Excitotoxicitet

excitotoxicitet, also called excitotoxicity, is a pathological process in which neurons are damaged and killed by excessive activation of glutamate receptors. It is driven by elevated extracellular glutamate levels that overstimulate ionotropic receptors, particularly NMDA, AMPA, and kainate receptors, leading to harmful intracellular cascades.

The mechanism involves excessive calcium influx through these receptors, which activates a range of calcium-dependent enzymes such as proteases, phospholipases, and endonucleases. This disruption damages cellular structures, impairs mitochondrial function, and increases production of reactive oxygen and nitrogen species. The resulting energy failure and oxidative stress promote neuronal apoptosis and necrosis. Astrocytic uptake of glutamate and overall neurotransmitter clearance are critical; when uptake is impaired or release is increased, neurons become vulnerable to excitotoxic damage.

Contexts in which excitotoxicity is implicated include acute brain injury such as ischemic stroke and traumatic brain injury, seizures, and various neurodegenerative conditions. Regions with high glutamatergic activity or limited blood flow, such as the hippocampus, are particularly susceptible.

Clinical relevance and responses to excitotoxicity focus on neuroprotection by reducing glutamate release, enhancing clearance, or modulating receptor activity. NMDA receptor antagonists have shown neuroprotective potential in models but face limited clinical use due to side effects. Some approved therapies in related conditions (for example, memantine in Alzheimer's disease) illustrate the therapeutic interest. Excitotoxicity is understood as a contributor to neuronal loss that often interacts with inflammation and oxidative stress in central nervous system disorders.