NEUROTOXICITY OF AMMONIA AND GLUTAMATE - MOLECULAR MECHANISMS AND PREVENTION

Ammonia is a main factor in the pathogenesis of hepatic encephalopathy . We found that acute ammonia toxicity is mediated by activation of NM DA receptors. Chronic moderate hyperammonemia prevents acute ammonia t oxicity in rats. Chronic exposure of cultured neurons to 1 mM ammonia leads to impaired response of the NMDA receptor to activation by its a gonists (due to decreased protein kinase C-mediated phosphorylation) a nd prevents glutamate (Glu) neurotoxicity. Compounds that prevent ammo nia toxicity in mice (e.g. carnitine) also prevent Glu toxicity in cul tured neurons. These compounds did not prevent activation of NMDA rece ptor or the rise of Ca2+. They interfered with subsequent steps in the toxic process. The protective effect of carnitine is mediated by acti vation of metabotropic Glu receptors. Agonists of mGluRs, especially o f mGluR5, prevent Glu toxicity. Agonists of muscarinic receptors also prevent Glu toxicity and there seems to be an interplay between muscar inic and metabotropic Glu receptors in the protective effect. We have fried to identify intracellular events involved in the process of neur onal death. If is known that the rise of Ca2+ is an essential step. Gl u leads to depletion of ATP; some compounds (e.g. carnitine) prevent G lu-induced neuronal death without preventing ATP depletion: additional events are required for neuronal death. Glu induces activation of Na/K+-ATPase, which could be involved in the toxic process. Inhibitors o f protein kinase C, calcineurin or nitric oxide synthase prevent Glu t oxicity. Our results indicate that Glu toxicity can be prevented at di fferent steps or by activating receptors coupled to the transduction p athways interfering with the toxic process. Agents acting on these ste ps could prevent excitotoxicity in vivo in animals. (C) 1998 Inter Pre ss, Inc.