FLUPIRTINE PARTIALLY PREVENTS NEURONAL INJURY-INDUCED BY PRION PROTEIN-FRAGMENT AND LEAD ACETATE

Flupirtine belongs to the class of triaminopyridines and is successful ly applied clinically as a non-opiate analgesic drug with additional m uscle relaxant properties. Recently it was reported that flupirtine ac ts like an antagonist of the N-methyl-D-aspartate (NMDA) receptor comp lex in neuronal cells both in vitro and in vivo. Here we have used pri mary cortical cells from rat embryos to demonstrate that this compound is also neuroprotective against the toxic effects caused by the prion agent PrPSc and lead acetate (Pb). These two agents display pleiotrop ic effects on neurons, which include activation of the NMDA receptor c omplex. At concentrations above 30 mu M the toxic-peptide fragment of PrPSc causes apoptotic fragmentation of DNA and is consequently neurot oxic. Pb is neurotoxic at concentrations above 10 mu M. Co-administrat ion of flupirtine (10 mu M) with either of these agents resulted in re duced neurotoxicity. These data indicate that the cytoprotective effec t of flupirtine is measurable in vitro against these noxious agents wh ich show their effects, including modulation of the NMDA receptor comp lex, pleiotropically. (C) 1995 Academic Press Limited.