L-CARNITINE INCREASES THE AFFINITY OF GLUTAMATE FOR QUISQUALATE RECEPTORS AND PREVENTS GLUTAMATE NEUROTOXICITY

We have shown that acute ammonia toxicity is mediated by activation of the NMDA type of glutamate receptors. Although it is well known that L-carnitine prevents acute ammonia toxicity, the underlying molecular mechanism is not clear. We suspected that L-carnitine would prevent am monia toxicity by preventing the toxic effects of glutamate. We have t ested this hypothesis using primary cultures of neurons. L-carnitine p revented glutamate neurotoxicity in a dose-dependent manner similar to that required to prevent ammonia toxicity in animals. It is also show n that L-carnitine increases selectively the affinity of glutamate for the quisqualate type of glutamate receptors, while the affinity for t he kainate and NMDA receptors is slightly decreased. L-carnitine preve nts the increase in cytoplasmic Ca2+ induced by addition of glutamate. The Ca2+ levels rose 4.8-fold following addition of 1 mM glutamate, h owever, when the neurons were incubated previously with 5 mM L-carniti ne, the Ca2+ levels increased only by 50%. Also, AP-3, an antagonist o f the metabotropic receptor prevents the protective effect of L-carnit ine against glutamate neurotoxicity. We suggest, therefore, that the p rotective effect of L-carnitine against glutamate toxicity is due to t he increased affinity of glutamate for the metabotropic receptor. This mechanism could also explain the protection by L-carnitine against ac ute ammonia toxicity.