ß-Carboline Analogues of MPP+ as Environmental Neurotoxins

  • Michael A. Collins
  • Edward J. Neafsey

Abstract

Carbolines (pyrido-indoles) are prevalent tryptophan-derived heterocyclics in the diet and environment that have been linked since the late 1970’s to carcinogenesis. Evidence from our and other laboratories suggests the possibility that the most common pyrido-indole isomers, the ß-carbolines, also might be “protoxicants” leading to neuronal damage and resultant idiopathic parkinsonism in susceptible individuals. There is a close structural similarity between the N-methylated cationic products of simple ß-carbolines (e.g., norharman or harman) and the parkinsonian neurotoxin, MPTP, or specifically, its active cationic metabolite, MPP+. The N-methylated ß-carbolinium species are formed in mammalian brain via one or possibly two enzymatic S-adenosylmethionine-dependent N-methylations. These chemical alterations metabolically bioactivate the molecules, greatly increasing both the mitochondrial inhibitory activity and the in vitro and in vivo dopaminergic toxicity of the ß-carboline nucleus. Furthermore, the second (indole nitrogen) methylating activity as well as the product (2,9-di-N-methylated) carbolinium cations appear to be elevated in parkinsonian brain. Matsubara’s studies (this volume) demonstrate nigrostriatal neurodegeneration and neurobehavioral impairment in mice given precursors of the ß-carbolinium cations. In view of these findings, epidemiological studies on the possible relationship between environmental carboline alkaloid exposure and idiopathic parkinsonism could be revealing.

Keywords

Respiration Neurol Tryptophan Smoke Dehydrogenation 

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Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Michael A. Collins
    • 1
    • 2
  • Edward J. Neafsey
    • 2
  1. 1.Division of Molecular & Cellular BiochemistryMaywood
  2. 2.Department of Cell Biology, Neurobiology & AnatomyLoyola University Stritch School of MedicineMaywoodUSA

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