Clearing the Smoke: What Protects Smokers from Parkinson’s Disease?

Abstract

The link between smoking and a lower risk of Parkinson’s disease (PD) is one of the strongest environmental or lifestyle associations in neuroepidemiology. Growing evidence supports the hypothesis that the association is based on a neuroprotective effect of smoking on PD, despite the plausible alternative that smoking serves as a marker for a proximal protective influence without itself conferring benefit. But how smoking could protect against neurodegeneration in PD is not well understood. Of several candidate molecules and mechanisms that have been nominated, nicotine has received the most attention. However, randomized controlled clinical trials of nicotine in PD have failed to demonstrate benefit on motor endpoints, including the NIC-PD study in which recently diagnosed participants were randomly assigned to placebo or nicotine treatment for 1 year. Given these results, the time is right to evaluate the neuroprotective potential of other molecules and biochemical cascades triggered by smoking. Here, we review the evidence supporting smoking’s possible protective effect on PD, compounds in tobacco and smoke that might mediate such benefit, and non-causal classes of explanation, including reverse causation and the prospect of shared genetic determinants of smoking and PD resistance. The therapeutic potential of non-nicotine components of smoke is suggested by studies supporting multiple alternative mechanisms ranging from monoamine oxidase inhibitors to gut microbiome disruption to antioxidant response induction by chronic exposure to low levels of carbon monoxide. Rigorous investigation is warranted to evaluate this molecule and others for disease-preventing and disease-modifying activity in PD models and, if warranted, in clinical trials.

Examining the Risk of Parkinson’s disease Among Smokers

Despite a panoply of symptomatic therapies for Parkinson’s disease (PD), the second most common neurodegenerative disease worldwide, no treatments are known to slow down, arrest, or reverse its course. One potentially promising strategy to identify neuroprotective therapies for PD is to exploit its environmental and genetic risk factors.^1,2 To this end, inverse risk factors that predict reduced PD risk are of particular interest.³ Of these, the most reproducible environmental association identified to date is smoking.⁴

In multiple studies, smokers have been found to have a substantially lower relative risk for PD than nonsmokers (pooled adjusted odds ratio of smokers vs. never-smokers, 0.2–0.5).^5–8 This risk reduction, which extends to reduced risk of Lewy-related neuropathologic changes,⁹ is not explained by selective mortality and increases with increased smoking dose, duration, and recency.^6,7 A causal relationship of smoking on PD risk is consistent with the inverse correlation between the male/female ratios of PD and smoking across countries,¹⁰ the lower PD risk among individuals whose parents were smokers,¹¹ and the persistence of a putative protective effect of smoking in genetic studies—including family-based case control studies⁸ as well as twin studies,¹² which control for the impact of genotype on disease. Reduced rates of smoking have also been cited as a potential explanation for increasing PD rates.^13,14

Potential Effects of Smoking on Disease Prevention and/or Progression

It is possible that the determinants underlying the epidemiological observation of a reduced risk of PD among smokers, once understood, could be exploited for therapeutic purposes. Such determinants would have a clear value to prevent PD, and some results suggest that they might also have activity on disease progression. Although smoking is strongly associated with increased mortality, mortality in PD does not appear to be influenced by smoking status.^15,16 Although PD smokers are more likely to die from smoking-related cancers than PD nonsmokers, they tend to have fewer deaths from neurologic causes.¹⁶ Although mixed results have been observed in the few studies of smoking and disease progression, compared to never smokers, current smokers at last follow-up have been observed to have a lower levodopa (L-dopa) equivalent dose, a proxy for disease severity.¹⁶

The inference that components of smoke may help prevent or treat PD is strengthened by preclinical studies demonstrating biological plausibility, where exposure to cigarette smoke was shown to confer protection in rodent models of the disease (with apparent toxicity or loss of effect at greater exposures to smoke).^17–19 However, these studies employed toxin models of PD, and the effects of smoke on α-synuclein or other PD gene-based models of neurodegeneration remain unknown.

Smoking-Associated Molecules and Effects Proposed to Confer Benefit

Although the inverse risk of PD among smokers is well established and multiple lines of evidence support a neuroprotective effect of smoking as its basis, it remains unclear what molecular exposure(s) among the myriad constituents within tobacco or the products of its combustion in smoke might account for such protection. We review some candidates here.

Nicotine

Nicotine has been the dominant candidate proposed to underlie the reduced risk of PD among smokers for nearly 50 years.²⁰ Its consistent presence in tobacco smoke, its high central nervous system (CNS) penetration, and its well-known psychoactive properties provided early, albeit indirect, support. Consistent with this possibility, the use of chewing tobacco has been reported to reduce PD risk, with hazard ratios of 0.4–0.5.^21,22 Moreover, findings of reduced PD risk in women (and less consistently men) who consume more dietary nicotine further implicate this tobacco component.^23,24 In laboratory studies, treatment with nicotine was shown to be protective in models of PD.²⁵ On the basis of these results and epidemiological context, clinical studies have been undertaken to assess nicotine’s potential as a PD therapeutic (NCT00873392). A randomized, placebo-controlled, single-blind end point 28-week phase II trial of high-dose transdermal nicotine in participants with L-dopa-treated PD showed no evidence for benefit of nicotine on motor function measured using the clinician-rated, objective motor subscale (part III) of the Unified Parkinson’s Disease Rating Scale (UPDRS).²⁶ However, the rather short duration of that trial limited interpretation with respect to disease course.

