Excitotoxins

Excitotoxins are substances that cause neuronal damage or death by excessively stimulating glutamate receptors in the nervous system. They disrupt normal synaptic signaling when present at high levels or when uptake mechanisms fail, leading to harmful intracellular events.

Most excitotoxicity results from overactivation of ionotropic glutamate receptors, particularly NMDA, AMPA, and kainate receptors, leading to sustained calcium influx. The resulting intracellular cascade includes activation of calcium-dependent enzymes, production of reactive oxygen species, mitochondrial dysfunction, and ultimately neuronal injury or death. Glutamate is the principal excitatory neurotransmitter in the mammalian brain; homeostatic mechanisms normally limit extracellular levels via uptake by excitatory amino acid transporters on astrocytes and neurons.

Excitotoxins can be endogenous, arising from pathological processes such as ischemia, trauma, or neurodegenerative diseases, or exogenous to the central nervous system. Substances with excitotoxic effects include the amino acid glutamate itself and kainic acid and domoic acid, natural marine and fungal toxins that overactivate kainate receptors. Monosodium glutamate (MSG) is a dietary additive that can briefly raise glutamate levels in the brain under certain conditions, though the clinical relevance of dietary MSG to excitotoxic risk is uncertain.

Clinical relevance: excitotoxicity is implicated in stroke and spinal cord injury and in various neurodegenerative diseases. It also helps explain some models of seizures and injury after hypoxic events. Therapeutic approaches aim to dampen excitotoxic signaling, such as NMDA receptor antagonists or strategies to limit glutamate release or enhance uptake. However, broad blockade of glutamate receptors can cause adverse effects, limiting their clinical use. Research continues to seek targeted neuroprotection that can reduce excitotoxic damage without impairing normal synaptic transmission.