DNA damage and neurotoxicity of chronic alcohol abuse

Abstract

Chronic alcohol abuse results in a variety of pathological effects including damage to the brain. The causes of alcohol-induced brain pathology are presently unclear. Several mechanisms of pathogenicity of chronic alcoholism have been proposed, including accumulation of DNA damage in the absence of repair, resulting in genomic instability and death of neurons. Genomic instability is a unified genetic mechanism leading to a variety of neurodegenerative disorders. Ethanol also likely interacts with various metabolic pathways, including one-carbon metabolism (OCM). OCM is critical for the synthesis of DNA precursors, essential for DNA repair, and as a methyl donor for various methylation events, including DNA methylation. Both DNA repair and DNA methylation are critical for maintaining genomic stability. In this review, we outline the role of DNA damage and DNA repair dysfunction in chronic alcohol-induced neurodegeneration.

Promoter hypermethylation of CDKN2A, MGMT, MLH1, and DAPK genes in laryngeal squamous cell carcinoma and their associations with clinical profiles of the patients

“…Despite the therapeutic advances in the treatment of laryngeal SCC and the intense efforts to develop early detection methods, the overall 5-year survival rate of 50% remains one of the lowest among cancers, 2,3 mainly because of local recurrence, and it has remained unchanged for the last 20 years. Tobacco smoking and alcohol consumption are the most important etiological risk factors affecting DNA repair, but also DNA methylation processes [4][5][6] and, when combined, these 2 factors seem to have a synergistic effect. 7 Both epigenetic alterations and accumulation of genetic aberrations have been established to play a role in laryngeal SCC and other types of HNSCC.…”

Ethanol consumption in the Sprague–Dawley rat increases sensitivity of the dorsal raphe nucleus to 5,7-dihydroxytryptamine

“…7). One possible explanation is that, via non-5-HT cytotoxic mechanisms, chronic intake of EtOH reduces the density of the brain tissue within the DRN (Kruman et al, 2012; McDevitt et al, 2014), increasing the diffusion depth of 5,7-DHT and causing greater depletion of 5-HT neurons. While there is no direct evidence of this specifically in the DRN, a significant decrease in brain volume and tissue density is present in human alcoholics (Badawy, 2002), thus this possibility should be considered.…”

“…A second consideration is that an interaction may be taking place between tryptophan hydroxylase metabolism and EtOH in the brain, such that the homeostatic properties of DRN 5-HT cells have been altered by CNS levels of EtOH, making this population more susceptible to neurotoxic agents and cell death (Agudelo et al, 2012; Badawy, 2002; Kruman et al, 2012). Ethanol readily perfuses the blood-brain barrier into the CNS and has varying, wide-spread effects on neuronal function and signaling.…”

“…Ethanol readily perfuses the blood-brain barrier into the CNS and has varying, wide-spread effects on neuronal function and signaling. The molecule interacts with the NMDA-receptor, increasing calcium influx and the production of reactive oxygen species within cells, altering homeostasis (Kruman et al, 2012). Although the specific actions of EtOH within the DRN have not been examined at the cellular or molecular level, there is an abundance of literature that suggests EtOH impacts 5-HT metabolism both in the periphery and in the CNS (see Badawy, 2002) and also 5-HT signaling via interactions with 5-HT receptors and transporters (Agudelo et al, 2012; Babu et al, 2009).…”

Chronic Alcohol Exposure Decreases 53BP1 Protein Levels Leading to a Defective DNA Repair in Cultured Primary Cortical Neurons

“…Among the mechanisms involved in the pathophysiology of ethanol-induced neuronal dysfunction are the oxidative damage of DNA and proteins, which seems to play an essential role (Lamarche et al 2003;Pandey et al 2008). Alcohol metabolism leads to the production of acetaldehyde and reactive oxygen species (ROS), which induce DNA damage and may trigger apoptosis via activation of mitochondrial pathways (Cherian et al 2008;Kruman et al 2012). Nevertheless, as shown by Lamarche et al (2004), acetaldehyde has a genotoxic potential which is different from that of ethanol, suggesting a different mode of action of both substances on DNA integrity.…”