More recently, the NIC-PD phase II trial (NCT01560754) has also been completed.²⁷ In this double-blind study conducted across 24 clinical sites in the USA and Germany, 163 participants not yet taking or needing L-dopa or dopamine agonist therapy were recruited and randomly assigned 1:1 to treatment with either transdermal nicotine (maximum tolerated dose, up to 28 mg/day) or a transdermal placebo patch. The primary end point was change in aggregate UPDRS parts I-III score between baseline and 60 weeks (52 weeks treatment and 8 weeks washout). The study showed no benefit of nicotine, and in fact a trend was observed toward an accelerated decline in function in the nicotine group, with UPDRS parts I–III score increased 3.5 points in the placebo arm (N = 54) versus 6.0 points in the nicotine arm (N = 47, P = 0.056) over the 60 weeks. Secondary analysis of the same measure over the full treatment period but prior to washout (ie, over 52 weeks) on a larger portion of the cohort (N=138) also showed greater worsening on nicotine compared to placebo (P = 0.010).

The failure of transdermal nicotine to show benefits in the NIC-PD trial warrants some reflection. One possible explanation is that smoking, for example on the basis of nicotine, reduces the risk of developing manifest PD but does not slow down its clinical course. Although this possibility is difficult to refute in its most general form, the trend toward more rapid clinical decline in the nicotine treatment arm suggests that nicotine exposure is, if anything, detrimental in PD. An alternative explanation of NIC-PD’s outcome is that other molecular constituent(s) of cigarette smoke underlie the reduced risk of PD among smokers. To date, only a few smoke-associated components beyond nicotine have been nominated for this purpose.

Carbon Monoxide

In smokers, the concentration of hemoglobin-bound carbon monoxide (CO-hemoglobin) typically ranges from 5% to 9%, compared to levels of 0%–2% in nonsmokers.²⁸ This concentration is well below the 50% CO-hemoglobin limit that when exceeded is well known to cause irreversible damage to multiple brain regions such as the globus pallidus.²⁹ Low levels of CO are generated endogenously and regulate multiple physiologic processes.^30,31 Indeed, at low concentrations, CO has been shown to have several physiological functions in models of oxidative injury and inflammation, activating diverse cytoprotective cascades through multiple well-characterized molecular pathways.³² CO has been shown to reduce oxidative stress³³ and to bias cytokine expression toward those that engage antiinflammatory pathways.³⁴ Notably, CO upregulates nuclear factor erythroid 2-related factor 2 (Nrf2), a gene strongly linked to PD molecular cascades that regulate the cell response to stress.³⁵ CO also activates hypoxia-inducible factor1α (HIF1α), a second gene implicated in PD protective pathways.³⁶ In addition, CO has been shown to inhibit poly (ADP-ribose) polymerase (PARP),³⁷ reduce caspase-3,³⁸ drive astrocytes to release adenosine,³⁹ and reduce cell death.^38,39

Accordingly, it is not surprising that CO has been shown to provide potent neuroprotection in an in vitro toxin model of PD,⁴⁰ in in vitro models of apoptosis and oxidative injury,⁴¹ as well as in in vivo models of other neurological diseases, including traumatic brain injury,³⁸ stroke,³⁵ multiple sclerosis,⁴² and Alzheimer’s.⁴³ In each instance, the protection observed was associated with a reduction in oxidative stress and cell death or inhibition of an inflammatory response. Additional support for CO’s neuroprotective potential for PD comes from a recent study demonstrating that treatment with low dose CO protected substantia nigra dopaminergic neurons in both a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model and an adeno-associated virus (AAV) α-synuclein rat model, in which it also reduced α-synuclein pathology.⁴⁴

An independent line of evidence in support of CO comes from studies of heme oxygenase 1 (HO-1), the primary inducible enzyme that degrades heme to generate endogenous CO, biliverdin, and Fe²⁺. HO-1 is ubiquitously expressed and upregulates with Nrf2 in response to stress.⁴⁵ In PD, HO-1 expression in the substantia nigra is increased, and HO-1 decorates Lewy bodies.⁴⁶ Intriguingly, upregulation of HO-1 is associated with reduced inflammatory cytokines in response to 1-methyl-4-phenylpyridinium (MPP+)⁴⁷ and with neuroprotection in PD toxin models,^39,48,49 including increased neurotrophic factors⁴⁷ and reduced dopamine cell loss.^47,49 Although neither HO-1 nor the constitutive CO-generating enzyme HO-2 has been identified in PD genome-wide association studies (GWAS) to date,⁵⁰ several smaller genetic studies have identified polymorphisms in both HO-1^51,52 and HO-2⁵³ in association with PD. Larger genome-wide environmental interaction studies (GWEIS) focused on smoking will be informative. A weakness of the hypothesis that CO in cigarette smoke mediates a truly protective effect of smoking on PD is the evidence that smokeless tobacco is also associated with a reduced PD risk.^6,22,54 However, this association may be more modest than that of tobacco smoking, which may result from multiple protective components. In any case, together with the studies of CO outlined earlier, including in animal models of PD, reports linking HO-1 and HO-2 to reduced PD risk support the hypothesis that CO may contribute to smoking’s neuroprotective potential in PD.

