Neuroprotective effects of galanthamine and tacrine against glutamate neurotoxicity

• Published in: European journal of pharmacology Vol. 549; no. 1; pp. 19 - 26
• Main Authors: Takada-Takatori, Yuki, Kume, Toshiaki, Sugimoto, Mitsuhiro, Katsuki, Hiroshi, Niidome, Tetsuhiro, Sugimoto, Hachiro, Fujii, Takeshi, Okabe, Susumu, Akaike, Akinori
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 07.11.2006; Elsevier
• Subjects: Acetylcholinesterase; Alzheimer's disease; Animals; Biological and medical sciences; Cell Survival - drug effects; Cells, Cultured; Cerebral Cortex; Cholinesterase Inhibitors - pharmacology; Cortical culture; Cysteine - analogs & derivatives; Cysteine - toxicity; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dihydro-beta-Erythroidine - pharmacology; Dose-Response Relationship, Drug; Fetus; Galantamine - pharmacology; Glutamate; Glutamic Acid - toxicity; Ionomycin - toxicity; Ionophores - toxicity; Mecamylamine - pharmacology; Medical sciences; Neurology; Neuroprotective Agents - pharmacology; Neurotoxicity; Nicotinic acetylcholine receptor; Nicotinic Antagonists - pharmacology; Nitric Oxide Donors - toxicity; Pharmacology. Drug treatments; Rats; Rats, Wistar; S-Nitrosothiols - toxicity; Tacrine - pharmacology; Cortical culture; Neurotoxicity; Acetylcholinesterase; Glutamate; Alzheimer's disease; Nicotinic acetylcholine receptor; Neuroprotection; Galantamine; Alzheimer disease; Toxicity; Benzazepine derivatives; Esterases; Alkaloid; Cholinergic receptor; Degenerative disease; Anticholinesterase agent; Nicotinic receptor; Tacrine; Nervous system diseases; Enzyme; Enzyme inhibitor; Antialzheimer agent; Carboxylic ester hydrolases; Cerebral disorder; Parasympathomimetic; Central nervous system disease; Excitatory aminoacid; Neurotransmitter; Hydrolases; Antidote
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2006.08.017

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-β-erythroidine, an α4-nicotinic receptor antagonist, and methyllycaconitine, an α7-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.