Tobacco Leaf, Smoke and Smoking, MAO Inhibitors, Parkinson’s Disease and Neuroprotection; Are There Links?
Section snippets
INTRODUCTION
Our long-term interests in the areas of neurotoxicity and neuroprotection and additional interests in (S)-nicotine (1) and other tobacco alkaloids were enhanced when very dramatic images of the brains of smokers were obtained using positron emission tomography (PET) (Fowler et al., 1996a, Fowler et al., 1996b). The images clearly demonstrated that monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) activities are significantly lower in the brains of smokers than in the brains of
PARKINSON’S DISEASE AND ITS RELATIONSHIP TO SMOKING
Parkinson’s disease, which first was described by Parkinson (1817), is an age-dependent, neurodegenerative disorder involving the selective loss of dopaminergic nigrostriatal neurons (Agid, 1991). Some studies have suggested a genetic link to PD (Duvoisin and Golbe, 1995, Golbe et al., 1996, Kruger et al., 1988, Papadimitriou et al., 1999, Polymeropoulos et al., 1997), particularly in families with multiple affected individuals all of whom have an earlier age of onset than is seen in typical,
Animal Studies
Essman (1977) published a report on the inverse relation of skin MAO activity and cigarette smoke in exposed mice. He reported that cigarette smoke exposure caused inhibition of the deamination of 5-hydroxytryptamine (3, 5HT) in a dose-dependent manner, as evidenced by an increased uptake of 5HT. Yu and Boulton (1987), have evaluated the effect of a cigarette smoke solution, a cigarette tobacco extract, whole smoke exposure and saliva obtained from an individual who smoked a single cigarette on
COMPOUNDS PRESENT IN TOBACCO OR TOBACCO SMOKE AND THEIR MAO INHIBITORY PROPERTIES
Among the many components present in tobacco and tobacco smoke, we considered (S)-nicotine, pharmacologically the most important tobacco constituent, and (R,S)-N-methylanatabine (8), a structural analog of the parkinsonian inducing neurotoxin MPTP, to be of potential importance with respect to MAO inhibition and neuroprotection.
Oreland et al. (1981) have reported that (S)-nicotine inhibits human platelet MAO-B activity, but at concentrations 2000 times higher than the circulating blood (S
Origin of the Model
Observations first reported in 1979 indicated a link to exposure to 1-methyl-4-phenyl-4-propyloxypiperidine, a meperidine congener, and the development of parkinsonism in a 23-year-old man (Davis et al., 1979). Subsequently, several drug abusers on the West Coast of the United States, were determined to be parkinsonian. These individuals had injected a new “designer drug” known as China White, which was being “marketed” as a “synthetic heroin”. It was eventually discovered that the parkinsonism
THE SEARCH FOR MAO INHIBITORS IN TOBACCO: EXTRACTION AND FRACTIONATION, ISOLATION AND CHARACTERIZATION
The studies described in Section 3 (Carr and Rowell, 1990) showed that exposure to cigarette smoke led to a reduction of MAO-B activity in the mouse brain (∼20%) and neuroprotection following MPTP treatment. These authors, however, argued that the observed neuroprotection may not be related to the reduction in MAO-B activity. This conclusion was based on additional results reported by the authors with respect to in vitro MPTP metabolism, and a statement in another study claiming that a 40% or
NEUROPROTECTION STUDIES
Having isolated this MAO inhibitor from tobacco, we then addressed the issue of the potential neuroprotective properties of TMN in the MPTP mouse model. We followed a protocol similar to the one utilized in the 7-NI studies discussed previously. We established the time (25 min) at which TMN, following administration, achieves maximal brain concentration and choose a dose (400 mg/kg) which led to a brain concentration more than six times the Ki value for the inhibition of MAO-B. Following the
CURRENT STUDIES AND FUTURE DIRECTIONS
The finding that TMN can provide neuroprotection in the MPTP mouse PD model does provide support for the possibility that components of tobacco may be neuroprotective; however, the competitive inhibition of MAO observed with TMN does not explain why the inhibition of MAO-A and MAO-B in the brains of smokers described by Fowler et al., 1996a, Fowler et al., 1996b was dependent on chronic exposure to tobacco smoke. The report by Yu and Boulton (1987) that aqueous extracts of tobacco cigarettes
Acknowledgements
Studies from the Harvey W. Peters Center were funded by National Institute of Drug Abuse DA11089, National Institute of Neurological Disorders and Stroke R01 NS29792-05, Reverend Stewart Bryant West, Philip Morris and the Harvey W. Peters Center, Department of Chemistry, Virginia Tech.
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