excitotoksilisuse

Excitotoxicity, sometimes referred to in Estonian as excitotoksilisuse, is the pathological process by which neurons are damaged and killed due to excessive activation of receptors for excitatory neurotransmitters, most notably glutamate. Under normal conditions glutamate mediates synaptic transmission and plasticity, but when extracellular levels rise markedly, glutamate overactivates NMDA, AMPA, and kainate receptors.

The core mechanism involves excessive calcium influx through NMDA receptors, which activates a cascade of enzymes such as proteases, lipases, and endonucleases. This leads to structural and cellular damage, including membrane breakdown, cytoskeletal disruption, and DNA fragmentation. Calcium overload also impairs mitochondria, promotes generation of reactive oxygen species, and triggers inflammatory signaling in glial cells. The resulting injury can cause neuronal death through necrosis or, in some circumstances, apoptosis, and may contribute to synaptic dysfunction.

Causes and relevance include acute brain injuries such as ischemic stroke, traumatic brain injury, and hypoxic-ischemic events, as well as seizures and certain neurodegenerative conditions. Impaired glutamate clearance by astrocytes, often via excitatory amino acid transporters, can exacerbate extracellular glutamate accumulation and excitotoxic damage.

Clinical significance and approaches to therapy focus on limiting excitotoxic injury during acute events and slowing progression in chronic diseases. NMDA receptor antagonists have shown limited success in trials due to side effects; agents that modulate receptor activity, enhance glutamate uptake, or reduce oxidative stress and inflammation are areas of ongoing research. While the term excitotoxin is used in popular discourse, robust dietary evidence does not support that typical dietary glutamate causes brain excitotoxicity in healthy individuals.