Monoamine Oxidase-B Inhibitors

Several monoamine oxidase-B (MAO-B) inhibitors, including naphthoquinones, 2-napthylamine, and norharman, have been identified in tobacco smoke and have also been nominated to underlie the reduced risk of PD among smokers.^55,56 The clinical use of MAO-B inhibitors for PD, where they provide modest improvements in motor function and delay the use of L-dopa, have been used as support. In antemortem brain positron emission tomography (PET) imaging studies using the selective MAO-B ligand [¹¹C]L-deprenyl-D2, smokers have been shown to have significantly reduced brain MAO-B binding sites compared to nonsmokers.⁵⁷ Although MAO-B inhibitors have not been demonstrated to clearly alter PD course, the ADAGIO study and post-hoc analyses of other trials have raised this possibility.^58–60 Thus, it is possible that MAO-B inhibitors in tobacco smoke may contribute to smoking’s reduction of PD risk.

Other Potential Mediators of Smoking’s Inverse Risk of PD

A number of molecular mechanisms have also been proposed to underlie smoking’s protective effects on PD risk. Prominent among these is the upregulation of several cytochrome p450 enzymes (CYPs) both peripherally and in the human brain,⁶¹ which, in principle, might enable more efficient detoxification of environmental exposures. While plausible, this hypothesis is difficult to test and will require more research.

Smoking’s effects on the gut microbiome have also been hypothesized to alter the course of PD.⁶² This interesting hypothesis builds on a growing body of evidence supporting the involvement of the gastrointestinal tract and the enteric nervous system in the development of α-synuclein pathology and PD.⁶³ However, the specific changes in the gut microbiome that smoking causes are only beginning to be understood.⁶⁴ Whether smoking-induced alterations in gut microflora composition can influence the spread of α-synuclein pathology, urate levels,⁶⁵ or otherwise alter PD progression is intriguing but speculative and remains to be determined.

Non-causal Classes of Explanation Linking Smoking to PD Risk

Non-causal associations have the potential to contribute to the link between smoking and the risk of PD via reverse causation. For one, PD patients have been shown to have reduced addictive tendencies, including increased ease of quitting smoking,⁶⁶ suggesting the possibility of a shared pathobiology between addiction and PD that could contribute to reduced smoking behavior. In addition to reverse causation, one can envision shared genetic determinants of smoking and PD resistance as one example of confounding. However, Mendelian randomization (MR) studies and related efforts to exclude reverse causality bias and address these issues have indicated a persistent protective effect of smoking, and smoking continuation, on PD risk,^67–70 that in some studies has been associated with human leukocyte antigen (HLA)-DRB1^71–73 though these analyses are complex and have some caveats.⁵⁴ In addition, the protective association of smoking with reduced PD risk appears to extend to passive smoking as well,^74–76 where addictive tendencies and genetic background would appear to be less relevant, but this has been somewhat controversial.

Mechanisms unrelated to components of tobacco smoke, such as reverse causation and the plausible alternative of sharing genetic determinants between smoking and resistance to PD, warrant further study and may prove informative. For example, studies of the genetic background of PD based on the inverse association with smoking might discover key mechanisms that can be exploited to develop novel therapies.

Conclusions

Although smoking is overall exceedingly unhealthful, its remarkably robust association with reduced PD risk remains a major yet underexplored clue to protection against the disease. In addition to the potential value for PD prevention, the basis for smoking’s effects on PD risk may have therapeutic potential in manifest PD. With nicotine now effectively struck from the list of potential neuroprotective treatments for manifest PD given the decisively null results of the NIC-PD trial, renewed efforts to identify and evaluate the disease-modifying potential of other constituents of smoke and associated molecular mechanisms are warranted. Only a small number of smoking-associated explanatory candidates have been identified to date. Several features of CO at the low doses self-administered by smokers support its therapeutic potential, including (1) engagement of several PD-linked molecular cascades, (2) evidence of neuroprotection in model systems relevant to PD, and (3) safety in 23 clinical trials to date at the target dose range (see, for example,^77–79). Research focused on CO and other smoking-associated molecules and mechanisms may light up clinical development to evaluate the safety and efficacy of leading candidates. Pursuing the potential protective effects of smoking on PD has the potential to ignite a new generation of PD prevention strategies and therapeutics.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.