STRESS AXIS, ACTIVATION, SITE SPECIFIC CNS NEURODEGENERATION AND ETHANOL

应激轴、激活、位点特异性中枢神经系统神经变性和乙醇

• 批准号: 6160378
• 负责人: R 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/6160378
• 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 axis; lateral olfactory area; neural degeneration; neuropharmacology; neurotoxins; pituitary adrenal axis; stress

Consumption of ethanol (Et) alters certain regulatory aspects of the hypothalamic-pituitary-adrenal axis (HPAA). Because the integrity of this system depends on the coordinated synthesis and secretion of specific regulatory substances at the hypothalamic (e.g., corticotropin- releasing hormone (CRH); vasopressin (AVP); biogenic amines), pituitary- gland (e.g., beta-endorphin; ACTH) and adrenal gland (e.g., catecholamines; glucocorticoids) level, we have been evaluating the impact of Et at each level of the 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. 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 alcohol administration, we have demonstrated site-specific CNS neurodegeneration in the dentate gyrus of the hippocampus, the entorherial cortex and the piriform cortex. Assessment of the role of increased glutamatergic neurotransmission, Ca++ uptake and levels of glucocorticoids in the observed neurodegeneration continues with hormonal and pharmacological replacement therapy. This project was formerly titled "Stress Axis, Immune System-Derived Cytokines and Ethanol."

消费乙醇（ET）改变了某些调节方面 下丘脑 - 垂体 - 肾上腺轴（HPAA）。 因为的完整性 该系统取决于协调的合成和分泌 下丘脑的特定调节物质（例如，皮质激素 - 释放激素（CRH）；加压素（AVP）;生物胺），垂体 - 腺体（例如，β-内啡肽； ACTH）和肾上腺（例如， 儿茶酚胺；糖皮质激素）水平，我们一直在评估 ET在HPAA的每个级别上的影响。 激活HPAA或 ET的短期和长期消费均伴随着超皮质醇 和ET戒断综合征。 酗酒者通常会出现伪 库欣综合症，其中约有17-40％的酒精饮料没有 在第一周的第一周回应地塞米松抑制测试 节制。 由于糖皮质激素升高的相对状态（慢性 连续或慢性间歇）可能导致神经变化，甚至 细胞死亡，尤其是在海马，逐渐丧失 许多酗酒者的认知能力确实可能部分是由于 高皮质血症以及随后的不可逆神经损害 海马和中枢神经系统的其他区域。 使用一个 胃内插管啮齿动物模型和短期（4天）间歇性 酒精给药，我们展示了特定地点的中枢神经系统 海马齿状回中的神经变性， 内部皮质和梨状皮层。 评估角色 增加谷氨酸能神经传递，Ca ++摄取和水平 观察到的神经退行性中的糖皮质激素继续用激素继续 和药理替代疗法。 这个项目以前是 标题为“应力轴，免疫系统衍生的细胞因子和乙醇”。