The role of excitotoxicity and metabolic failure in the pathogenesis of neurological disorders.

Glutamate neurotoxicity has been implicated in acute neurological disorders such as ischemia, and in chronic neurodegenerative diseases such as Huntington's disease (HD). Recently, a link between excitotoxicity and impairment of energy metabolism has been proposed. Important evidence suggests that metabolic inhibition exacerbates the toxic effect of glutamate. During hypoxic/ischemia metabolic disturbances are obvious, and several metabolic defects have been found in HD patients. Disruption of the ionic gradients during inhibition of metabolism can lead to glutamate release, impairment of glutamate transport, and activation of NMDA receptors. Glutamate receptor activation results in calcium influx which is a determinant step leading to cell death. Additionally mitochondrial failure results in an inadequate buffering of the calcium load induced by glutamate contributing to cell death.