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: 6097594
• 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/6097594
• 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-Cushing's 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 Et's 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, an anion transport inhibitor; however, our finding that LY-644,711, an equally potent anion transport inhibitor, is not neuroprotective would argue against a primary 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 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.

中等至大量的消费 乙醇（ET）激活下丘脑 - 垂体 - 肾上腺轴 （HPAA）。 HPAA或高皮质醇的激活伴随 ET的短期和长期消费以及ET撤离 综合征。酗酒者经常出现伪库的 大约17-40％的酗酒者综合征 在第一次响应地塞米松抑制测试 禁欲的一周，表明持续的高皮层血症状态 在这组患者中。由于相对升高的状态 糖皮质激素（慢性连续或慢性间歇性）可以 导致神经变化甚至细胞死亡，尤其是在 海马，许多人的认知能力逐渐丧失 确实，酗酒者可能部分归因于高皮质血症和 随后在海马和 中枢神经系统的其他区域。使用胃内 插管啮齿动物模型和短期（4天）间歇性或 暴饮暴食和管理，我们已经证明了特定地点 海马齿状回中的CNS神经变性， 内河皮质和梨状皮层。 ET诱导的神经变性在功能上验证如前所述 通过ET处理的学习和记忆能力的下降 海马依赖的莫里斯水迷宫测试中的动物。 持续的努力来定义ET细胞毒性的机制 继续我们和其他人。令人惊讶的是，共同管理 谷氨酸受体亚型拮抗剂或钙吸收阻滞 ET的药物不是神经保护的，这反对 神经退行性的兴奋性基础；但是，抬高了 糖皮质激素加剧ET诱导的神经变性 大概是通过兴奋性机制。迄今为止最多 暴饮暴食啮齿动物模型中有效的细胞保护剂具有 被证明是速尿，一种阴离子的转运抑制剂； 但是，我们发现LY-644,711，同样有效的阴离子 运输抑制剂，不是神经保护剂会反对 基于原发性水肿的神经毒性机制。最后，与 知道某些大麻素是神经保护的我们 与ET共同管理大麻二酚，发现 神经变性。由于体外研究表明 大麻二醇阻断谷氨酸-NMDA，-AMPA或-Kainate 受体介导的毒性，似乎大麻二醇 作用部位是受体激活的下游，也许有 神经保护的一般代谢机制。能力 大麻二醇可预防活性氧的毒性 物种可能是其在我们的暴饮暴食和啮齿动物中的细胞保护作用的基础 模型。