Formation of oxygen radicals and NO induced by glutamate: roles in neurotoxicity

摘要

Glutamate plays a dual role in the central nervous system (CNS). In the 1970s and 1980s a neurotransmitter role for glutamate, previously considered to be solely a metabolic precursor, was accepted. In fact, it is believed that 70% of the excitatory CNS synapses use glutamate as a transmitter. Glutamate activates four major types of glutamate receptors, namely three ionotropic receptors, AMPA (a-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropionoic acid), kainate and NMDA (N-rnethyl-D-aspartate) [1,2] and several types of metabotropic receptors [3, 4]. Glutamate is a very important element in governing physiological functions such as synapse and memory formation. However, excessive activation of glutamate receptors is neurotoxic. The earliest indications of the neurotoxic properties of glutamate was obtained by Olney and Ho in 1970 when they demonstrated that young mice (lacking a tight blood brain barrier) treated orally with glutamate show neurodegenerative changes in the brain [5]. This neurotoxic effect of glutamate is easily observed in cultured neurons after a few minutes of stimulation with NMDA. In humans, consumption of some compounds known to activate glutamate receptors, leads to neuronal damage. Several subjects were intoxicated in Canada by eating mussels containing concentrated domoate, a kainate agonist contained in diatoms (fig. 1) Four subjects died, some experienced epileptic fits, others suffered from loss of memory [5].