Antioxidant/Stress Response Peptides & Ethanol Toxicity

抗氧化/应激反应肽

• 批准号: 7146659
• 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/7146659
• 关键词: Rodentias; alcoholic beverage consumption; alcoholism /alcohol abuse; antioxidants; behavior test; behavioral /social science research tag; cannabinoids; cerebral degeneration; cortisol; dentate gyrus; disease /disorder model; entorhinal cortex; ethanol; furosemide; glucocorticoids; hippocampus; hormone regulation /control mechanism; hypercortisolism; hypothalamic pituitary adrenal axis; neuropharmacology; neuroprotectants; neurotoxins; oxidative stress; tocopherols

Alcohol is a widely abused drug and long term, excessive alcohol consumption leads to permanent organ damage or death. Alcoholism results in multiple organ damage and alcohol-induced brain damage is an insidious disease that leads to cognitive deficits in learning and memory. The most damaging pattern of alcohol consumption is episodic or binge drinking (consumption of 4-5 drinks or more per episode) and a high percentage of college students and older adult alcoholics are illustrative of binge drinkers. In order to understand the deleterious consequences of alcoholism, particularly binge type drinking,, and hopefully develop protective therapies, we have been studying a rodent model of alcoholism designed to mimic a single cycle of binge drinking in human alcoholics. Alcohol-induced brain damage has been demonstrated to occur in well-defined populations of neurons in specific brain regions. Binge ethanol consumption in the rodent reduces the ability of the rat to learn new information, similar to memory difficulties seen in humans. Particular regions of the brain that are most sensitive to alcohol toxicity are the entorhinal cortex and the hippocampus, two regions known to be vital for normal memory and cognitive processes. The mechanism underlying ethanol-induced neuronal damage is not well understood, although several explanations have been proposed. Prominent proposals include excitotoxicity associated with excessive glutamate neurotransmitter release, oxidative stress leading to free radical damage and edema related to altered control of ion transport. Neuroprotection or reversal of binge ethanol-induced neurotoxicity in our model was examined with diverse compounds previously shown to be cytoprotective. The nonpsychoactive cannabinoid cannabidiol(CBD), earlier shown to reduce gluteamate toxicity by reducing oxidative stress in cell culture, was evaluated as a a neuroprotectant. When co-administered with ethanol, CBD reduced hippocampal and entorhinal cortical neurodegeneration in a dose-related manner. Supportive of the notion that CBD neuroprotection was due to its antioxidant properties, the common antioxidants butylated hydroxytoluene and alpha-tocopherol provided substantial protection. In contrast, NMDA receptor antagonists, such as dizocilpine and memantine were not neuroprotective. Of the several ion exchange modulators which could counteract alcohol induced edema that leads to cytotoxicity, only furosemide was neuroprotective. It?s interesting to note that furosemide is a potent antioxidant, whereas the non-protective diuretics are not. It would appear that the antioxidant properties of furosemide and not its diuretic properties mediate neuroprotection.. The likelihood that multiple mechanisms mediate alcohol-induced neurotoxicity is high and even the mechanism of alcohol-induced oxidative damage is largely unknown. The search for neuroprotective compounds efficacious in the treatment of alcohol-induced brain damage is ongoing and findings will likely be applicable to the treatment of neurodegenerative diseases, hypoxia and toxin exposure. In addition, a number of endogenous compounds have been shown to be neuroprotective in diverse settings and conditions and protect against oxidative or ethanol insult. For example, pituitary adenylate cyclase-activating polypeptide(PACAP) appears to have both neurotrophic and neuroprotective abilities. Furthermore, the ability of PACAP to reduce alcohol toxicity, which is mimicked by dibutyrl cAMP, suggests this effect is mediated via activation of adenylate cyclase. The development of pharmacotherapeutics that include antioxidant characteristics and anti-inflammatory properties should reduce alcohol-induced cell injury and neurodegeneration.

