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 peptide (A beta)-induced neurotoxicity. Cortical neurons from rat embryos were treated with the toxic fragment A beta25-35 at 1 microM in the presence or absence of flupirtine, a triaminopyridine, successfully applied clinically as a nonopiate analgesic drug. Five days later 1 microM A beta25-35 caused reduction of cell viability to 31.1%. Preincubation of cells with flupirtine (1 or 5 microg/ml) resulted in a significant increase of the percentage of viable cells (74.6 and 65.4%, respectively). During incubation with A beta25-35 the neurons undergo apoptosis as determined by appearance of the characteristic stepladder-like DNA fragmentation pattern and by the TUNEL technique. A beta25-35-induced DNA fragmentation could be abolished by preincubation of the cells with 1 microg/ml flupirtine. Incubation with A beta25-35 reduces the intraneuronal level of GSH from 21.4 to 7.4 nmol/10(6) cells. This depletion could be partially prevented by preincubation of the cells with flupirtine. Thus, flupirtine may be adequate for the treatment of the neuronal loss in Alzheimer's disease (where A beta accumulates in senile plaques) and probably other neurological diseases such as amyotrophic lateral sclerosis.
Müller
W E
WE
Institut für Physiologische Chemie, Abteilung Angewandte Molekularbiologie, Universität, Mainz, Germany.
Romero
F J
FJ
Perovic
S
S
Pergande
G
G
Pialoglou
P
P
D000631:Aminopyridines / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology; D005978:Glutathione / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D000631:Aminopyridines; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D005978:Glutathione; C034161:flupirtine