EXCITATORY AMINO-ACIDS IN HEALTH AND DISEASE

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 modifica tion of excitatory synaptic transmission as an important new pharmacol ogical principle. These principles are discussed, with special emphasi s on diseases of importance to older adults. DATA SOURCES: A MEDLINE s earch from 1966 to May 1995 was undertaken, as well as a manual search of current issues of clinical and basic neuroscience journals, for ar ticles that addressed glutamate N-methyl-D-aspartate and/or excitotoxi city. STUDY SELECTION: A total of 5398 original and 68 review articles were identified that addressed animal and human experimentation relev ant to excitotoxic neuronal death. There were 364 articles with potent ial significance for clinical application identified; 132 of the most recent references are provided. DATA EXTRACTION: All articles were cla ssified into three categories: general receptor, biology pathogenesis of disease, and pharmacotherapy. RESULTS: Glutamic and aspartic acids are the physiological mediators of most excitatory synaptic transmissi on. This is critical to several normal nervous system functions, inclu ding memory and long-term modification of synaptic transmission and no ciception. Activation of the inotropic NMDA and non-NMDA receptors inc reases transmembrane calcium and sodium fluxes, and the metabotropic g lutamate receptor activation results in generation of inositol triphos phate and inhibition of adenylate cyclase. Numerous modulatory sites e xist, especially on the NMDA receptor. Nitric oxide, arachidonic acid, superoxide, and intracellular calcium overload are the ultimate media tors of neuronal death. Glutamate re-uptake transporters belong to a u nique family of amino acid transport systems, the malfunction of which is intricately involved in disease pathogenesis. Ischemic stroke, hyp oglycemia, Parkinson's disease, alcohol intoxication and withdrawal, A lzheimer's disease, epilepsy, and chronic pain syndromes are only some of the important clinical neurological disorders with a major pathoge nic 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 neurotra nsmission, such as remacemide, lamotrigine, and tizanidine, have an ac ceptable therapeutic index. The identification of numerous receptor su btypes, topographic variabilities of distribution, and multiple modula tory sites will provide a true challenge to the neuropharmacologist.