PHARMACOLOGICAL INTERVENTION IN AGE-ASSOCIATED BRAIN DISORDERS BY FLUPIRTINE - ALZHEIMERS AND PRION-DISEASES

Alzheimer's disease, a major form of dementia in the elderly has becom e an increasingly important health problem in developed countries. In vitro studies on primary neurons demonstrate that Flupirtine (Katadolo n(R)) at a concentration of 1 mu g/ml, significantly reduces the neuro toxic (apoptotic) effect displayed by A beta 25-35, a segment of the a myloid beta-protein precursor the etiologic agent of Alzheimer's disea se. Flupirtine, which has been in clinical use since 10 years ago, pre vents the toxic effect of PrP, the presumed etiologic agent of the Cre utzfeldt-Jakob disease as well as the excitatory amino acid glutamate on cortical neurons. Flupirtine displays a bimodal activity. Its stron gest cytoprotective effect against glutamate-induced neurotoxicity was measured if administered at least 120 min prior to the addition of th e glutamate. A likewise potent anti-apoptotic activity was measured if cells were simultaneously incubated with Flupirtine and the apoptotic inducers. Administration of Flupirtine during postincubation time in the experiments with glutamate did not result in neuroprotection. In p arallel with the determination of the effect of Flupirtine on the toxi n (A beta, PrP or glutamate)-induced neuronal death the effect of the drug on the intracellular Ca2+ level [Ca2+](i), was measured. It is we ll established that incubation of neurons with glutamate causes an inc rease in [Ca2+](i). It was found that a simultaneous administration of Flupirtine and glutamate did not reduce the glutamate-induced high Ca 2+ level. Only if the cells had been preincubated for approximate to 3 0 min with the drug the intracellular Ca2+ level was significantly low er. Experimental evidence given here shows that the molecular basis fo r the antiapoptotic effect of Flupirtine against glutamate, triggered during pre-incubation, is an increased expression of the protooncogene bcl-2. The neuroprotective effect determined during coincubation with the inducer is attributed to a normalization of the glutathione level which dropped in the presence of the inducers. It is concluded that F lupirtine is a promising drug to treat neurodegenerative disorders occ urring with age, e.g. Alzheimer's disease and prion based diseases, li ke Creutzfeldt-Jakob disease. This conclusion is corroborated by the f avourable pharmacokinetic profile of Flupirtine. (C) 1998 Elsevier Sci ence Ireland Ltd. All rights reserved.