AGING AND NEURONAL 5 LIPOXYGENASE

衰老与慢性神经退行性疾病有关， 大脑脆弱性增加，可能导致更糟糕的结果 老年人比年轻受试者更易受大脑侮辱。炎症是一种 慢性和急性心肌梗死的病理生理机制 神经退行性变。白三烯是炎性脂质介质，其 花生四烯酸的形成是由5-脂氧合酶(5-LO)启动的。 5-LO在神经元中也有表达，并可被大脑激活 而5-LO抑制剂可以提供神经保护。这个 5-LO基因的表达似乎受到松果体的抑制 荷尔蒙，褪黑激素，也是一种有效的神经保护剂。 褪黑激素缺乏症通常会随着年龄的增长而发展。我们发现了那件旧的 或松果体摘除，即褪黑激素缺乏，大鼠更容易受到影响 红藻氨酸引发的兴奋性中毒性边缘脑损伤 相应的年轻或假松果体摘除对照组，以及 松果体摘除或衰老导致边缘5-LO表达增强 结构。我们假设大脑老化的风险更高 衰老抑制的褪黑素分泌导致的神经退行性变和 由此导致5-LO表达上调，并抑制5-LO 表达和/或活动会增加大脑对 受伤。这些假设将在以下目标中得到检验：(1) 以衰老的大鼠(即2、6、12和24个月龄)为特征： 5-LO基因和蛋白在神经元中的表达及其活化 蛋白瓣；红藻氨酸对白三烯形成和 海马区和内嗅区皮质的神经元损伤；血液和 脑褪黑素水平(2)青少年边缘结构的特征 褪黑素核受体激动剂对老年大鼠的影响 CGp-52608或褪黑素对红藻氨酸诱导的5-L0表达的影响 白三烯的形成与神经元损伤；(3)研究其作用 不同种类5-LO抑制剂对红藻氨酸诱导的白三烯的影响 形成和神经元损伤；以及(4)调查红藻氨酸是否 5-LO缺陷(即，基因敲除)小鼠的神经毒性较低，以及 衰老同样影响5-LO缺乏和KA的易感性 年龄匹配的野鼠。将使用的技术包括：量化 逆转录/聚合酶链式反应检测5-LO和Flat mRNAs， 5-LO和免疫细胞化学/免疫印迹，酶或放射- 免疫分析、气相色谱/质谱仪、TUNEL/NISIL 染色和计算机辅助形态定量测量。结果是 有望阐明5-LO在衰老和衰老中的作用 神经退行性变和指示神经保护性治疗 靶向5-LO通路。

Aging is associated with chronic neurodegenerative diseases and increased brain vulnerability that may lead to a worse outcome from brain insults in elderly than in young subjects. Inflammation is one of the pathophysiological mechanisms of both chronic and acute neurodegeneration. Leukotrienes are inflammatory lipid mediators whose formation from arachidonic acid is initiated by 5-lipoxygenase (5-LO). 5-LO is also expressed in neurons and can be activated by brain injuries, whereas 5-LO inhibitors can provide neuroprotection. The expression of the 5-LO gene appears to be inhibited by the pineal hormone, melatonin, which also is a potent neuroprotective agent. Melatonin deficiency normally develops with aging. We found that old or pinealectomized, i.e., melatonin-deficient, rats are more susceptible to kainate-triggered excitotoxic limbic brain injury than the corresponding young or sham-pinealectomized controls, and that pinealectomy or aging result in an enhanced expression of 5-LO in limbic structures. We hypothesize that an aging brain is at a higher risk of neurodegeneration via aging-suppressed melatonin secretion and the resultant upregulation of 5-LO expression, and that suppressing the 5-LO expression and/or activity will increase the brain's resistance to injury. These hypotheses will be tested in the following AIMS: (1) Characterize in aging rats (i.e., at 2, 6, 12, and 24 months of age): the neuronal expression of mRNAs and proteins of 5-LO and its activating protein FLAP; the effect of kainate on leukotriene formation and neuronal damage in the hippocampus and the entorhinal cortex; blood and brain melatonin levels (2) Characterize in limbic structures of young and old rats the effects of the nuclear melatonin receptor agonist CGP-52608 or melatonin on 5-L0 expression and kainate-induced leukotriene formation and neuronal damage; (3) Investigate the action of different classes of 5-LO inhibitors on kainate-induced leukotriene formation and neuronal damage; and (4) Investigate whether kainate is less neurotoxic in 5-LO-deficient (i.e., knockout) mice, and whether aging equally affects the vulnerability to kainate of 5-LO-deficient and age-matched wild mice. Techniques to be used include: quantitative reverse transcription/polymerase chain reaction for 5-LO and FLAP mRNAs, 5-LO and FLAP immunocytochemistry/immonobloting, enzyme- or radio- immunoassays, gas chromatography/mass spectrometry, TUNEL/Nissl stainings, and computer-assisted quantitative morphometry. The results are expected to elucidate the role of 5-LO in aging and neurodegeneration and to indicate neuroprotective therapies that would target the 5-LO pathway.