Excitatory Amino Acids in Health and Disease

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PURPOSE: To review the role of excitatory neurotransmitters in normal mammalian brain function, the concept of excitotoxic neuronal death as an important final common path in a variety of diseases, and modification of excitatory synaptic transmission as an important new pharmacological principle. These principles are discussed, with special emphasis on diseases of importance to older adults. DATA SOURCES: A MEDLINE search from 1966 to May 1995 was undertaken, as well as a manual search of current issues of clinical and basic neuroscience journals, for articles that addressed glutamate N-methyl-D-aspartate and/or excitotoxicity. STUDY SELECTION: A total of 5398 original and 68 review articles were identified that addressed animal and human experimentation relevant to excitotoxic neuronal death. There were 364 articles with potential significance for clinical application identified; 132 of the most recent references are provided. DATA EXTRACTION: All articles were classified into three categories: general receptor, biology pathogenesis of disease, and pharmacotherapy. RESULTS: Glutamic and aspartic acids are the physiological mediators of most excitatory synaptic transmission. This is critical to several normal nervous system functions, including memory and long-term modification of synaptic transmission and nociception. Activation of the inotropic NMDA and non-NMDA receptors increases transmembrane calcium and sodium fluxes, and the metabotropic glutamate receptor activation results in generation of inositol triphosphate and inhibition of adenylate cyclase. Numerous modulatory sites exist, especially on the NMDA receptor. Nitric oxide, arachidonic acid, superoxide, and intracellular calcium overload are the ultimate mediators of neuronal death. Glutamate re-uptake transporters belong to a unique family of amino acid transport systems, the malfunction of which is intricately involved in disease pathogenesis. Ischemic stroke, hypoglycemia, Parkinson's disease, alcohol intoxication and withdrawal, Alzheimer's disease, epilepsy, and chronic pain syndromes are only some of the important clinical neurological disorders with a major pathogenic role for the excitatory amino acids. CONCLUSIONS: Pharmacological manipulation of the excitatory amino acid receptors is likely to be of benefit in important and common diseases of the nervous system. Only a few of the currently available drugs that modify excitatory neurotransmission, such as remacemide, lamotrigine, and tizanidine, have an acceptable therapeutic index. The identification of numerous receptor subtypes, topographic variabilities of distribution, and multiple modulatory sites will provide a true challenge to the neuropharmacologist.