Antioxidants Reduce Ethanol Induced CNS Neurodegeneratio

抗氧化剂减少乙醇引起的中枢神经系统退化

• 批准号: 6690249
• 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/6690249
• 关键词: Cushing's syndrome; Rodentias; alcoholic beverage consumption; alcoholism /alcohol abuse; antioxidants; behavior test; calcium metabolism; cognition disorders; cortisol; dentate gyrus; disease /disorder model; drug withdrawal; entorhinal cortex; ethanol; furosemide; glucocorticoids; hippocampus; hormone regulation /control mechanism; hypercortisolism; hypothalamic pituitary adrenal axis; lateral olfactory area; neural degeneration; neuropharmacology; neuroprotectants; neurotoxins; stress

Acute or chronic consumption of ethanol(Et), which achieves blood Et levels of 150 mg % or higher, activates the hypothalamic-pituitary-adrenal axis (HPAA) and chronic, excessive Et intake can lead to permanent brain damage. Activation of the HPAA or hypercortisolism accompanies both short- and long-term consumption of Et and the Et withdrawal syndrome. 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 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 coadministration of glutamate receptor subtype antagonists or calcium uptake blocking drugs with Et are not neuroprotective in the binge model, which argues against a glutamate-receptor dependent excitotoxic basis for the neurodegeneration; however, evidence for a glutamate-dependent, non-receptor or metabolic mechanism of excitotoxicity exists. Furthermore, 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 similar to FUR, are not neuroprotective would argue against a primary ionic, edema-based mechanism of neurotoxicity. With the knowledge that certain cannabinoids are neuroprotective, we coadministered cannabidiol with Et and found a significant reduction 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. To confirm that the protection with cannabidiol was due to its antioxidant properties, two other common antioxidants, Vitamin E and butylated hydroxytoluene (BHT), were tested. Both Vitamin E, a well known antioxidant, and BHT, an antioxidant commonly used as a food preservative, protected to a similar degree as cannabidiol in our binge-type animal model of alcoholism. Given the dissimilar nature of the compounds screened, which were found to be potent neuroprotectants against alcohol-induced brain damage, we tested the possibility that FUR might function as an antioxidant in our model. Results from Fenton reaction and cyclic voltametry tests clearly indicated that FUR possesses intrinsic antioxidant properties. The neuroprotection afforded by diverse antioxidant compounds in our binge-type model of alcoholism suggests that oxidative stress and the generation of reactive oxygen species are partially responsible for the brain damage associated with excessive Et consumption. Formerly titled 'Stress axis activation, ethanol and site-specific CNS neurodegeneration'

乙醇（ET）的急性或长期消耗达到150 mg％或更高的血液水平，可激活下丘脑 - 垂体 - 肾上腺轴（HPAA）和慢性ET摄入量可能导致永久性脑损伤。 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。由于糖皮质激素升高的相对状态（慢性连续或慢性间歇性）可能导致神经变化甚至细胞死亡，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的高度血症血症和随后的Hippocampus和Hippocampus和其他中心神经系统的不可逆神经损害。使用胃内插管的啮齿动物模型和短期（4天）间歇性或暴饮暴食型和给药，我们在海马，内嗅皮层和梨状皮层的齿状回合中证明了位点特异性的CNS神经变性。正如海马依赖性莫里斯水迷宫检验中ET处理的动物的学习和记忆能力下降所述，观察到的ET诱导的神经变性在功能上得到了验证。我们和其他人仍在继续进行定义ET细胞毒性机制的努力。令人惊讶的是，在暴饮暴食模型中，谷氨酸受体亚型拮抗剂或钙吸收药物的共同给药并非神经保护药物，该模型反对谷氨酸 - 受体受体依赖性的兴奋性兴奋性毒性基础。然而，存在谷氨酸依赖性，非受体或代谢机制的证据。此外，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和坐着是具有类似于皮毛的作用机制的药物，不是神经保护性的，它会反对一种基于离子的，基于湿气的神经毒性机制。知道某些大麻素是神经保护作用的知识，我们将大麻二醇与ET共同辅助，发现神经退行性变化显着降低。由于体外研究表明大麻二醇可阻断谷氨酸-NMDA，-AMPA或 - 凯纳酸盐受体介导的毒性，因此大麻二醇的作用部位似乎是受体激活的下游，并且也许具有广义的代谢或抗氧化剂机制。为了确认大麻二酚的保护是由于其抗氧化特性引起的，测试了另外两种常见的抗氧化剂，维生素E和丁基羟基甲苯（BHT）。维生素E（一种众所周知的抗氧化剂）和BHT（一种通常用作食品防腐剂）的抗氧化剂，在我们的暴饮暴食性动物酒精中毒模型中受到与大麻二醇相似的程度。鉴于筛选的化合物的不同性质，被发现是针对酒精引起的脑损伤的有效神经保护剂，我们测试了毛皮在模型中起作用的抗氧化剂的可能性。芬顿反应和环状伏安测试的结果清楚地表明，毛皮具有内在的抗氧化特性。酒精中毒模型中各种抗氧化剂化合物提供的神经保护作用表明，氧化应激和活性氧的产生是部分造成与过度ET消耗相关的脑损伤的部分原因。以前称为“应力轴激活，乙醇和特定位点的CNS神经变性”