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。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。在重度抑郁症中，海马体积减小，皮质神经胶质细胞数量减少。主要基于动物研究，应激诱导的高皮质醇血症，导致神经毒性和/或主动细胞死亡（凋亡）是抑郁症海马体积损失的可能原因。已知主动细胞死亡涉及NMDA谷氨酸受体（NMDA-R）激活和一氧化氮过量产生。胍丁胺是一种内源性多胺，来源于精氨酸的脱羧作用，主要储存在神经元的突触囊泡中，已发现胍丁胺可拮抗NMDA-R和一氧化氮合酶，从而具有天然的神经保护特性（即，显示抗缺氧缺血）。在慢性应激的动物模型中，海马体积损失已经得到了很好的证实。 胍丁胺通常在海马中是丰富的，在那里它通常可以与谷氨酸共同释放，以通过正常大鼠的NMDA-R中的多胺位点保护免受兴奋性神经毒性。我们推测，在患有重度抑郁症的受试者中，胍丁胺由于在长期压力下的长期释放而耗尽，因此海马神经元暴露于神经元损伤。我的建议的目的是检查胍丁胺对兴奋毒素或更高浓度的糖皮质激素诱导的神经毒性的神经保护特性，如已检测到的抑郁症患者。为了解决这个目标，胍丁胺的神经保护作用将在1）体外暴露于谷氨酸盐以及相关化学物质或高浓度糖皮质激素的培养的胎鼠海马神经元（其模拟在体内抑郁患者中发现的条件），2）用兴奋性毒素处理的大鼠的海马，和（3）经历慢性轻度应激后的大鼠的海马中测量。海马中内源性胍基丁胺的浓度将与海马原代培养物中神经元和神经胶质细胞的结构损伤程度以及经处理大鼠和大鼠慢性轻度应激模型的海马体内的结构损伤程度相关。 本研究旨在阐明胍丁胺作为一种内源性神经保护剂与慢性应激效应相关的功能意义，如抑郁症。慢性轻度应激动物模型海马结构和生化变化的澄清将增加抑郁症海马神经元丢失的证据，并有望提出增强胍丁胺天然神经保护作用的方法。