酒精是一种被广泛滥用的药物，长期饮酒，过量的饮酒会导致永久器官损害或死亡。酒精中毒会导致多器官损伤和酒精引起的脑损伤是一种阴险的疾病，可导致学习和记忆的认知缺陷。饮酒的最具破坏性模式是情节性或暴饮暴食（每集4-5饮料或更多饮料），而高比例的大学生和老年人酒精饮料是暴饮暴食者的说明。为了了解酒精中毒的有害后果，尤其是暴饮暴食，并希望开发保护性疗法，我们一直在研究一种啮齿动物的酒精中毒模型，旨在模仿人类酒精中毒中的一次性暴饮暴食。 已经证明，在特定的大脑区域的神经元人群中，酒精诱导的脑损伤发生。啮齿动物中的暴饮暴食乙醇消耗降低了大鼠学习新信息的能力，类似于人类中的记忆困难。对酒精毒性最敏感的大脑的特定区域是内嗅皮层和海马，这两个区域已知对于正常记忆和认知过程至关重要。尽管提出了一些解释，但尚不清楚乙醇引起的神经元损伤的基础机制。突出的建议包括与过度谷氨酸神经递质释放相关的兴奋性毒性，导致自由基损伤的氧化应激以及与离子转运控制改变有关的水肿。 在我们的模型中，研究了狂暴乙醇诱导的神经毒性的神经保护作用或逆转，研究了先前显示为细胞保护作用的各种化合物。早期证明，非精神活性大麻素大麻二醇（CBD）通过减少细胞培养中的氧化应激来降低麸质毒性，评估为一种神经保护剂。当与乙醇共同辅助时，CBD以剂量相关的方式降低了海马和内嗅性皮质神经退行性。支持CBD神经保护是由于其抗氧化特性引起的，公共抗氧化剂丁基化的羟基甲苯和α-生育酚提供了实质性保护。相比之下，NMDA受体拮抗剂（例如二唑达和美灵）不是神经保护作用。在可能抵消酒精诱发的水肿的几个离子交换调节剂中，只有速尿为神经保护剂。有趣的是，速气剂是有效的抗氧化剂，而非保护利尿剂却没有。似乎源自源自的抗氧化特性，而不是其利尿特性介导神经保护作用。 多种机制介导酒精诱导的神经毒性的可能性很高，甚至酒精诱导的氧化损伤的机制在很大程度上尚不清楚。正在持续寻找有效的神经保护性化合物，可有效地治疗酒精诱发的脑损伤，发现可能适用于治疗神经退行性疾病，缺氧和毒素暴露。此外，许多内源性化合物已被证明在不同的环境和条件下具有神经保护作用，并预防氧化或乙醇损伤。例如，垂体腺苷酸环化酶激活多肽（PACAP）似乎具有神经营养和神经保护能力。此外，PACAP降低酒精毒性的能力（由Dibutyrl CAMP模仿）表明，这种作用是通过激活腺苷酸环化酶来介导的。包括抗氧化剂特征和抗炎特性的药物治疗剂的发展应减少酒精诱导的细胞损伤和神经变性。

项目成果

Leptin suppresses food intake and body weight in corticosterone-replaced adrenalectomized rats.

• DOI: 10.1093/jn/133.2.504
• 发表时间: 2003-02
• 期刊: The Journal of nutrition
• 作者: M. E. Gemmill;R. Eskay;N. Hall;L. Douglass;T. Castonguay

Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult.

内源性 PACAP 作为应激反应肽，保护小脑神经元免受乙醇或氧化损伤。

• DOI: 10.1016/j.peptides.2005.05.015
• 发表时间: 2005
• 期刊: Peptides
• 影响因子: 3
• 作者: Vaudry,David;Hamelink,Carol;Damadzic,Ruslan;Eskay,RobertL;Gonzalez,Bruno;Eiden,LeeE
• 通讯作者: Eiden,LeeE