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.
Li
Wenming
W
Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, China.
Lee
Nelson T K
NT
Fu
Hongjun
H
Kan
Kelvin K W
KK
Pang
Yuanping
Y
Li
Mingtao
M
Tsim
Karl W K
KW
Li
Xiaoyuan
X
Han
Yifan
Y
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