Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action.
Epidemiological studies have reported that smoking is associated with a lower incidence of Parkinson's disease (PD), leading to theories that smoking in general and nicotine in particular might be neuroprotective. Recent studies suggested cholinergic anti-inflammatory pathway-regulating microglial activation through alpha7 nicotinic receptors. In the present study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether nicotine has a protective effect on the dopaminergic system through an anti-inflammatory mechanism. Nicotine pretreatment considerably decreased microglial activation with significant reduction of tumour necrosis factor (TNF)-alpha mRNA expression and TNF-alpha release induced by LPS stimulation. In co-cultures of microglia and mesencephalic neurons, nicotine pretreatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells, approximately twice more than the LPS-only treatment. alpha-Bungarotoxin, an alpha7 nicotinic acetylcholine receptor subunit-selective blocker, considerably blocked the inhibitory effects of nicotine on microglial activation and TH-ip neuronal loss. Chronic nicotine pretreatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the substantia nigra was dramatically decreased, which was clearly accompanied by a reduction in the formation of TNF-alpha. The present study demonstrated that nicotine has a neuroprotective effect on dopaminergic neurons via an anti-inflammatory mechanism mediated by the modulation of microglial activation. Along with various neuroprotective effects of nicotine, the anti-inflammatory mechanism of nicotine could have a major therapeutic implication in the preventive treatment of PD.
Park
Hyun Jung
HJ
Department of Neurology, Ajou University School of Medicine, Suwon, Korea.
Lee
Phil Hyu
PH
Ahn
Young Whan
YW
Choi
Yun Jung
YJ
Lee
Gwang
G
Lee
Da-Yong
DY
Chung
Eun S
ES
Jin
Byung Kwan
BK
D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents; D002038:Bungarotoxins / Q000494:pharmacology; D002452:Cell Count; D018920:Coculture Techniques; D004298:Dopamine / Q000502:physiology*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D017628:Microglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D002038:Bungarotoxins; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D018733:Nicotinic Antagonists; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009538:Nicotine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine