Abstract
The prefrontal cortex (PFC) is a brain region responsible for executive functions including working memory, impulse control and decision making. The loss of these functions may ultimately lead to addiction. Using histological analysis combined with stereological technique, we demonstrated that the PFC is more vulnerable to chronic alcohol-induced oxidative stress and neuronal cell death than the hippocampus. This increased vulnerability is evidenced by elevated oxidative stress-induced DNA damage and enhanced expression of apoptotic markers in PFC neurons. We also found that one-carbon metabolism (OCM) impairment plays a significant role in alcohol toxicity to the PFC seen from the difference in the effects of acute and chronic alcohol exposure on DNA repair and from exaggeration of the damaging effects upon additional OCM impairment in mice deficient in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR). Given that damage to the PFC leads to loss of executive function and addiction, our study may shed light on the mechanism of alcohol addiction.
Highlights
Alcohol abuse is a serious health issue worldwide
We demonstrated that acute ethanol exposure does not activate the expression of apoptotic markers but notably activates DNA repair in the cerebral cortex [14] which is a typical response to DNA damage [38]
one-carbon metabolism (OCM) impairment and neurotoxic effect of ethanol To determine the involvement of OCM impairment in alcohol effects on prefrontal cortex (PFC), we examined the impact of additional OCM impairment caused by deficiency in the key OCM enzyme methylenetetrahydrofolate reductase (MTHFR) in Mthfr+/2 mice on alcohol-induced damage to the PFC
Summary
Alcohol abuse is a serious health issue worldwide. Alcoholics experience a number of health problems including neurological and psychiatric disorders [1]. Chronic ethanol exposure is associated with reduced DNA repair [14,15], and elevated blood homocysteine (Hcy) level, a marker of OCM dysfunction, is typical for alcoholics [14,16,17]. While OCM function is essential for DNA repair and the latter is critical for maintaining genomic stability [18,19], genomic instability is central to carcinogenesis and is implicated in neurodegeneration [20,21]. This can explain both carcinogenic and neurodegenerative effects of chronic alcohol abuse
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