The Troubling Link Between Parkinson’s and Smoking: Can We Deny the Benefits?

A Mechanism Yet to be Uncovered

Smoke contains nicotine and many other chemicals, so experts cannot be sure that it is the nicotine that is neuroprotective, but lead researcher Harvey Checkoway, PhD, told Neurology Advisor, “My opinion — and it’s pretty well-established — is that nicotine is the clear candidate.” Nicotine is known to block monoamine oxydase-b (MAO-B), the enzyme that metabolizes dopamine. According to Dr. Checkoway, a professor in the Department of Family Medicine and Public Health at the University of California, San Diego, the prevailing hypothesis as to how nicotine may reduce PD risk is that this inhibiting action of nicotine allows dopamine neurons to survive, thus possibly preventing PD or reducing its symptoms.

In animal studies, researchers use the chemical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce parkinsonian features. MPTP is converted by MAO-B into the neurotoxin c 1-methyl-4-phenylpyridinium (MPP⁺⁾ that destroys dopaminergic neurons.⁵ In rodent and primate studies^6,7, researchers have found nicotine administration to be partially protective against MPTP-induced damage.

In addition to the protective effect of nicotine on dopaminergic neurons, another potential mechanism by which nicotine may act on PD is via a symptomatic role.

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“Smoking could improve symptoms of Parkinson’s disease, thus masking the beginning of the disease. Nicotine may modulate dopamine transmission,” said Claire Thiriez, MD, of the University Hospital Henri Mondor and Paris 12 University, who co-authored a 2011 review on the topic.⁸ It is possible, however, that the epidemiological data has been misinterpreted altogether. “A recent study⁹ hypothesized that it could be solely due to the fact that the modifications in the brain of Parkinson’s patients — even before the motor signs appear — could ease” cessation of smoking, Dr. Thiriez told Neurology Advisor. “In that case, the epidemiological link would be the reflection not of neuroprotection, but only of a diminution of the addiction’s trend due to PD.”

Interestingly, though, a population-based study¹⁰ conducted by Dr. Checkoway and colleagues discovered lower rates of PD in people who consumed nicotine from another source altogether: peppers. They found an inverse association between PD and “consumption of nicotine-containing edibles from the same botanical family as tobacco, Solanaceae, including peppers, tomatoes, and potatoes.” The strongest effect was found for peppers, which appeared to reduce risk among non-smokers almost as much as active smoking. No such link was found for other types of vegetables.

Other research findings indicate that genetic variation may be responsible for the protective effect of nicotine. Research published in 2014 in Pharmacogenomics ¹¹ shows that the “effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful,” suggesting that “SV2C plays a role in the pathogenesis of PD and that SV2C genotype might be a useful marker for pharmacogenomics studies of PD involving nicotine.”

In Pursuit of Safer Options

While researchers continue to elucidate the mechanisms behind the nicotine-Parkinson’s connection, they are closer than ever to discovering whether nicotine in safer forms — without the risk of lung cancer and other smoking-related diseases — could effectively treat PD symptoms. Before the use of nicotine can be recommended for PD patients, “there is a need for placebo-controlled human studies with a long-term follow-up,” said Dr. Thiriez, who noted that 5 such studies are currently underway in various parts of the world. One of these studies is a randomized, placebo-controlled, double-blind trial¹² investigating whether a transdermal nicotine patch can slow the progression of PD in 160 patients with PD in the U.S. and Germany. The trial is being funded by The Michael J. Fox Foundation and led by James T. Boyd, MD, an associate professor of Neurological Sciences at the University of Vermont.

References

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12. Boyd JT. Disease-modifying Potential of Transdermal NICotine in Early Parkinson’s Disease (NIC-PD). Retrieved on November 11, 2015 from https://www.clinicaltrials.gov/ct2/show/NCT01560754?term=NIC-PD&rank=1.