Studies in rats suggest how a drug that is used to slow cognitive decline in adults with Alzheimer’s disease (AD) may also reverse brain inflammation and damage to neurons in adolescent binge drinkers. The research, reported by scientists at Duke University Medical Center and the University of North Carolina (UNC), Chapel Hill, showed that drinking in adolescence—or adolescent intermittent ethanol (AIE) exposure—reduced the formation of neurons in the hippocampus, a region of the brain that is known to be critical for learning and memory. Treating previously AIE-exposed animals using the reversible acetylcholinesterase inhibitor donepezil during early adulthood partially reversed alcohol-related detrimental changes to the hippocampus dentate gyrus in the brain.
“We don’t know if the reversal of these alcohol effects by donepezil is permanent, but it at least transiently reverses them,” said Scott Swartzwelder, PhD, a professor of psychiatry at Duke, who is senior author of the team’s paper in Scientific Reports, which is titled, “Changes in Neuroimmune and Neuronal Death Markers after Adolescent Alcohol Exposure in Rats are Reversed by Donepezil.”
Adolescence is a critical time of behavioral and neurological change, the authors explained. This period of development starts with the onset of puberty, spans teenage years, and progresses well into a young adult’s 20s, particularly in men. “The hippocampal dentate gyrus continues neurogenesis, i.e., the formation of new neurons, into adulthood, although neurogenesis in adolescence is high and declines with increasing age in adulthood,” they wrote. Evidence also suggests that the negative effects of intermittent, repeated alcohol exposure during this key developmental period may persist into adulthood. “ … the distinctive characteristics of the adolescent brain may contribute to the high rate of drinking among some adolescents and young adults, and render them vulnerable to permanent neurological changes as a result of drinking during those periods.”
“Research has begun to show that human adolescents who drink early and consistently across the adolescent years have some deficits in brain function that can affect learning and memory, as well as anxiety and social behaviors,” said Swartzwelder. “The changes can be subtle, but who wants even subtle deficits in their brain function or how they think and feel. Studies in animal models show that adolescent alcohol exposure can change the ways nerve cells communicate with each other, and the level of plasticity in brain circuits—compromising the ability of the brain to change and adapt. These changes can be seen in adulthood—long after the alcohol exposure has ended.”
It’s widely thought that AIE exposure may change hippocampal structure and function through triggering neurotoxic inflammatory mechanisms, and the authors reasoned that donepezil may help to reduce these effects. “Thus, it is possible that post-AIE treatment with donepezil could reverse hippocampal deficits through a cholinergically mediated anti-inflammatory mechanism.”
As part of their studies the investigators first looked at the effects of AIE on a key hippocampal region of the brain. The researchers repeatedly administered alcohol to adolescent male rats, in amounts that would result in blood-alcohol levels similar to those reached by human adolescent drinkers. They found that in addition to brain inflammation, AIE exposure inhibited generation of new neurons in the hippocampus dentate gyrus. Swartzwelder said this might even accelerate neuronal death—making it is easier to lose existing cells and more difficult to produce new ones. AIE exposure also appeared to increase mechanisms that trigger cell death.
When the AIE-exposed rats reached adulthood, one group of animals was given donepezil, a cognition-enhancing drug used to hold back cognitive decline in adult Alzheimer’s disease patients. “Donepezil is an anti-cholinesterase drug that inhibits acetylcholine breakdown and increases its levels in the brain where it is known to be anti-inflammatory,” the researchers pointed out. “Cholinergic innervation of the hippocampus is known to influence neurogenesis, but has also been shown to inhibit several inflammatory mechanisms, independent of those cholinergic effect.” Interestingly, prior studies had shown that donepezil can protect against hippocampal damage in rodents. “In rodents donepezil pre-treatment protects against the heightened vulnerability to hippocampally mediated learning deficits after cholinergic lesions, and against increases of caspase-3 (a marker of synaptic and neuronal degeneration) in the hippocampus,” they wrote.
Detailed analysis of the hippocampus in rats that had received four days of donepezil treatment in early adulthood, after prior adolescent alcohol exposure, showed that there was less inflammation, increased ability to produce new neurons, and less cell death compared with the brains of animals that hadn’t received the donepezil treatment. “These findings suggest AIE increases neuroimmune gene expression that persistently blunts neurogenesis through increased progenitor cell death,” the scientists noted.
Their results with donepezil treatment were also “consistent with the hypothesis that donepezil reversal of AIE loss of neurogenesis is linked to a reversal of both neuroimmune and epigenetic changes that persist into adulthood … The reversal of the AIE-induced loss of neurogenesis suggests persistent down regulation of neurogenesis that can be reversed, rather than a permanent loss of neural progenitor cells and stem cells that cannot be reversed.”
Swartzwelder said the study helps to highlight the subtle health risks associated with heavy drinking during early adulthood, something that has previously been hard to define. “It’s obvious that not everyone who drinks during adolescence grows up and completely fails at life,” he acknowledged. “You might not notice the deficits in obvious ways every day, but you run the risk of losing your edge. Sometimes a small impairment of brain function can have a broad ripple effect in someone’s life.”
Importantly, the research demonstrates the potential to repair some types of damage caused by adolescent alcohol exposure, he said. The new results could also provide a greater insight into the cellular mechanisms and pathways that make the adolescent brain particularly vulnerable to substances such as alcohol.