Smoking, nicotine and Parkinson's disease

doi:10.1016/j.tins.2004.06.008

Trends in Neurosciences

Volume 27, Issue 9, September 2004, Pages 561-568

https://doi.org/10.1016/j.tins.2004.06.008 Get rights and content

Abstract

Epidemiological studies show that smoking is associated with a lower incidence of Parkinson's disease (PD). This finding is important because it could provide clues about therapeutic strategies for protection against this debilitating movement disorder. Smoke contains numerous chemicals that could be responsible for the apparent protective effect. Here, a role for nicotine is considered, because this chemical stimulates brain dopaminergic systems and provides some symptomatic benefit in PD. Nicotine also has a neuroprotective action. Putative factors and signaling pathways involved in the actions of nicotine are discussed. An understanding of the molecular basis for the reduced occurrence of PD in tobacco users is crucial for the development of intervention strategies to reduce or halt disease progression.

Section snippets

Presence of specific nACh receptor subtypes in the nigrostriatal system

Neuronal nACh receptors are pentameric ligand-gated ion channels composed of α subunits (homomeric receptors) or of α and β subunits (heteromeric receptors) [11]. Identification of receptor composition is proving challenging, with six different α subunits (α2–α7) and three different β subunits (β2–β4) expressed in mammalian brain [11]. mRNA encoding α2–α7 and β2–β4 subunits is present in the nigrostriatal system, with a very restricted localization of α6 and β3 mRNA in the substantia nigra, the

Nigrostriatal damage reduces expression of specific nACh receptor subtypes

In PD there is a loss of nigrostriatal dopaminergic neurons. Thus, a crucial question is whether nACh receptors are affected by denervation, as this would have an impact on subsequent actions of administered nicotine. Results from animal models with selective lesion of nigrostriatal dopaminergic neurons and in PD (Figure 2 and Table 1) demonstrate significant declines in select nACh receptor populations 5, 19, 20, 21, 22, 23, 24, 25. In rodent and monkey striatum, both nicotine-binding sites

Role of nACh receptors in modulating dopamine release

One important action of nicotine is modulation of dopamine release from nigrostriatal dopaminergic terminals 26, 27, 28, 29. The finding that nACh receptors are decreased with nigrostriatal damage suggests that nicotine-evoked dopamine release might also be reduced. Indeed, studies in mice [23] show that there is a decrease in nicotine-evoked dopamine release with nigrostriatal damage that parallels the nACh receptor decline (Figure 4). Drugs that target the subtypes of nACh receptor that

How nicotine-evoked dopamine release might benefit PD

The modulatory effect of nicotine on nigrostriatal dopamine release 26, 27, 28, 29 is most likely of direct relevance to PD because there are major deficits in nigrostriatal function in this disorder. Conceivably, enhanced nicotine-evoked dopamine release could benefit PD (i) from an immediate symptomatic standpoint, by alleviating the motor symptoms, and (ii) by protecting against nigrostriatal damage in the long term.

Other mechanisms whereby nicotine could protect against PD

Extensive literature suggests that nicotine protects against different toxic insults in culture systems 5, 35, including against MPTP-induced toxicity in nigral neurons [36]. These in vitro results extend to the in vivo situation. Smoking and/or nicotine exposure protect against nigrostriatal damage in several rodent models. However, reproducibility is an issue (Box 1), with only some studies showing protection 5, 35. Identification of the biological bases for these inconsistencies is important

Does nicotine therapy benefit PD?

The finding that smoking protects against PD raises the question whether nicotine treatment is beneficial either to relieve PD symptoms or for neuroprotection. With regard to use of nicotine in symptomatic treatment, initial reports had suggested that smoking, nicotine patches or nicotine gum alleviate some movement disabilities 58, 59. More recently, several small-scale clinical trials tested the effect of short-term nicotine therapy on motor and cognitive deficits in PD. Overall, these

What about other chemicals in tobacco products?

