Environmentally-Derived Carbolinium Analogs of MPP+ are Toxic to Dopaminergic Neurons in Vitro and in Vivo
The possibility exists that certain environmentally prevalent heterocyclics may have important roles in the development and progression of idiopathic Parkinson’s disease. The ß-carboline (ßC) heterocyclic class derived from tryptophan has received our study, primarily because of the close structural likeness between their N-methylated forms (carbolinium derivatives) and the highly selective parkinsonian neurotoxin, N-methyl-4-phenylpyridinium cation (MPP+; structure shown in Figure 1),1 and because S-adenosylmethionine (SAM)-dependent brain methylating enzymes can produce 2-mono-[N]-methyl and 2,9-di-[N,N’]-methyl carbolinium cations from the environmental/endogenous ßCs, norharman and harman.2 Electron density considerations suggest that other environmental (alpha or gamma) carbolines resulting from tryptophan (often referred to as tryptophan pyrolysis products)---notably the mutagenic/carcinogenic tryp-P-2 and AαC compounds3---may be methylated on the heterocyclic nitrogens by the same enzymes that produce potentially neurotoxic ß-carbolinium ions.
KeywordsPC12 Cell DOPAC Level Heterocyclic Aromatic Amine Ipsilateral Striatum Mesencephalic Culture
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