STRESS AXIS ACTIVATION, ETHANOL AND SITE-SPECIFIC CNS NEURODEGENERATION

应激轴激活、乙醇和位点特异性中枢神经系统神经变性

• 批准号: 6288664
• 负责人: Robert L Eskay
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6288664
• 关键词: Cushing's syndrome; Rodentias; alcoholic beverage consumption; alcoholism /alcohol abuse; calcium metabolism; cognition disorders; cortisol; dentate gyrus; dexamethasone suppression test; disease /disorder model; drug withdrawal; entorhinal cortex; ethanol; glucocorticoids; hippocampus; hormone regulation /control mechanism; hypercortisolism; hypothalamic pituitary adrenal axis; lateral olfactory area; neural degeneration; neuropharmacology; neurotoxins; stress

Consumption of moderate to large amounts of ethanol (Et) activates the hypothalamic-pituitary-adrenal axis (HPAA). Activation of the HPAA or hypercortisolism accompanies both short- and long-term consumption of Et and the Et withdrawal syndrome. Alcoholics often present with a pseudo-Cushings syndrome in which some 17-40 percent of alcoholics do not respond to the dexamethasone suppression test during the first week of abstinence, suggesting an ongoing hypercortisolemic state in this group of patients. Since a relative state of elevated glucocorticoids (chronic continuous or chronic intermittent) can lead to neural changes and even cell death, particularly in the hippocampus, the progressive loss of cognitive capacity in many alcoholics may indeed be due in part to hypercortisolemia and subsequent irreversible neural damage in the hippocampus and other areas of the central nervous system. Using an intragastric cannulated rodent model and short-term (4 days) intermittent or binge-type Et administration, we have demonstrated site-specific CNS neurodegeneration in the dentate gyrus of the hippocampus, the entorhinal cortex and the piriform cortex.The observed Et-induced neurodegeneration was functionally validated as noted by the decline in learning and memory capacity in the Et-treated animals in the hippocampal-dependent Morris water maze test. Ongoing efforts to define the mechanism of Ets cytotoxicity continue by us and others. Surprisingly, the co-administration of glutamate receptor subtype antagonists or calcium uptake blocking drugs with Et are not neuroprotective, which argues against an excitotoxic basis for the neurodegeneration; however, elevated glucocorticoids exacerbate the Et- induced neurodegeneration presumably through excitotoxic mechanisms. To date the most potent cytoprotective agent in the binge-type rodent model has been shown to be furosemide(FUR), an anion transport inhibitor; however, our finding that LY-644,711, bumetanide and SITS, which are drugs with mechanisms of action similiar to FUR, are not neuroprotective would argue against a primary ionic, edema-based mechanism of neurotoxicity. Finally, with the knowledge that certain cannabinoids are neuroprotective we co-administered cannabidiol with Et and found an attenuation of neurodegeneration. Since in vitro studies have demonstrated that cannabidiol blocked glutamate-NMDA, -AMPA or - kainate receptor- mediated toxicity, it would appear that the cannabidiol site of action is downstream of receptor activation and perhaps has a generalized metabolic or anti-oxidant mechanism of neuroprotection. The ability of cannabidiol to protect against the toxicity of reactive oxygen species may underlie its cytoprotection in our binge-type Et rodent model. - mental health, stress axis, neuroscience, CNS, neurodegeneration, neuroprotection, glucocorticoids, ethanol, neuroendocrine

中度至大量乙醇（ET）的消耗会激活下丘脑 - 垂体 - 肾上腺轴（HPAA）。 HPAA或过度皮质醇的激活伴随ET的短期和长期消费以及ET戒断综合征。酗酒者通常出现伪清除综合征，其中大约17-40％的酒精中毒在禁欲的第一周不对地塞米松抑制测试反应，这表明在这组患者中，持续的高皮质血质血症状态。由于糖皮质激素升高（慢性连续或慢性间歇性）的相对状态可能导致神经变化，甚至会导致细胞死亡，尤其是在海马中，因此许多酒精中毒的认知能力的逐渐丧失可能部分归因于高皮质血症，以及随后的Hippocampus和Hippocappus和其他中心神经系统的不可逆神经损害。使用潮内插管的啮齿动物模型和短期（4天）间歇性或暴饮效率的给药，我们已经证明了海马齿状回流中的位点特异性CNS神经退行性代理，内嗅性皮质和梨状皮质的脑质皮质的降低，并在诱导的神经降低的过程中，与诱导的神经降落相关，并在诱导的神经变质中，与功能相关的有效性，是在有效的效果。海马依赖的莫里斯水迷宫测试中的动物。我们和其他人仍在继续进行定义ETS细胞毒性机制的努力。令人惊讶的是，谷氨酸受体亚型拮抗剂或ET钙吸收药物的共同给药不是神经保护作用，这反对神经变性的兴奋性基础。然而，升高的糖皮质激素大概通过兴奋性机制加剧了ET诱导的神经退行性。迄今为止，在暴饮暴食啮齿动物模型中，最有效的细胞保护剂已显示为阴离子转运抑制剂（毛皮）。但是，我们的发现，LY-644,711，bumetanide和坐着是具有与毛皮相似的作用机制的药物，不是神经保护性的，它会反对基于离子的，基于湿气的神经毒性的机制。最后，在知道某些大麻素是神经保护剂的情况下，我们与ET共同管理大麻二酚，并发现神经变性的衰减。由于体外研究表明大麻二醇可阻断谷氨酸-NMDA，-AMPA或 - 海藻酸盐受体介导的毒性，因此似乎大麻二醇的作用部位是受体激活的下游，并且也许具有广义的代谢或抗氧化剂机制。大麻二醇预防活性氧毒性的能力可能是其在我们的暴饮暴食型啮齿动物模型中的细胞保护作用。 - 心理健康，应力轴，神经科学，CNS，神经变性，神经保护，糖皮质激素，乙醇，神经内分泌