N-methylation of pyridines in Parkinson's disease

Green, Sandra; S, Buttrum; Molloy, Helen; Steventon, Glyn B.; Sturman, Stephen; Waring, R. H.; Pall, Hardev; Williams, Adrian

doi:10.1016/0140-6736(91)90113-4

Cited by 41 publications

(11 citation statements)

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“…In PD an enhanced synthesis of N-methylated compounds was observed probably due to the failure of further catabolisation and detoxification of those N-methylated compounds (Green et al, 1991). It was suggested, that dysfunction of hydroxylation is mediated by an isoenzyme of cytochrome P-450 or perhaps xanthine-or aldehyde oxidases leading to accumulation of Nmethylated substances (Green et al, 1991).…”

Section: Discussionmentioning

confidence: 97%

“…It was suggested, that dysfunction of hydroxylation is mediated by an isoenzyme of cytochrome P-450 or perhaps xanthine-or aldehyde oxidases leading to accumulation of Nmethylated substances (Green et al, 1991). Interestingly precursors of those N-methylated [3-carbolines, like norharman and harman, were found significantly higher in the substantia nigra than in the cortex in samples from brains without degeneration of substantia nigra (Matsubara et al, 1993).…”

Section: Discussionmentioning

confidence: 98%

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Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients

Kühn

Müller

Große

et al. 1996

J. Neural Transmission

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Death of dopaminergic neurons in Parkinson's disease (PD) may partially be caused by synthesis and accumulation of endogenous and exogenous toxins. Because of structural similarity to MPTP, beta-carbolines, like norharman and harman, have been proposed as putative neurotoxins. In vivo they may easily be formed by cyclization of indoleamines with e.g. aldehydes. For further elucidation of the role of beta-carbolines in neurodegenerative disorders harman and norharman levels in cerebrospinal fluid (CSF) were measured in 14 patients with PD and compared to an age- and sex-matched control group (n = 14). CSF levels of norharman and harman in PD were significantly higher compared to controls. These results may suggest a possible role of harman and norharman or its N-methylated carbolinium ions in the pathophysiological processes initiating PD. However the origin of increased levels of these beta-carbolines remains unclear. On the one hand one may speculate, that unknown metabolic processes induce the increased synthesis of harman and norharman in PD. On the other hand a possible impact of exogenous sources may also be possible.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients

Kühn

Müller

Große

et al. 1996

J. Neural Transmission

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“…29,30 PD patients given a dose of nicotinamide excrete high concentrations of N-methyl nicotinamide in urine. [31][32][33][34] However, as these are charged compounds like MPP+, none of these putative toxins, (and N-methyl nicotinamide itself cannot yet be excluded), [35][36][37] would cross the blood brain barrier. Being water soluble, they would also be excreted easily.…”

Section: Nicotinamide Metabolismmentioning

confidence: 99%

Autotoxicity, methylation and a road to the prevention of Parkinson’s disease

Williams

Ramsden

2005

Journal of Clinical Neuroscience

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“…2-Methylated β-carbolines are comparable to MPP + as inhibitors of mitochondrial respiration (Albores et al, 1990). In Parkinson's diseases, the biosynthesis of N-methylated β-carboline derivatives is enhanced probably due to the failure of further catabolisation and detoxification of those N-methylated compounds (Green et al, 1991). These results suggest that N-methylated derivatives are more toxic than the parent compounds.…”

Section: Discussionmentioning

confidence: 60%

The Harman and Norharman Reduced Dopamine Content and Induced Cytotoxicity in PC12 Cells

Yang¹,

Lim²,

Lee³

2008

Biomolecules and Therapeutics

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-The effects of harman and norharman on dopamine content and L-DOPA-induced cytotoxicity were investigated in PC12 cells. Harman and norharman decreased the intracellular dopamine content for 24 h. The IC 50 values of harman and norharman were 20.4 µM and 95.8 µM, respectively. Tyrosine hydroxylase (TH) activity and TH mRNA levels were also decreased by 20 µM harman and 100 µM norharman. Under the same conditions, the intracellular cyclic AMP levels were decreased by harman and norharman. In addition, harman and norharman at concentrations higher than 80 µM and 150 µM caused cytotoxicity at 24 h in PC12 cells. Non-cytotoxic ranges of 10-30 µM harman and 50-150 µM norharman inhibited L-DOPA (20-50 µM)-induced increases of dopamine content at 24 h. Harman at 20-150 µM and norharman at 100-300 µM also enhanced L-DOPA (20-100 µM)-induced cytotoxicity at 24 h. These results suggest that harman and norharman decrease dopamine content by reducing TH activity and aggravate L-DOPA-induced cytotoxicity in PC12 cells.

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N-methylation of pyridines in Parkinson's disease

Cited by 41 publications

References 0 publications

Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients

Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients

Autotoxicity, methylation and a road to the prevention of Parkinson’s disease

The Harman and Norharman Reduced Dopamine Content and Induced Cytotoxicity in PC12 Cells

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