COBRE: UMMC: AGMATINE, NEUROPROTECTION & DEPRESSION

COBRE：UMMC：胍丁胺，神经保护

• 批准号: 7381914
• 负责人: MENG-YANG ZHU
• 金额: $ 14.31万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381914
• 关键词: COBRE; UMMC; AGMATINE; NEUROPROTECTION; DEPRESSION

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Decreased hippocampal volume and reduced glial cell number in the cortex have been documented in major depression. Based largely on animal studies, stress-induced hypercortisolemia, leading to neurotoxicity and/or active cell death (apoptosis) is the probable cause of the hippocampal volume loss in depression. Active cell death is known to involve NMDA glutamate receptor (NMDA-R) activation and nitric oxide overproduction. Agmatine, an endogenous polyamine derived from decarboxylation of arginine and mainly stored in synaptic vesicles of neurons, has been found to antagonize both NMDA-R and nitric oxide synthase, and thereby to possess natural neuroprotective properties (ie., shown against hypoxic ischemia). Hippocampal volume loss has been well-established to occur in animal models of chronic stress. Agmatine is normally abundant in the hippocampus where it may normally be co-released with glutamate to protect from excito-neurotoxicity through a polyamine site in the NMDA-R of normal rats. We hypothesize that in subjects suffering from major depression, agmatine becomes depleted as a consequence of long term release under prolonged stress, and therefore the hippocampal neurons become exposed to neuronal damage. The goal of my proposal is to examine the neuroprotective properties of agmatine against neurotoxicity induced by excitoxins or higher concentrations of glucocoticoids as have been detected in patients with major depression. To address this goal, the neuroprotective effects of agmatine will be measured in 1) cultured fetal rat hippocampal neurons exposed to glutamate as well as related chemicals, or high concentrations of glucocoticoids in vitro which mimic conditions found in depressed patients in vivo, 2)the hippocampi of rats treated with excitotoxins, and (3) the hippocampi of rats after undergoing chronic mild stress. Concentrations of endogenous agmatine in hippocampi will be correlated with the extent of structural injury to neurons and glial cells in the hippocampal primary culture and in the hippocampus in vivo of treated rats and the rat chronic mild stress model. This research is designed to elucidate the functional significance of agmatine as an endogenous neuroprotective agent of relevance to the effects of chronic stress as occurs in depression. Clarification of structural and biochemical changes in the hippocampus of the chronic mild stress animal model will add to evidence of hippocampal neuron loss in depression, and hopefully suggest ways to augment agmatine's natural neuroprotective effects.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。在严重抑郁症中，海马体积减少和皮质中的神经胶质细胞数量减少。主要基于动物研究，压力诱导的高皮质血症，导致神经毒性和/或活性细胞死亡（凋亡）是抑郁症海马体积损失的可能原因。已知活性细胞死亡涉及NMDA谷氨酸受体（NMDA-R）活化和一氧化氮过量生产。琼脂氨酸是一种由精氨酸脱羧并主要储存在神经元突触囊泡中的内源性多胺，可以拮抗NMDA-R-R氧化物合酶，从而具有天然神经保护性能（IE。）。海马体积损失已经建立了良好的慢性压力动物模型。 在海马中，吻山氨酸通常很丰富，通常可以与谷氨酸共同发行，以防止正常大鼠NMDA-R中的多胺位点保护兴奋性神经毒性。我们假设在患有严重抑郁症的受试者中，由于长期释放在长期压力下长期释放而枯竭，因此海马神经元暴露于神经元损伤。我的提议的目的是检查a a茶碱对兴奋毒素或较高浓度的葡萄糖毒素诱导的神经毒性的神经保护特性，如大抑郁症患者所检测到的那样。为了解决这一目标，将在1）暴露于谷氨酸的胎儿大鼠海马神经元以及相关化学物质以及高浓度的体外葡萄糖剂中的神经保护作用。轻度压力。海马中的内源性a邻苯胺的浓度将与海马原发性培养的神经元和神经胶质细胞的结构性损伤以及治疗大鼠体内的海马和大鼠慢性轻度应激模型相关。 这项研究旨在阐明琼脂氨酸作为与抑郁症发生的慢性应激作用相关的内源性神经保护剂的功能意义。阐明慢性轻度压力​​动物模型海马的结构和生化变化将增加抑郁症中海马神经元丧失的证据，并希望提出增加a arematine自然神经保护作用的方法。