids, especially glutamate. Overactivation of ionotropic glutamate receptors, particularly NMDA receptors, causes a sustained rise in intracellular calcium that activates degradative enzymes and disrupts cellular metabolism, leading to cell injury.

Under normal conditions glutamate is released during synaptic transmission and rapidly cleared by astrocytic transporters (EAAT1/GLAST and EAAT2/GLT-1) and uptake mechanisms. Ischemia, trauma, seizures, or metabolic stress can cause excessive glutamate accumulation, receptor overactivation, and calcium influx. The resulting Ca2+ overload triggers enzymes such as calpains and phospholipases, generates reactive oxygen and nitrogen species via nitric oxide synthase and mitochondrial dysfunction, and promotes lipid, protein, and DNA damage. These cascades culminate in necrotic or apoptotic neuronal death; glial cells can both release glutamate and fail to clear it, intensifying excitotoxic injury.

Clinical relevance: Excitotoxicity is implicated in acute CNS injuries such as ischemic stroke and traumatic brain injury, as well as in seizures and some chronic neurodegenerative conditions where glutamate homeostasis is disrupted.

Therapies: Approaches include glutamate receptor antagonists, strategies to enhance astrocytic glutamate uptake, and agents that limit calcium overload or oxidative stress. Although NMDA antagonists showed neuroprotection in models, many failed in humans due to side effects; memantine provides modest benefit in Alzheimer's disease. Research continues for safer, targeted interventions to mitigate excitotoxicity in CNS disorders.