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

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.

Effect of Freeze-Thaw Cycles on the Oxidation of Protein and Fat and Its Relationship with the Formation of Heterocyclic Aromatic Amines and Advanced Glycation End Products in Raw Meat

“…These products can participate in a Maillard reaction to generate heterocyclic aromatic amines (HAAs) [ 9 ] and advanced glycation end products (AGEs). It has been reported that high HAA intake is associated with a variety of acute diseases, such as nonalcoholic fatty liver disease and neuronal damage [ 10 , 11 ]. Excessive intake of AGE will result in their accumulation in the human body.…”

9-Methyl-β-carboline inhibits monoamine oxidase activity and stimulates the expression of neurotrophic factors by astrocytes

“…They structurally resemble the Parkinson’s disease (PD) causing substance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and showed neurotoxic effects on dopaminergic neurons, especially as methylated forms (e.g. 2,9-dimethyl-β-carbolinium ion [2,9-dime-BC +]) (Hamann et al 2006 ; Neafsey et al 1995 ; Cruz-Hernandez et al 2018 ; Sammi et al 2018 ). Inhibition of the complex I of the respiratory chain, induction of apoptosis and activation of microglia are the main compounds of this toxic effects of 2,9-dime-BC + (Ostergren et al 2006 ; Polanski et al 2010 ; Hamann et al 2006 ; Hans et al 2005 ).…”

Inhibition of organic cation transporter (OCT) activities by carcinogenic heterocyclic aromatic amines

“…It may be postulated that the inhibition of OCTs by HAAs may block the transport of endogenous OCT substrates, especially that of catecholamines, known to act as neurotransmitters. By this way, OCT inhibition may contribute to the possible neurotoxicity of HAAs, including PhIP, Trp-P-1 and Trp-P-2 (Cruz-Hernandez et al, 2018;Naoi et al, 1989). In particular, OCT inhibition by harmane and norharmane may be involved in the neurological diseases thought to be promoted by these two HAAs, such as essential tremor and the Parkinson disease (Esmaeili et al, 2012;Lavita et al, 2016).…”