Distinct and Additive Effects of Alcohol and Thiamine Deficiency in the Developing Brain: Relevance to Fetal Alcohol Spectrum Disorder
Distinct and Additive Effects of Alcohol and Thiamine Deficiency in the Developing Brain: Relevance to Fetal Alcohol Spectrum Disorder作者机构：Departments of Pathology (Neuropathology) Neurology and Neurosurgery Brown University Providence RI USA Department of Medicine Brown University Providence RI USA Rhode Island Hospital Providence RI USA Women & Infants Hospital Providence RI USA Warren Alpert Medical School of Brown University Providence RI USA Portland VA Medical Center Oregon Health & Science University Portland OR USA
出 版 物：《Journal of Behavioral and Brain Science》 (行为与脑科学期刊（英文）)
年 卷 期：2024年第14卷第6期
页 面：161-186页
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
主 题：Fetal Alcohol Spectrum Disorder Thiamine Deficiency Cerebellum Slice Culture Pyrithiamine
摘 要：Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse e
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