Neuroprotective effects of galanthamine and tacrine against glutamate neurotoxicity.
We examined the mechanisms of the neuroprotective effects of two central-type acetylcholinesterase inhibitors, galanthamine and tacrine, on nitric oxide-mediated glutamate neurotoxicity using primary cultures from the cerebral cortex of fetal rats. Galanthamine and tacrine showed prominent protective effects against glutamate neurotoxicity. Mecamylamine, a nicotinic acetylcholine receptor antagonist, but not scopolamine, a muscarinic acetylcholine receptor antagonist, inhibited the protective effects of these inhibitors on glutamate neurotoxicity. Furthermore, dihydro-beta-erythroidine, an alpha4-nicotinic receptor antagonist, and methyllycaconitine, an alpha7-nicotinic receptor antagonist, inhibited the neuroprotective effects of galanthamine but not tacrine. Next, we investigated the site of action where galanthamine and tacrine prevent glutamate neurotoxicity. Both these acetylcholinesterase inhibitors prevented glutamate- and ionomycin-induced neurotoxicity, but only tacrine prevented S-nitrosocysteine-induced neurotoxicity. These results suggest that galanthamine and tacrine protect cortical neurons from glutamate neurotoxicity via different mechanisms.
Takada-Takatori
Yuki
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Kume
Toshiaki
T
Sugimoto
Mitsuhiro
M
Katsuki
Hiroshi
H
Niidome
Tetsuhiro
T
Sugimoto
Hachiro
H
Fujii
Takeshi
T
Okabe
Susumu
S
Akaike
Akinori
A
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000633:toxicity; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D005702:Galantamine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D015759:Ionomycin / Q000633:toxicity; D007476:Ionophores / Q000633:toxicity; D008464:Mecamylamine / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D026403:S-Nitrosothiols / Q000633:toxicity; D013619:Tacrine / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D007476:Ionophores; D018696:Neuroprotective Agents; D018733:Nicotinic Antagonists; D020030:Nitric Oxide Donors; D026403:S-Nitrosothiols; D005702:Galantamine; D004079:Dihydro-beta-Erythroidine; D018698:Glutamic Acid; D013619:Tacrine; D015759:Ionomycin; D008464:Mecamylamine; C021315:S-nitrosocysteine; D003545:Cysteine