Abstract and Introduction

Abstract

The risk of Parkinson's disease is reduced by cigarette smoking, which raises some unanswered questions. Nicotine, a major component of tobacco smoke, could exert either nonreceptor-mediated biological effects or, more importantly, act on the different subtypes of nicotinic brain receptors, in particular those associated with the nigrostriatal dopaminergic pathway. There is now robust experimental evidence for a neuroprotective effect of nicotine upon dopaminergic neurons. By contrast, in animal models of Parkinson's disease, nicotine alone has slight or no motor effects. However, nicotine may modulate dopamine transmission and has clear motor effects when associated with L -DOPA, reducing L -DOPA-induced dyskinesias. Clinical trials have yielded inconclusive results thus far and are hampered by different designs and small cohorts. Ongoing studies address either symptomatic motor or nonmotor symptoms, or neuroprotection. There is still no agreement on the daily dosage of nicotine or the method of administration. Together, these data suggest that nicotine or nicotinic receptor drugs have therapeutic potential for Parkinson's disease, although the specific treatment regimens remain to be determined.

Introduction

Although many symptoms of Parkinson's disease (PD) are related to the neurodegeneration of the nigrostriatal dopaminergic pathway, other neurotransmitter systems are involved in PD, such as the nicotinic cholinergic system. The exact role of the latter system in the pathophysiology of PD is not fully understood; however, some major results should be highlighted. First, numerous studies converge to support a role of smoking in protection against PD.[1] Nicotine might be responsible for such an effect and experimental data suggest that it has a neuroprotective action.[2] Second, there is an interaction between the stimulation of nicotinic receptors and the release of dopamine in the striatum.[3,4] Interestingly, post-mortem and recent imaging studies show that the density of nicotinic receptors is reduced in the brain and especially in the nigrostriatal dopaminergic system of PD patients[5] and experimental models of PD.[4] Finally, despite controversial results, the question has been raised of a possible clinical benefit of nicotine in PD patients. The goal of the present article is to answer, to the best of our current knowledge, the actual question: 'What is the evidence that medicinal use of nicotine in PD is clinically useful?', using epidemiological, preclinical and clinical data. We searched the literature (PubMed) with several keywords: 'nicotine and Parkinson' yielded 154 results, and 'smoking and Parkinson' yielded 655. The Cochrane database reported no review, but nine clinical trials. We added papers from our personal files and older papers quoted among the reviews. Among search results, we mainly selected reviews for experimental data and original papers for all clinical trials. Ongoing trials were searched on the NIH website; more data were collected on the websites of Neuraltus Inc. and the Michael J Fox foundation website.[101,102]