The triaminopyridine flupirtine prevents cell death in rat cortical cells induced by N-methyl-D-aspartate and gp120 of HIV-1.
Flupirtine, a triaminopyridine derivative, is a non-opiate centrally acting analgesic agent with muscle relaxant properties. Now we show that this drug displays a potent cytoprotective effect on neurons (rat cortical cells) treated with (i) the excitatory amino acid N-methyl-D-aspartate (NMDA) or (ii) with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120. In the absence of the drug the two agents cause a > 90% reduction of cell viability after a 18 h incubation. During this period the DNA in the cells undergoes fragmentation and shows a pattern which is typical for cell death. If the neurons were preincubated with flupirtine for 2 h and subsequently exposed to the cytotoxic agents an almost complete protection was achieved. The cytoprotective effect of flupirtine in vitro was significant (above 10 microM). Because flupirtine displays almost no clinical side effects and in light of the data presented here, flupirtine may be a promising drug also for the treatment of NMDA-mediated neurodegenerative disorders in general and for the treatment of AIDS-related encephalopathy in particular.
Perovic
S
S
Institut für Physiologische Chemie, Abteilung Angewandte Molekularbiologie, Universität, Mainz, Germany.
Schleger
C
C
Pergande
G
G
Iskric
S
S
Ushijima
H
H
Rytik
P
P
Müller
W E
WE
D015526:AIDS Dementia Complex / Q000188:drug therapy; D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1 / Q000378:metabolism; D008970:Molecular Weight; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000631:Aminopyridines; D000700:Analgesics; D015699:HIV Envelope Protein gp120; D016202:N-Methylaspartate; C034161:flupirtine