Exercise neuroprotection in a rat model of binge alcohol consumption

Abstract

Background: Excessive alcohol intake produces structural and functional deficits in corticolimbic pathways that are thought to underlie cognitive deficits in the alcohol use disorders (AUDs). Animal models of binge alcohol administration support the direct link of high levels of alcohol consumption and neurotoxicity in the hippocampus and surrounding cortex. In contrast, voluntary wheel running enhances hippocampal neurogenesis and generally promotes the health of neurons.

Methods: We investigated whether voluntary exercise prior to binge alcohol exposure could protect against alcohol-induced cell loss. Female Long-Evans rats exercised voluntarily for 14 days before undergoing 4 days of binge alcohol consumption. Brains were harvested immediately after the last dose of alcohol and examined for various histological markers of neurodegeneration, including both cell death (FluoroJade B) and cell birth (Ki67) markers.

Results: Rats that exercised prior to binge exposure were significantly less behaviorally intoxicated, which was not a result of enhanced hepatic metabolism. Rats that exercised prior to binge alcohol consumption had reduced loss of dentate gyrus granule cells and fewer FluoroJade B positive cells in the dentate gyrus and associated entorhinal-perirhinal cortex compared to nonexercisers. However, exercise did not protect against cell death in the piriform cortex nor protect against alcohol-induced decreases in cell proliferation, evidenced by a similar alcohol-induced reduction in Ki67 labeled cells between exercise and sedentary rats.

Conclusions: We conclude that exercise can reduce behavioral sensitivity to ethanol intoxication and protect vulnerable brain areas from alcohol-induced cell death. Exercise neuroprotection of alcohol-induced brain damage has important implications in understanding the neurobiology of the AUDs as well as in developing novel treatment strategies.

Figure 1

There was no difference between the groups for body weight, although all rats gained weight during the course of the experiment (A). There was no difference for distance traveled between exercising rats that received ethanol, and those that received isocaloric control diet (B).

Figure 2

Rats that exercised prior to binge ethanol administration acted significantly less intoxicated than sedentary rats (n=7; A), despite having received more ethanol (B). Arrow in B shows the point at which tail bloods were taken. The BECs of the exercising rats (n=10) were significantly higher than sedentary rats (C). * p < 0.05, significantly different from sedentary.

Figure 3

The decreased intoxication scores in rats that exercised were not due to enhanced metabolism of alcohol. There were no significant differences in BECs between sedentary rats (n=6) and rats that exercised (n=6) prior to a single 5 g/kg dose of ethanol.

Figure 4

Binge alcohol consumption caused significant loss of granule cells in the dentate gyrus (A). Exercise was partially protective against this loss, although the degree of neuroprotection was dependent on the average distance run; longer distances correlated with fewer remaining granule cells (B). In control animals, there was no correlation between average distance and number of remaining granule cells (C). * p<0.05 posthoc comparison to SE.

Figure 5

Exercise had regionally-specific effects on alcohol-induced cell death, evidenced by FJB labeling (A). As all control groups averaged 0.2 cells per section or less, only ethanol groups are graphed in A. Exercise reduced the number of degenerating cells (FJB+ cells) in the dentate gyrus and combined entorhinal-perirhinal cortices, but not in the piriform cortex. Representative photomicrographs are shown for SE rats for the entorhinal -perirhinal cortex (B), piriform cortex (D) and dentate gyrus (F) and for EE rats for the entorhinal perirhinal (C) piriform cortex (E) and dentate gyrus (G). Arrows highlight FJB+ cells and * indicates cells shown in the inset. * p < 0.05 posthoc comparison to SE.

Figure 6

Binge ethanol administration decreases the number of Ki67+ cells in the dentate gyrus of adult female rats (A). Representative photomicrographs show clusters of Ki67+ cells along the subgranular zone of the dentate gyrus in SC (n=6, B), EC (n=4, C), SE (n=4, D) and EE rats (n=4, E). Scale bar = 100µm. * p < 0.05 ethanol-exposed versus controls.