Therapeutic Effects of Myriocin in Experimental Alcohol-Related Neurobehavioral Dysfunction and Frontal Lobe White Matter Biochemical Pathology

Background & Objective: Chronic excessive alcohol consumption causes white matter degeneration with myelin loss and impaired neuronal conductivity. Subsequent rarefaction of myelin accounts for the sustained deficits in cognition, learning, and memory. Correspondingly, chronic heavy or repeated binge alcohol exposures in humans and experimental models alter myelin lipid composition leading to build-up of ceramides which can be neurotoxic and broadly inhibitory to brain functions. Methods: This study examined the effects of chronic + binge alcohol exposures (8 weeks) and intervention with myriocin, a ceramide inhibitor, on neurobehavioral functions (Open Field, Novel Object Recognition, and Morris Water Maze tests) and frontal lobe white matter myelin lipid biochemical pathology in an adult Long-Evans rat model. Results: The ethanol-exposed group had significant deficits in executive functions with increased indices of anxiety and impairments in spatial learning acquisition. Myriocin partially remediated these effects of ethanol while not impacting behavior in the control group. Ethanol-fed rats had significantly smaller brains with broadly reduced expression of sulfatides and reduced expression of two of the three sphingomyelins detected in frontal white matter. Myriocin partially resolved these effects corresponding with improvements in neurobehavioral function. Conclusion: Therapeutic strategies that support cerebral white matter myelin expression of sulfatide and sphingomyelin may help remediate cognitive-behavioral dysfunction following chronic heavy alcohol consumption in humans.