Glutamate in the Mammalian CNS

The excitatory amino acid glutamate plays an important role in the mammalian CNS. Studies conducted from 1940 to 1950 suggested that oral administration of glutamate could have a beneficial effect on normal and retardate intelligence. The neurotoxic nature of glutamate resulting in excitotoxic lesions (neuronal death) is thought possibly to underlie several neurological diseases including Huntington's disease, status epilepticus. Alzheimer's dementia and olivopontocerebellar atrophy. This neurodegenerative effect of glutamate also appears to regulate the formation, modulation and degeneration of brain cytoarchitecture during normal development and adult plasticity, by altering neuronal outgrowth and synaptogenesis. In addition to its function as a neurotransmitter in several regions of the CNS, glutamate seems to be specifically implicated in the memory process. Long-term potentiation (LTP) and long-term depression (LTD), two forms of synaptic plasticity associated with learning and memory, both involve glutamate receptors. Studies with antagonists of glutamate receptors reveal a highly selective dependency of LTP and LTD on the N-methyl-D-aspartate and quisqualate receptors respectively. The therapeutic value of glutamate receptor antagonists is being actively investigated. The most promising results have been obtained in epilepsy and to some extent in ischaemia and stroke. The major drawback remains the inability of antagonists to permeate the blood-brain barrier when administered systemically. Efforts should be directed towards finding antagonists that are lipid soluble and able to cross the blood-brain barrier and to find precursors that would yield the antagonist intracerebrally.