Weg. Muller et al., PROTECTION OF FLUPIRTINE ON BETA-AMYLOID-INDUCED APOPTOSIS IN NEURONAL CELLS IN-VITRO - PREVENTION OF AMYLOID-INDUCED GLUTATHIONE DEPLETION, Journal of neurochemistry, 68(6), 1997, pp. 2371-2377
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.