Pharmacological intervention in age-associated brain disorders by Flupirtine: Alzheimer's and prion diseases.
Alzheimer's disease, a major form of dementia in the elderly has become an increasingly important health problem in developed countries. In vitro studies on primary neurons demonstrate that Flupirtine (Katadolon) at a concentration of 1 microg/ml, significantly reduces the neurotoxic (apoptotic) effect displayed by A beta25-35, a segment of the amyloid beta-protein precursor the etiologic agent of Alzheimer's disease. Flupirtine, which has been in clinical use since 10 years ago, prevents the toxic effect of PrP, the presumed etiologic agent of the Creutzfeldt-Jakob disease as well as the excitatory amino acid glutamate on cortical neurons. Flupirtine displays a bimodal activity. Its strongest cytoprotective effect against glutamate-induced neurotoxicity was measured if administered at least 120 min prior to the addition of the 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 parallel with the determination of the effect of Flupirtine on the toxin (A beta, PrP or glutamate)-induced neuronal death the effect of the drug on the intracellular Ca2+ level [Ca2+]i, was measured. It is well established that incubation of neurons with glutamate causes an increase in [Ca2+]i. It was found that a simultaneous administration of Flupirtine and glutamate did not reduce the glutamate-induced high Ca2+ level. Only if the cells had been preincubated for approximately 30 min with the drug the intracellular Ca2+ level was significantly lower. Experimental evidence given here shows that the molecular basis for 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 Flupirtine is a promising drug to treat neurodegenerative disorders occurring with age, e.g. Alzheimer's disease and prion based diseases, like Creutzfeldt-Jakob disease. This conclusion is corroborated by the favourable pharmacokinetic profile of Flupirtine.
Perovic
S
S
Institut für Physiologische Chemie, Abteilung Angewandte Molekülarbiologie, Universität, Mainz, Germany.
Böhm
M
M
Meesters
E
E
Meinhardt
A
A
Pergande
G
G
Müller
W E
WE
D000375:Aging; D000544:Alzheimer Disease / Q000188:drug therapy*; D000595:Amino Acid Sequence; D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D005971:Glutamates / Q000494:pharmacology; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000494:pharmacology; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000631:Aminopyridines; D016229:Amyloid beta-Peptides; D005971:Glutamates; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011328:Prions; D019253:Proto-Oncogene Proteins c-bcl-2; C074636:amyloid beta-protein (25-35); C082632:prion protein (106-126); C034161:flupirtine; D002118:Calcium