In addition to nicotine, numerous agents in tobacco products could modulate biological functions and, thus, the development of PD. Cigarette smoking is associated with decreased (40%) brain monoamine oxidase B activity, an effect not mediated by nicotine (at least not acutely) [64]. This could contribute to a lower incidence of PD by decreasing levels of hydrogen peroxide, a by-product of dopamine metabolism, or by reducing enzymatic conversion of endogenous or exogenous compounds to toxic

Concluding remarks and future challenges

A systematic review of the existing literature shows that there is an undoubted inverse correlation between smoking and PD; that is, disease incidence is unexpectedly reduced in smokers. The challenge at present is to identify the active component(s) in smoke that contributes to this beneficial effect. This is no easy task because exposure to the agent(s) of interest could occur many years before the onset of symptoms. Some of the key issues for future research are outlined in Box 2. Although a

Acknowledgements

Research support is gratefully acknowledged from the TRDRP and NIH. Thanks to T. Bordia, A. Collins, B. Collier, D. Di Monte, A. Lai and S. McCallum for helpful comments and discussion.

References (71)

M. Quik et al.
Nicotine and nicotinic receptors; relevance to Parkinson's disease
Neurotoxicology
(2002)
C. Gotti
Human neuronal nicotinic receptors
Prog. Neurobiol
(1997)
J.A. Court
Nicotinic receptors in human brain: topography and pathology
J. Chem. Neuroanat
(2000)
Z.Z. Guan
Selective changes in the levels of nicotinic acetylcholine receptor protein and of corresponding mRNA species in the brains of patients with Parkinson's disease
Brain Res
(2002)
S. Wonnacott
Presynaptic nicotinic ACh receptors
Trends Neurosci
(1997)
M. Quik et al.
Nicotine administration reduces striatal MPP+ levels in mice
Brain Res
(2001)
G. Jeyarasasingam
Stimulation of non-α7 nicotinic receptors partially protects dopaminergic neurons from 1-methyl-4-phenylpyridinium-induced toxicity in culture
Neuroscience
(2002)
G. Costa
Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra
Brain Res
(2001)
L.W. Role et al.
Nicotinic receptors in the development and modulation of CNS synapses
Neuron
(1996)
F.A. Dajas-Bailador
The α7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca²⁺ dependent mechanism
Neuropharmacology
(2000)

M. Toborek

Nicotine attenuates arachidonic acid-induced overexpression of nitric oxide synthase in cultured spinal cord neurons

Exp. Neurol

(2000)

H. Mai

A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis

J. Biol. Chem

(2003)

C.F. Orr

An inflammatory review of Parkinson's disease

Prog. Neurobiol

(2002)

S.J. Hopkins et al.

Cytokines and the nervous system. I: Expression and recognition

Trends Neurosci

(1995)

T. Obata

Nicotine suppresses 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in rat striatum

Neurosci. Lett

(2002)

R. Soto-Otero

Effects of (-)-nicotine and (-)-cotinine on 6-hydroxydopamine-induced oxidative stress and neurotoxicity: relevance for Parkinson's disease

Biochem. Pharmacol

(2002)

A. Cormier

Nicotine protects rat brain mitochondria against experimental injuries

Neuropharmacology

(2003)

M.B. Newman

Nicotine's oxidative and antioxidant properties in CNS

Life Sci

(2002)

S. Miksys

Regional and cellular induction of nicotine-metabolizing CYP2B1 in rat brain by chronic nicotine treatment

Biochem. Pharmacol

(2000)

J.J. Buccafusco et al.

The potential role of cotinine in the cognitive and neuroprotective actions of nicotine

Life Sci

(2003)

A. Ishikawa et al.

Effects of smoking in patients with early-onset Parkinson's disease

J. Neurol. Sci

(1993)

S. Lemay

Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson's disease

Prog. Neuropsychopharmacol. Biol. Psychiatry

(2004)

K. Castagnoli et al.

Tobacco leaf, smoke and smoking, MAO inhibitors, Parkinson's Disease and neuroprotection; are there links?

Neurotoxicology

(2004)

P.B. Clarke et al.

Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons

Brain Res

(1985)

E. Bezard

Pathophysiology of levodopa-induced dyskinesia: potential for new therapies

Nat. Rev. Neurosci

(2001)

C.W. Olanow et al.

Etiology and pathogenesis of Parkinson's disease

Annu. Rev. Neurosci

(1999)

B.M. Ravina

Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment

Neurology

(2003)

A.H. Schapira et al.

Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions

J. Am. Med. Assoc

(2004)

J.A. Baron

Beneficial effects of nicotine and cigarette smoking: the real, the possible and the spurious

Br. Med. Bull

(1996)

J.M. Gorell

Smoking and Parkinson's disease: a dose-response relationship

Neurology

(1999)

D.M. Morens

Cigarette smoking and protection from Parkinson's disease: false association or etiologic clue?

