Neuroprotection via inhibition of nitric oxide synthase by bis(7)-tacrine.
Here we report that bis(7)-tacrine, a novel acetylcholinesterase inhibitor, exerts neuroprotective effects by inhibition of nitric oxide synthase. In cortical neurons at 12 days in vitro, bis(7)-tacrine concentration-dependently reduced cell death induced by glutamate, beta-amyloid and L-arginine, but not by nitric sodium nitroprusside. N-monomethyl-L-arginine, a nitric oxide synthase inhibitor, also prevented the former three types but not the last type of the cytotoxicity; however, nitric oxide scavengers blocked all of these insults, indicating that nitric oxide mediated these neuronal injuries. Furthermore, with nitric oxide synthase activity assays, it was found that bis(7)-tacrine not only suppressed the activation of nitric oxide synthase caused by glutamate in cortical neurons, but also directly inhibited the activity of nitric oxide synthase in vitro.
Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, China.
Wenming
W
Li
Nelson T K
NT
Lee
Hongjun
H
Fu
Kelvin K W
KK
Kan
Yuanping
Y
Pang
Mingtao
M
Li
Karl W K
KW
Tsim
Xiaoyuan
X
Li
Yifan
Y
Han
D000818:Animals; D001562:Benzimidazoles; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D005452:Fluoresceins; D005456:Fluorescent Dyes; D018698:Glutamic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D009498:Neurotoxins / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D001562:Benzimidazoles; D005452:Fluoresceins; D005456:Fluorescent Dyes; D018696:Neuroprotective Agents; D009498:Neurotoxins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D018698:Glutamic Acid; D013619:Tacrine; D052248:Nitric Oxide Synthase Type I; C017807:bisbenzimide ethoxide trihydrochloride; C018506:diacetylfluorescein