Synergistic effect of galantamine on nicotine-induced neuroprotection in hemiparkinsonian rat model.
Recent studies have reported that smokers tend to be less susceptible to Parkinson's disease (PD) and the stimulation of nicotinic acetylcholine receptor (nAChR) is considered to confer a neuroprotective effect. Galantamine is an acetylcholinesterase inhibitor and an allosteric potentiating ligand for nAChRs. However, the effects of galantamine and nicotine on dopaminergic neurons remain unclear. This study evaluated the neuroprotective effects of galantamine and nicotine in a rat 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model. 6-OHDA with or without galantamine and/or nicotine were injected into unilateral substantia nigra of rats. Although methamphetamine-stimulated rotational behavior and dopaminergic neuronal loss induced by 6-OHDA were not inhibited by galantamine alone, those were moderately inhibited by nicotine alone. In addition, 6-OHDA-induced neuronal loss and rotational behavior were synergistically inhibited by co-injection of galantamine and nicotine. These protective effects were abolished by mecamylamine, an nAChR antagonist. We further found that alpha7 nAChR was expressed on both tyrosine hydroxylase (TH)-immunopositive and TH-immunonegative neurons in the SNpc. A combination of galantamine and nicotine greatly suppressed 6-OHDA-induced reduction of TH-immunopositive/alpha7 nAChR-immunopositive neurons. These results suggest that galantamine synergistically enhances the neuroprotective effect of nicotine against 6-OHDA-induced dopaminergic neuronal loss through an allosteric modulation of alpha7 nAChR activation.
Department of Neurobiology, 21st Century COE Program, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Takashi
T
Yanagida
Hiroki
H
Takeuchi
Yoshihisa
Y
Kitamura
Kazuyuki
K
Takata
Hideaki
H
Minamino
Tomonori
T
Shibaike
Jun
J
Tsushima
Koji
K
Kishimoto
Hiroyuki
H
Yasui
Takashi
T
Taniguchi
Shun
S
Shimohama
D000818:Animals; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D007839:Functional Laterality; D005702:Galantamine / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008694:Methamphetamine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009538:Nicotine / Q000627:therapeutic use*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D045442:Rotarod Performance Test; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579165:Chrna7 protein, rat; D018765:Dopamine Uptake Inhibitors; D018696:Neuroprotective Agents; D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005702:Galantamine; D008694:Methamphetamine; D008464:Mecamylamine; D009538:Nicotine; D014446:Tyrosine 3-Monooxygenase