Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline.

The neurotoxic properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are dependent on its metabolic activation in a reaction catalyzed by centrally located monoamine oxidase B (MAO-B). This reaction ultimately leads to the permanently charged 1-methyl-4-phenylpyridinium species MPP(+), a 4-electron oxidation product of MPTP and a potent mitochondrial toxin. The corresponding 5-membered analogue, 1-methyl-3-phenyl-3-pyrroline, is also a selective MAO-B substrate.

Inhibition of human MAO-A and MAO-B by a compound isolated from flue-cured tobacco leaves and its neuroprotective properties in the MPTP mouse model of neurodegeneration.

Prompted by the findings that smokers have lowered brain and blood platelet monoamine oxidase-A and -B activities compared to non-smokers and that smokers have a lowered incidence of Parkinson's disease, we have examined the neuroprotective properties of an MAO inhibitor, 2,3,6-trimethyl-1,4-naphthoquinone (TMN), which is present in the tobacco plant and smoke in the MPTP C57BL/6 mouse model of neurodegeneration. Dopamine (DA) levels in the striata of mice treated with TMN prior to the administration of MPTP were significantly higher than DA levels in the striata of mice receiving MPTP only, thus indicating a degree of neuroprotection in this model of Parkinson's disease. The potential consequences on MAO activity of long term exposure to this compound need to be evaluated.

Tobacco leaf, smoke and smoking, MAO inhibitors, Parkinson's disease and neuroprotection; are there links?

The potential neuroprotective properties of monoamine oxidase B (MAO-B) inhibitors have been of interest in part because of the role that this enzyme plays in the bioactivation of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Interestingly, tobacco smokers have lowered levels of brain and blood platelet MAO-B activity and a well documented lowered incidence of Parkinson's disease (PD) compared to non-smokers. This correlation has led to the intriguing question of whether there are possible relationships between smoking, MAO-B activity and PD.

Monoamine oxidase B inhibition and neuroprotection: studies on selective adenosine A2A receptor antagonists.

The principal therapeutic agents used in the management of Parkinson's disease (PD) enhance nigrostriatal dopaminergic flux through either replenishment of depleted dopamine stores or the action of dopaminergic agonists. Adenosine A2A receptor antagonists (e.g.

Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of Parkinson's disease.

A remarkable convergence of epidemiologic and laboratory data has raised the possibility that caffeine reduces the risk of developing Parkinson's disease (PD) by preventing the degeneration of nigrostriatal dopaminergic neurons. The authors review the evidence that caffeine and more specific antagonists of the adenosine A2A receptor protect dopaminergic neurons in several toxin models of PD. Other studies demonstrating protection by A2A receptor inactivation in animal models of stroke, Huntington's disease, and Alzheimer's disease suggest a more global role of A2A receptors in neuronal injury and degeneration.