N-methylation underlying Parkinson's disease.
The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is maybe initiated or precipitated by environmental or endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. Endogenous analogs of MPTP, such as beta-carbolines (betaCs) and tetrahydroisoquinolines, have been proposed as possible causative candidates causing PD and are bioactivated into potential neurotoxins by N-methylation enzyme(s). These N-methylated betaCs and tetrahydroisoquinoline have been higher cerebrospinal levels in parkinsonian patients than age-matched controls. Thus, there is a hypotheses to influence the pathogenesis of PD, that is, the excess enzyme activity to activate neurotoxins, such as N-methyltransferase, might be higher in PDs. Indeed, simple betaCs, via N-methylation steps, induced bradykinesia with the decreased dopamine contents in the striatum and midbrain in C57/BL mice. In younger (65 years old) PD patients, the excretion amount of N(1)-methyl-nicotinamaide was significantly higher than that in younger controls. The protein amount of nicotinamide N-methyltransferase (NNMT) was also significantly higher in younger PD patients than that in younger controls. These findings described here would indicate that the excess N-methylation ability for azaheterocyclic amines, such as betaCs, before the onset had been implicated in PD pathogenesis. On the other hand, the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.
Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical College, Asahikawa 078-8510, Japan. kmatsuba@asahikawa-med.ac.jp
Kazuo
K
Matsubara
Koji
K
Aoyama
Manabu
M
Suno
Toshio
T
Awaya
D002243:Carbolines / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism*; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology*; D009536:Niacinamide; D010300:Parkinson Disease / Q000201:enzymology* / Q000503:physiopathology; D013378:Substantia Nigra / Q000201:enzymology* / Q000503:physiopathology
D002243:Carbolines; D007546:Isoquinolines; D009536:Niacinamide; D008780:Methyltransferases; C045058:azaheterocycle N-methyltransferase