Nicotine as a potential neuroprotective agent for Parkinson's disease - PubMed (original) (raw)

Review

Nicotine as a potential neuroprotective agent for Parkinson's disease

Maryka Quik et al. Mov Disord. 2012 Jul.

Abstract

Converging research efforts suggest that nicotine and other drugs that act at nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinson's disease. This idea initially stemmed from the results of epidemiological studies that demonstrated that smoking is associated with a decreased incidence of Parkinson's disease. The subsequent finding that nicotine administration protected against nigrostriatal damage in parkinsonian animal models led to the idea that nicotine in tobacco products may contribute to this apparent protective action. Nicotine most likely exerts its effects by interacting at nAChRs. Accumulating research indicates that multiple subtypes containing nAChRs, including α4β2, α6β2, and/or α7, may be involved. Stimulation of nAChRs initially activates various intracellular transduction pathways primarily via alterations in calcium signaling. Consequent adaptations in immune responsiveness and trophic factors may ultimately mediate nicotine's ability to reduce/halt the neuronal damage that arises in Parkinson's disease. In addition to a potential neuroprotective action, nicotine also has antidepressant properties and improves attention/cognition. Altogether, these findings suggest that nicotine and nAChR drugs represent promising therapeutic agents for the management of Parkinson's disease.

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Conflict of interest statement

Relevant conflict of interest: M. Quik is on a patent for the use of nicotine for L-dopa-induced dyskinesias. There are no other conflicts of interest.

Figures

FIG. 1

Nicotine is neuroprotective when administered before/during but not after nigrostriatal damage. For the pre-treatment studies, rats were first given nicotine in drinking water (50 μg/ml) for 2 wk after which they were lesioned with 6-hydroxydopamine, with nicotine maintained. Amphetamine-induced rotations were determined 2–3 wk later as an index of motor disability. The rats were then killed 2–3 wk later and the dopamine transporter measured. In the nicotine post-treatment study, rats were first lesioned and amphetamine-induced rotation measured 2 wk later. Immediately after behavioral assessment, nicotine treatment was initiated and maintained throughout. Rotational behavior was re-evaluated 3–4 wk after the start of nicotine dosing and the rats killed 3–4 wk later, such that the total number of wk on nicotine treatment was similar in the two paradigms. Top panels: Parkinsonism assessed by amphetamine-induced ipsilateral turning. Three-way ANOVA analyses showed a significant (p < 0.001) main effect of 6-OHDA lesioning and a significant (p < 0.05) interaction between nicotine treatment and 6-OHDA lesioning in rats treated with nicotine prior to the onset of nigrostriatal lesion. By contrast, nicotine treatment after completion of nigrostriatal damage yielded a significant main effect of 6-OHDA lesioning (p < 0.001) but no interaction. Bottom panels: Effects of nicotine pre- and post-treatment on neuronal damage. Dopamine transporter expression was significantly elevated in lesioned rats with nicotine pre- but not post-treatment. Significance of difference by two-way ANOVA followed by a Bonferroni post hoc test from the saccharin-sham group, ***p < 0.001; from the saccharin-lesioned group, #p < 0.05. Values represent the mean ± SEM of 6–9 rats per group. Taken with permission .

FIG. 2

Primary nAChR subtypes in the mammalian CNS. The α6α4β2β3 and α6β2β3 nAChRs have a relatively restricted distribution in the CNS, including the nigrostriatal system. By contrast the α4β2 nAChRs, which exists in two unique conformations, and the α4α5β2 nAChR are widely present throughout the brain, including the nigrostriatal pathway. The homomeric α7 nAChR also exhibits an extensive distribution in the mammalian CNS, although this subtype is not densely expressed in the rat and monkey nigrostriatal system.

FIG. 3

Molecular mechanisms through which nicotine mediates its effects in the nervous system.

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Nicotine as a potential neuroprotective agent for Parkinson's disease - PubMed (original) (raw)