Bioenergetics and glutamate excitotoxicity

Bioenergetic defects and abnormalities in glutamate neurotransmission have both been proposed to play important roles in neurological diseases of varying chronology, etiology and pathology. Recent experimental evidence suggests an intimate relationship between these two systems. Metabolic inhibition predisposes neurons to glutamate-mediated “excitotoxic” damage. The exact mechanism of this increased susceptibility is yet to be defined, but may involve, singly or in combination, decreased voltage-dependent Mg²⁺ blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, abnormalities in cellular Ca²⁺ homeostasis, or elevated production of reactive oxygen species. It is believed that enhancement of excitotoxicity by impaired metabolism may be a ubiquitous mechanism of neuronal death in neurological disease. Further elucidation of the exact mechanism of this enhancement may lead to the discovery of new targets for therapeutic intervention.