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Potential bioactivated neurotoxicants, N-methylated beta-carbolinium ions, are present in human brain
K Matsubara1, M A Collins, A Akane
1Department of Legal Medicine, Shimane Medical University, Izumo, Japan.
Abstract:
Potential bioactivated neurotoxicants, 2-N-methyl-beta-carbolinium and 2,9-N,N'-dimethyl-beta-carbolinium ions, as well as N-methylation activities which form these charged species, were analyzed for the first time in the parietal association cortex and the substantia nigra of human brain using GC/MS and HPLC. The brains were taken during forensic autopsies from corpses without obvious degeneration of substantia nigra. In the cortex, 2-methyl-norharmanium ion (2-MeNH) and 2,9-dimethyl-norharmanium ion (2,9-Me2NH) were detected in almost all samples. 2-Methyl-harmanium ions (2-MeHA) and 2,9-dimethyl-harmanium ions (2,9-Me2HA) were detectable in only two samples. In substantia nigra samples pooled from 3 or 4 brains for analysis, 2-MeNH and 2,9-Me2NH levels were higher than those in the cortex, whereas 2-MeHA and 2,9-Me2HA were below detection limits. Their precursors, norharman (NH) and harman (HA), were also measured using HPLC/fluorescence detection. In both regions, NH and HA were present in almost all samples; levels of NH and HA were also significantly higher in the nigra than in the cortex. Using 9-methyl-NH and 2-MeNH as substrates, in vitro N-methylation of the 2[beta] and 9[indole] nitrogens toward beta-carbolines was measured both in the cortex and in the nigra. 2[beta]-N-Methylation activity was significantly higher than 9[indole]-N-methylation activity in both regions. Recent studies show that beta-carbolinium ions resemble the synthetic parkinsonian toxicant, MPP+, with respect to structure and neurotoxic activity. Such 'bioactivated' carbolinium ions could be endogenous causative factors in Parkinson's disease.
Insights
This study detected potential neurotoxic beta-carbolinium ions in human brain regions. These ions and their formation activity may contribute to Parkinson
Area of Science:
- Neuroscience and Neurochemistry
- Biochemistry of Neurotoxicants
- Human Brain Autopsy Studies
Background:
- Beta-carbolinium ions, such as 2-N-methyl-beta-carbolinium and 2,9-N,N'-dimethyl-beta-carbolinium, are potential endogenous neurotoxicants.
- These compounds share structural and neurotoxic similarities with MPP+, a known parkinsonian toxicant.
- Understanding their presence and formation in the human brain is crucial for neurodegenerative disease research.
Purpose of the Study:
- To analyze the presence and levels of specific beta-carbolinium ions and their precursors in human parietal cortex and substantia nigra.
- To investigate N-methylation activities responsible for forming these charged beta-carbolinium species in different brain regions.
- To explore the potential role of these endogenous neurotoxicants in the pathogenesis of Parkinson's disease.
Main Methods:
- Analysis of beta-carbolinium ions (2-MeNH, 2,9-Me2NH, 2-MeHA, 2,9-Me2HA) using Gas Chromatography-Mass Spectrometry (GC/MS) and High-Performance Liquid Chromatography (HPLC).
- Quantification of beta-carboline precursors (norharman and harman) via HPLC with fluorescence detection.
- In vitro measurement of N-methylation activities at the 2[beta] and 9[indole] positions of beta-carbolines using specific substrates.
Main Results:
- 2-methyl-norharmanium (2-MeNH) and 2,9-dimethyl-norharmanium (2,9-Me2NH) ions were detected in most cortical samples.
- Levels of 2-MeNH and 2,9-Me2NH were significantly higher in the substantia nigra compared to the cortex.
- N-methylation activity at the 2[beta] position was significantly higher than at the 9[indole] position in both brain regions.
Conclusions:
- The study provides the first evidence of specific beta-carbolinium ions and their N-methylation activities in human parietal cortex and substantia nigra.
- Higher levels of these potential neurotoxicants in the substantia nigra suggest a possible link to Parkinson's disease pathology.
- These endogenous 'bioactivated' carbolinium ions represent plausible causative factors in the development of Parkinson's disease.