Nicotine as a potential neuroprotective agent for Parkinson's disease

Quik, Maryka; Perez, Xiomara A.; Bordia, Tanuja

doi:10.1002/mds.25028

Cited by 212 publications

(170 citation statements)

References 129 publications

(182 reference statements)

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“…These findings support evidence of nicotinedependent structural plasticity in the DAergic system (Janson et al, 1988a,b;Bunnemann et al, 2000;Mudo et al, 2007) and clarify the role of specific intracellular pathways involved in growth and survival (Doura et al, 2010;Quik et al, 2012). In our work, nicotine produced structural changes in DAergic Fig.…”

Section: Discussionsupporting

confidence: 91%

Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signaling

et al. 2013

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Although long-term exposure to nicotine is highly addictive, one beneficial consequence of chronic tobacco use is a reduced risk for Parkinson's disease. Of interest, these effects both reflect structural and functional plasticity of brain circuits controlling reward and motor behavior and, specifically, recruitment of nicotinic acetylcholine receptors (nAChR) in mesencephalic dopaminergic neurons. Because the underlying cellular mechanisms are poorly understood, we addressed this issue with use of primary cultures of mouse mesencephalic dopaminergic neurons. Exposure to nicotine (1-10 mM) for 72 hours in vitro increased dendritic arborization and soma size in primary cultures. These effects were blocked by mecamylamine and dihydro-b-erythroidine, but not methyllycaconitine. The involvement of a4b2 nAChR was supported by the lack of nicotineinduced structural remodeling in neurons from a4 null mutant mice (KO). Challenge with nicotine triggered phosphorylation of the extracellular signal-regulated kinase (ERK) and the thymoma viral proto-oncogene (Akt), followed by activation of the mammalian target of rapamycin complex 1 (mTORC1)-dependent p70 ribosomal S6 protein kinase. Upstream pathway blockade using the phosphatidylinositol 3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride] resulted in suppression of nicotine-induced phosphorylations and structural plasticity. These effects were dependent on functional DA D3 receptor (D3R), because nicotine was inactive both in cultures from D3R KO mice and after pharmacologic blockade with D3R antagonist trans-N-4-2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethylcyclohexyl-4-quinolinecarboxamide (SB-277011-A) (50 nM). Finally, exposure to nicotine in utero (5 mg/kg/day for 5 days) resulted in increased soma area of DAergic neurons of newborn mice, effects not observed in D3 receptor null mutant mice mice. These findings indicate that nicotine-induced structural plasticity at mesencephalic dopaminergic neurons involves a4b2 nAChRs together with dopamine D3R-mediated recruitment of ERK/Akt-mTORC1 signaling.

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Section: Discussionsupporting

confidence: 91%

Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signaling

et al. 2013

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“…Thus, a4 nAChRs may play a central role in the actions of nicotine on T cells and inflammation, leading to an increased susceptibility to immune diseases such as Crohn's disease and rheumatoid arthritis (Sopori, 2002). Interestingly, these same receptors may also contribute to the protective effects of nicotine in conditions such as ulcerative colitis and Parkinson's disease (Guslandi, 1999;Quik et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Theα4 Nicotinic Receptor Promotes CD4⁺T-Cell Proliferation and a Helper T-Cell Immune Response

et al. 2013

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Smoking is a common addiction and a leading cause of disease. Chronic nicotine exposure is known to activate nicotinic acetylcholine receptors (nAChRs) in immune cells. We demonstrate a novel role for a4 nAChRs in the effect of nicotine on T-cell proliferation and immunity. Using cell-based sorting and proteomic analysis we define an a4 nAChR expressing helper T-cell population (a4 1 CD3 1 CD4 1 ) and show that this group of cells is responsive to sustained nicotine exposure. In the circulation, spleen, bone marrow, and thymus, we find that nicotine promotes an increase in CD31 CD4 1 cells via its activation of the a4 nAChR and regulation of G protein subunit o, G protein regulated-inducer of neurite outgrowth, and CDC42 signaling within T cells. In particular, nicotine is found to promote a helper T cell 2 adaptive immunologic response within T cells that is absent in a4 2 / 2 mice. We thus present a new mechanism of a4 nAChR signaling and immune regulation in T cells, possibly accounting for the effect of smoking on the immune system.

