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

Abstract

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.

Tissue Microarray Lipidomic Imaging Mass Spectrometry Method: Application to the Study of Alcohol-Related White Matter Neurodegeneration

“…The methods herein detail our TMA-MALDI-Lipidomics protocol, including the critical reagents and procedural steps needed to generate TMAs that are suitable for lipidomic research. The example illustrated is an established experimental rat model of chronic alcohol exposure that causes WM degeneration together with deficits in spatial learning and memory tasks as demonstrated using the Morris Water Maze [ 37 ]. This section includes a brief description of the model and a summary of the technical details pertaining to the acquisition of MALDI-IMS data.…”

Differential Early Mechanistic Frontal Lobe Responses to Choline Chloride and Soy Isoflavones in an Experimental Model of Fetal Alcohol Spectrum Disorder

“…Multiple studies of white matter pathology have demonstrated loss of volume due to the depletion of myelin and axons [12,17,24,50,51], and oligodendrocyte dysfunction manifested by impaired survival due to increased apoptosis [52], altered myelin-associated protein expression [48,49] and shifts in sphingolipid and phospholipid profiles [53][54][55][56]. Alcohol-related shifts in brain lipid profiles linked to neurobehavioral dysfunction may be due to dysregulated metabolism.…”

“…Alcohol-related shifts in brain lipid profiles linked to neurobehavioral dysfunction may be due to dysregulated metabolism. Correspondingly, partial normalization of ethanolinduced neurobehavioral deficits was achieved by treatment with myriocin, which reduced the white matter accumulations of toxic ceramides and increased sphingomyelin and sulfatide [53]. However, ethanol's neurotoxic, neurodevelopmental, and neurodegenerative effects in white matter have been mechanistically linked to impairments in insulin/IGF-1 signaling through Akt pathways [57].…”