Dementia Drug for Alcohol-Related Brain Damage?

Megan Brooks

February 20, 2018

Heavy alcohol drinking during adolescence leads to long-lasting structural and genetic changes in the brain that can be reversed with a short course of the Alzheimer's drug donepezil (multiple brands), preliminary research suggests.

The current study identifies both neuromorphologic changes and changes in gene expression that suggest specific mechanisms by which  alcohol exposure during adolescence may alter hippocampal function. The researchers, from Duke University, Durham, North Carolina, also identified an anticholinesterase agent that reverses those effects in adulthood, long after the last exposure to alcohol.

The study was published online February 15 in Alcoholism: Clinical and Experimental Research.

Binging Bad for the Brain

"Clinical studies are starting to show that adolescents who drink early and consistently across the college years have some deficits in learning and memory. It's not a sledgehammer...but there are demonstrable, if subtle, effects on their cognitive function," senior author Scott Swartzwelder, PhD, said in a statement.

The researchers assessed the effects of alcohol exposure on the adolescent rat brain by exposing the animals to alcohol in amounts equivalent to an amount that, if consumed by a human being, would yield a blood-alcohol level of .08 (the legal limit for driving while impaired). The rats were exposed to this amount of alcohol 3 or 4 nights a week.

The researchers found that alcohol exposure in adolescent rats was associated with a significant reduction in dendritic spine density and altered morphologic characteristics of subclasses of dendritic spines in adult rats. The findings add to a growing body of evidence that exposure to alcohol during adolescence has "an enduring detrimental impact on hippocampal structure and function," the authors write.

"We have shown an actual physical change in single individual neurons in a part of the brain that is critical to cognitive function, particularly learning and memory," Swartzwelder told Medscape Medical News.

"These dendritic spines inhabit the dendrites of the neurons — that's where all the action is in terms of receiving information from other cells. If you compromise the number of spines or change their conformation or the way they work, that can have a huge effect on how neural circuits function," he added.

Donepezil to the Rescue?

The alcohol-induced changes in dendritic spines were accompanied by genetic and epigenetic changes in the fragile X mental retardation 1 (Fmr 1) gene.

A short course of cholinesterase inhibitor donepezil (2.5 mg/kg once daily for 4 days starting 20 days after alcohol exposure) reversed the adaptations in the rats' dendritic spines as well as the genetic and epigenetic changes in Fmr1, the researchers report.

The effect of donepezil on Fmr1 is "extremely exciting," said Swartzwelder.

"Not only do we have a drug that we can start to look at and explore in terms of a possible clinical application, but the fact that we saw the epigenetic change gives us a mechanistic direction to drill down into and ask more molecular questions about the long-term effects of alcohol and how we might reverse them."

The study was supported by the National Institute on Alcohol Abuse and Alcoholism and the US Department of Veterans Affairs. The authors have disclosed no relevant financial relationships.

Alcohol Clin Exp Res. Published online February 15, 2018. Abstract

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