Neurology

(1995)

C. Tzourio

Smoking and Parkinson's disease. An age-dependent risk effect? The Europarkinson Study Group

Neurology

(1997)

C.M. Tanner

Smoking and Parkinson's disease in twins

Neurology

(2002)

R.J. Lukas

International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits

Pharmacol. Rev

(1999)

M. Quik

Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization

J. Comp. Neurol

(2000)

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Citation Excerpt :
Nicotine administration may protect dopaminergic neurons in normal mice, but not in mice without nicotine receptors [126]. Although the nicotine receptor agonist, varenicline, shows only a restricted protective effect, it is clear that more research on the role of the nicotinic receptors, especially the α7nAChR, is required in the course of PD [127–130]. The differential LPS and epigenetic regulation of the α7nAChR and its duplicant, dup7α, suggest that the effects of α7nAChR agonists in PD will be complicated by changes in gut permeability and perhaps the epigenetic, HDAC inhibitory effects of butyrate.
Restoring the lost physiological functions of the substantia nigra in Parkinson's disease (PD) is an important goal of PD therapy. The present article reviews a) novel drug targets that should be targeted to slow PD progression, and b) clinical and experimental research data reporting new treatments targeting immune-inflammatory and oxidative pathways. A systematic search was performed based on the major databases, i.e., ScienceDirect, Web of Science, PubMed, CABI Direct databases, and Scopus, on relevant studies performed from 1900 to 2020. This review considers the crucial roles of mitochondria and immune-inflammatory and oxidative pathways in the pathophysiology of PD. High levels of oxidative stress in the substantia nigra, as well as modifications in glutathione regulation, contribute to mitochondrial dysfunction, with a decline in complex I of the mitochondrial electron transport chain reported in PD patients. Many papers suggest that targeting antioxidative systems is a crucial aspect of preventive and protective therapies, even justifying the utilization of N-acetylcysteine (NAC) supplementation to fortify the protection afforded by intracellular glutathione. Dietary recommended panels including ketogenetic diet, muscular exercise, nutraceutical supplementation including NAC, glutathione, nicotine, caffeine, melatonin, niacin, and butyrate, besides to nonsteroidal anti-inflammatory drugs (NSAIDs), and memantine treatment are important aspects of PD therapy. The integration of neuro-immune, antioxidant, and nutritional approaches to treatment should afford better neuroprotection, including by attenuating neuroinflammation, nitro-oxidative stress, mitochondrial dysfunction, and neurodegenerative processes. Future research should clarify the efficacy, and interactions, of nicotine receptor agonists, gut microbiome-derived butyrate, melatonin, and NSAIDs in the treatment of PD.
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Trends in Neurosciences

Smoking, nicotine and Parkinson's disease

Abstract

Section snippets

Presence of specific nACh receptor subtypes in the nigrostriatal system

Nigrostriatal damage reduces expression of specific nACh receptor subtypes

Role of nACh receptors in modulating dopamine release

How nicotine-evoked dopamine release might benefit PD

Other mechanisms whereby nicotine could protect against PD

Does nicotine therapy benefit PD?

What about other chemicals in tobacco products?

Concluding remarks and future challenges

Acknowledgements

Neurotoxicology

Prog. Neurobiol

J. Chem. Neuroanat

Brain Res

Trends Neurosci

Brain Res

Neuroscience

Brain Res

Neuron

Neuropharmacology

Exp. Neurol

J. Biol. Chem

Prog. Neurobiol

Trends Neurosci

Neurosci. Lett

Biochem. Pharmacol

Neuropharmacology

Life Sci

Biochem. Pharmacol

Life Sci

J. Neurol. Sci

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neurotoxicology

Brain Res

Pathophysiology of levodopa-induced dyskinesia: potential for new therapies

Nat. Rev. Neurosci

Etiology and pathogenesis of Parkinson's disease

Annu. Rev. Neurosci

Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment

Neurology

Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions

J. Am. Med. Assoc

Beneficial effects of nicotine and cigarette smoking: the real, the possible and the spurious

Br. Med. Bull

Smoking and Parkinson's disease: a dose-response relationship

Neurology

Cigarette smoking and protection from Parkinson's disease: false association or etiologic clue?

Neurology

Smoking and Parkinson's disease. An age-dependent risk effect? The Europarkinson Study Group

Neurology

Smoking and Parkinson's disease in twins

Neurology

International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits

Pharmacol. Rev

Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization

J. Comp. Neurol