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Journal of Toxicologic Pathology
Vol. 21 (2008) No. 3 P 133-173

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http://doi.org/10.1293/tox.21.133

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Seventy years ago it was discovered that glutamate plays a central role in brain metabolism and is abundant in the brain. Glutamate was then found to be the principal excitatory neurotransmitter in the brain. As stated in the first article of this series, there are three families of ionotropic receptors with intrinsic cation permeable channels: N-methyl-D-aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and kainate [Ka]. Among these there are three groups of metabotropic, G protein-coupled glutamate receptors [mGluR] that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Although glutamate is the most abundant amino acid in the diet, there is no evidence for brain damage in humans resulting from dietary glutamate. However, a Ka analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury by activating NMDA, AMPA or mGluR1 receptors. Glutamate may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's disease. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis. In this second part of this review, we will explore those diseases in which the pathophysiology and pathology are associated, in part, with the glutamate system.

Copyright © 2008 The Japanese Society of Toxicologic Pathology

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