Selective dopaminergic neurotoxicity of three heterocyclic amine subclasses in primary rat midbrain neurons

  • Neurotoxicology. 2018 Mar:65:68-84. doi: 10.1016/j.neuro.2018.01.009.
Angela Cruz-Hernandez  1 ,  Zeynep Sena Agim  2 ,  Paola C Montenegro  3 ,  George P McCabe  4 ,  Jean-Christophe Rochet  5 ,  Jason R Cannon  6
Affiliations
  • 1. School of Health Sciences, Purdue University, West Lafayette, IN, 47907, United States; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, 47907, United States. Electronic address: [email protected].
  • 2. School of Health Sciences, Purdue University, West Lafayette, IN, 47907, United States; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, 47907, United States. Electronic address: [email protected].
  • 3. Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, 47907, United States; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, United States. Electronic address: [email protected].
  • 4. Department of Statistics, Purdue University, West Lafayette, IN, 47907, United States. Electronic address: [email protected].
  • 5. Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, 47907, United States; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, United States. Electronic address: [email protected].
  • 6. School of Health Sciences, Purdue University, West Lafayette, IN, 47907, United States; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, 47907, United States. Electronic address: [email protected].
PMID: 29408373 DOI: 10.1016/j.neuro.2018.01.009
Abstract

Heterocyclic amines (HCAs) are primarily produced during high temperature meat cooking. These compounds have been intensively investigated as mutagens and carcinogens. However, converging data suggest that HCAs may also be neurotoxic and potentially relevant to neurodegenerative diseases such as Parkinson's disease (PD). The identification of new potential etiological factors is important because most PD cases are sporadic. Our group previously showed that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was selectively neurotoxic to dopaminergic neurons. However, PhIP is one of many HCAs, a class of compounds that exhibits wide structural variability. The goal of this study was to determine the neurotoxicity of the most prevalent and best studied HCAs from three subclasses: aminoimidazoaazarenes (AIA), α-carbolines, and β-carbolines. Using E17 rat primary midbrain cultures, we tested dopaminergic and non-dopaminergic neurotoxicity elicited by the following compounds: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), PhIP, 1-methyl-9H-pyrido[3,4-b]indole (harmane), 9H-pyrido[3,4-b]indole (norharmane) and 2-amino-9H-pyrido[2,3-b]indole (AαC) at concentrations ranging from 100 nM-5 μM. All tested HCAs were selectively neurotoxic, though the dose required to elicit selective loss of dopaminergic neurons or decreases in dopaminergic neurite length was compound specific. Non-dopaminergic neurons were unaffected at all tested doses. The sensitivity (determined by threshold dose required to elicit selective neurotoxicity) appears to be unrelated to published mutagenic potency. Both AIA and α/β-carbolines produced oxidative damage, which was magnified in dopaminergic neurons vs. non-dopaminergic neurons as further evidence of selective neurotoxicity. These studies are expected to prompt clinical and mechanistic studies on the potential role of HCA exposure in PD.

Keywords
Aminoimidazoaazarene; Carboline; Heterocyclic amine; Parkinson’s disease; Primary midbrain culture.
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