From the Cover: Harmane-Induced Selective Dopaminergic Neurotoxicity in Caenorhabditis elegans

Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disease. Although numerous exposures have been linked to PD etiology, causative factors for most cases remain largely unknown. Emerging data on the neurotoxicity of heterocyclic amines suggest that this class of compounds should be examined for relevance to PD. Here, using Caenorhabditis elegans as a model system, we tested whether harmane exposure produced selective toxicity to dopamine neurons that is potentially relevant to PD. Harmane is a known tremorigenic β-carboline (a type of heterocyclic amine) found in cooked meat, roasted coffee beans, and tobacco. Thus, this compound represents a potentially important exposure. In the nematode model, we observed dopaminergic neurons to be selectively vulnerable, showing significant loss in terms of structure and function at lower doses than other neuronal populations. In examining mechanisms of toxicity, we observed significant harmane-induced decreases in mitochondrial viability and increased reactive oxygen species levels. Blocking transport through the dopamine transporter (DAT) was not neuroprotective, suggesting that harmane is unlikely to enter the cell through DAT. However, a mitochondrial complex I activator did partially ameliorate neurodegeneration. Further, mitochondrial complex I activator treatment reduced harmane-induced dopamine depletion, measured by the 1-nonanol assay. In summary, we have shown that harmane exposure in C. elegans produces selective dopaminergic neurotoxicity that may bear relevance to PD, and that neurotoxicity may be mediated through mitochondrial mechanisms.

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

“…Interestingly, our data using an AIA (PhIP) and a β-carboline (harmane) have suggested that transport through the dopamine transporter (DAT) was unlikely, whereas studies in non-neuronal cell lines expressing DAT suggest that 2[N]-methylated β-carboline toxicity is mediated through DAT. Thus, the uptake and toxicity mechanisms may differ between subclasses (Griggs et al , 2014; Sammi et al , 2017; Storch et al , 2004).…”

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 ).…”

Neurotoxicity and Underlying Mechanisms of Endogenous Neurotoxins

“…Additionally, harman is obtained by endogenous condensation of tryptamine and pyruvate ( Figure 10 b) [ 76 , 77 , 78 ]. Harman can be generated either endogenously or exogenously through the diet (meat, roasted coffee beans, tobacco) [ 79 ], and exogenous acquisition is considered to be the main source [ 80 ]. Harman is associated with essential tremor (ET), but the mechanism is not clear [ 81 ].…”

“…Additionally, harman and norharman reduce the DA content in PC12 cells by down-regulating the activity of TH, thus increasing cytotoxicity [ 82 ]. Using Caenorhabditis elegans as the model, it is found that harman reduces mitochondrial activity and increases ROS in dopaminergic neurons, linking it to PD [ 79 ].…”