Abstract
The healthy human body contains small amounts of metabolic formaldehyde (FA) that mainly results from methanol oxidation by pectin methylesterase, which is active in a vegetable diet and in the gastrointestinal microbiome. With age, the ability to maintain a low level of FA decreases, which increases the risk of Alzheimer's disease and dementia. It has been shown that 1,2-dithiolane-3-pentanoic acid or alpha lipoic acid (ALA), a naturally occurring dithiol and antioxidant cofactor of mitochondrial α-ketoacid dehydrogenases, increases glutathione (GSH) content and FA metabolism by mitochondrial aldehyde dehydrogenase 2 (ALDH2) thus manifests a therapeutic potential beyond its antioxidant property. We suggested that ALA can contribute to a decrease in the FA content of mammals by acting on ALDH2 expression. To test this assumption, we administered ALA in mice in order to examine the effect on FA metabolism and collected blood samples for the measurement of FA. Our data revealed that ALA efficiently eliminated FA in mice. Without affecting the specific activity of FA-metabolizing enzymes (ADH1, ALDH2, and ADH5), ALA increased the GSH content in the brain and up-regulated the expression of the FA-metabolizing ALDH2 gene in the brain, particularly in the hippocampus, but did not impact its expression in the liver in vivo or in rat liver isolated from the rest of the body. After ALA administration in mice and in accordance with the increased content of brain ALDH2 mRNA, we detected increased ALDH2 activity in brain homogenates. We hypothesized that the beneficial effects of ALA on patients with Alzheimer's disease may be associated with accelerated ALDH2-mediated FA detoxification and clearance.
Highlights
In mammals, the oxidation of metabolic short-chain alcohols, such as methanol (MeOH) and ethanol (EtOH), occurs with the participation of enzymes from the class of alcohol dehydrogenase 1 (ADH1) (Cederbaum, 2012; Wang et al, 2012; Edenberg and Foroud, 2013; Dorokhov et al, 2015)
We concluded that the ability of alpha lipoic acid (ALA) to exert a diminishing effect on the metabolic content of MeOH and FA does not appear to be directly related to its antioxidant properties
We demonstrated that ALA is able to reduce the level of endogenous FA in mice
Summary
The oxidation of metabolic short-chain alcohols, such as methanol (MeOH) and ethanol (EtOH), occurs with the participation of enzymes from the class of alcohol dehydrogenase 1 (ADH1) (Cederbaum, 2012; Wang et al, 2012; Edenberg and Foroud, 2013; Dorokhov et al, 2015). FA is converted to formic acid by the participation of enzymes mainly from the class of aldehyde dehydrogenase 2 (AlDH2) (Sládek, 2003; Sophos and Vasiliou, 2003). The ADH1 enzyme oxidizes most of the MeOH in the human liver, while in brain cells, its activity is close to zero (Julià et al, 1987; Galter et al, 2003; Tulpule and Dringen, 2013). The low activity of the ADH1 enzyme in human brain cells acts as a mechanism of protection against the harmful effects of FA on neurons (Tulpule and Dringen, 2013)
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