Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson's disease models.
Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic (DA) neuronal cell loss in the substantia nigra. Although the entire pathogenesis of PD is still unclear, both environmental and genetic factors contribute to neurodegeneration. Epidemiologic studies show that prevalence of PD is lower in smokers than in nonsmokers. Nicotine, a releaser of dopamine from DA neurons, is one of the candidates of antiparkinson agents in tobacco. To assess the protective effect of nicotine against rotenone-induced DA neuronal cell toxicity, we examined the neuroprotective effects of nicotine in rotenone-induced PD models in vivo and in vitro. We observed that simultaneous subcutaneous administration of nicotine inhibited both motor deficits and DA neuronal cell loss in the substantia nigra of rotenone-treated mice. Next, we analyzed the molecular mechanisms of DA neuroprotective effect of nicotine against rotenone-induced toxicity with primary DA neuronal culture. We found that DA neuroprotective effects of nicotine were inhibited by dihydro-beta-erythroidine (DHbetaE), alpha-bungarotoxin (alphaBuTx), and/or PI3K-Akt/PKB (protein serine/threonine kinase B) inhibitors, demonstrating that rotenone-toxicity on DA neurons are inhibited via activation of alpha4beta2 or alpha7 nAChRs-PI3K-Akt/PKB pathway or pathways. These results suggest that the rotenone mouse model may be useful for assessing candidate antiparkinson agents, and that nAChR (nicotinic acetylcholine receptor) stimulation can protect DA neurons against degeneration.
Takeuchi
Hiroki
H
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yanagida
Takashi
T
Inden
Masatoshi
M
Takata
Kazuyuki
K
Kitamura
Yoshihisa
Y
Yamakawa
Kentaro
K
Sawada
Hideyuki
H
Izumi
Yasuhiko
Y
Yamamoto
Noriyuki
N
Kihara
Takeshi
T
Uemura
Kengo
K
Inoue
Haruhisa
H
Taniguchi
Takashi
T
Akaike
Akinori
A
Takahashi
Ryosuke
R
Shimohama
Shun
S
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D018678:Cholinergic Agents / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D012402:Rotenone / Q000633:toxicity; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014475:Uncoupling Agents / Q000633:toxicity
D018678:Cholinergic Agents; D011978:Receptors, Nicotinic; D014475:Uncoupling Agents; D012402:Rotenone; D009538:Nicotine; D004298:Dopamine