Potential bioactivated neurotoxicants, N-methylated β-carbolinium ions, are present in human brain

Abstract

Potential bioactivated neurotoxicants, 2- N-methyl-β-carbolinium and 2,9- N,N′-dimethyl-β-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-norhamanium ion (2-MeNH) and 2,9-dimethyl-norharmanium ion (2,9-Me 2NH) were detected in almost alll samples. 2-Methyl-harmanium ions (2-MeHA) and 2,9-dimethyl-harmanium ions (2,9-Me 2HA) were detectable in only two samples. In substantia nigra samples pooled from 3 or 4 brains for analysis, 2-MeNH and 2,9-Me 2NH levels were higher than those in the cortex, whereas 2-MeHA and 2,9-Me 2HA 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[β] and 9[indole] nitrogens toward β-carbolines was measured both in the cortex and in the nigra. 2[β]- N-Methylation activity was significantly higher than 9[indole]- N-methylation activity in both regions. Recent studies show that β-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.