PROTECTION OF FLUPIRTINE ON BETA-AMYLOID-INDUCED APOPTOSIS IN NEURONAL CELLS IN-VITRO - PREVENTION OF AMYLOID-INDUCED GLUTATHIONE DEPLETION

Effective drugs are not available to protect against beta-amyloid pept ide (A beta)-induced neurotoxicity. Cortical neurons from rat embryos were treated with the toxic fragment A beta 25-35 at 1 mu M in the pre sence or absence of flupirtine, a triaminopyridine, successfully appli ed clinically as a nonopiate analgesic drug. Five days later 1 mu M A beta 25-35 caused reduction of cell viability to 31.1%. Preincubation of cells with flupirtine (1 or 5 mu g/ml) resulted in a significant in crease of the percentage of viable cells (74.6 and 65.4%, respectively ). During incubation with A beta 25-35 the neurons undergo apoptosis a s determined by appearance of the characteristic stepladder-like DNA f ragmentation pattern and by the TUNEL technique. A beta 25-35-induced DNA fragmentation could be abolished by preincubation of the cells wit h 1 mu g/ml flupirtine. Incubation with A beta 25-35 reduces the intra neuronal level of GSH from 21.4 to 7.4 nmol/10(6) cells. This depletio n could be partially prevented by preincubation of the cells with flup irtine. Thus, flupirtine may be adequate for the treatment of the neur onal loss in Alzheimer's disease (where A beta accumulates in senile p laques) and probably other neurological diseases such as amyotrophic l ateral sclerosis.