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“…4 While this is counterintuitive given the otherwise adverse health effects of smoking, common biases including confounding, selection, or measurement error do not explain this finding. Alternatively, the possibility exists that biological mechanisms responsible for PD result in smoking avoidance or the ability to quit smoking more easily among those at risk of developing PD.…”

Section: Introductionmentioning

confidence: 96%

Parkinson disease and smoking revisited

et al. 2014

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Objective: To assess whether being able to quit smoking is an early marker of Parkinson disease (PD) onset rather than tobacco being "neuroprotective," we analyzed information about ease of quitting and nicotine substitute use.Methods: For this case-control study, we identified 1,808 patients with PD diagnosed between 1996 and 2009 from Danish registries, matched 1,876 population controls on sex and year of birth, and collected lifestyle information. We estimated odds ratios and 95% confidence intervals with logistic regression adjusting for matching factors and confounders.Results: Fewer patients with PD than controls ever established a smoking habit. Among former smokers, those with greater difficulty quitting or using nicotine substitutes were less likely to develop PD, with the risk being lowest among those reporting "extremely difficult to quit" compared with "easy to quit." Nicotine substitute usage was strongly associated with quitting difficulty and duration of smoking, i.e., most strongly among current smokers, followed by former smokers who had used nicotine substitutes, and less strongly among former smokers who never used substitutes.Conclusions: Our data support the notion that patients with PD are able to quit smoking more easily than controls. These findings are compatible with a decreased responsiveness to nicotine during the prodromal phase of PD. We propose that ease of smoking cessation is an aspect of premanifest PD similar to olfactory dysfunction, REM sleep disorders, or constipation and suggests that the apparent "neuroprotective" effect of smoking observed in epidemiologic studies is due to reverse causation. Neurology ® 2014;83:1396-1402 GLOSSARY CI 5 confidence interval; GWAS 5 genome-wide association study; OR 5 odds ratio; PD 5 Parkinson disease.According to epidemiologic studies, patients with Parkinson disease (PD) are less likely to smoke.1-3 Also, those who smoke for longer are at lower risk while lengthening time since quitting increases PD risk, causing some to argue that smoking may protect against PD and even prompting nicotine PD prevention trials. 4 While this is counterintuitive given the otherwise adverse health effects of smoking, common biases including confounding, selection, or measurement error do not explain this finding. Alternatively, the possibility exists that biological mechanisms responsible for PD result in smoking avoidance or the ability to quit smoking more easily among those at risk of developing PD. That is, individuals who develop PD may not experience the positive reinforcement from, and possibly the addictive response to, nicotine many years before motor symptom development, and thus are able to quit more easily than smokers who never develop PD. This distinction is important because smoking may either provide leads for treatment/prevention of PD or be plainly no more than an early marker of insidious PD onset. To explore this, we examined difficulty quitting and use of nicotine substitutes in relation to PD risk in the Danish PASIDA (Parkinson...

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Nicotine as a potential neuroprotective agent for Parkinson's disease

Cited by 212 publications

References 129 publications

Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signaling

Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signaling

Theα4 Nicotinic Receptor Promotes CD4⁺T-Cell Proliferation and a Helper T-Cell Immune Response

Parkinson disease and smoking revisited

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Nicotine as a potential neuroprotective agent for Parkinson's disease

Cited by 212 publications

References 129 publications

Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signaling

Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signaling

Theα4 Nicotinic Receptor Promotes CD4+T-Cell Proliferation and a Helper T-Cell Immune Response

Parkinson disease and smoking revisited

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Theα4 Nicotinic Receptor Promotes CD4⁺T-Cell Proliferation and a Helper T-Cell Immune Response