Aging-associated up-regulation of neuronal 5-lipoxygenase expression: putative role in neuronal vulnerability
Aging-associated up-regulation of neuronal 5-lipoxygenase expression: putative role in neuronal vulnerability
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DOI：
10.1096/fasebj.12.6.439
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发表时间：
1998-04-01
期刊：
影响因子：
4.8
通讯作者：
Manev, H
中科院分区：
文献类型：
--
作者：
Uz, T;Pesold, C;Manev, H
衰老与神经退行性变过程有关，5-脂氧合酶（5-LO）也在神经元中表达，是能够促进神经退行性变的炎性类二十烷酸（eicosanoids）的白三烯合成的关键酶。我们假设神经元5-LO表达在衰老中可以上调，这可能增加大脑对神经退行性变的脆弱性。我们观察到5-LO样免疫反应性在成年青年人不同脑区的分布差异，（2个月大）vs，老年（24月龄）雄性大鼠，在老年大鼠与年轻大鼠中发现更大的5-LO样免疫反应性，特别是在边缘结构（包括海马）的锥体神经元树突和额顶叶皮质的V层锥体细胞及其顶树突中，应用定量逆转录聚合酶链反应（RT-PCR）和5-LO特异性寡核苷酸引物及其突变的内标物，我们观察到老年大鼠海马5-LO mRNA含量增加约2.5倍，在小的非锥体细胞中也观察到5-LO样免疫反应阳性，其谷氨酸脱羧酶或胶质细胞酸性蛋白阳性，这种类型的5-LO免疫染色在老年大鼠中不增加，红藻氨酸全身注射诱导的海马兴奋性毒性损伤在老年大鼠中更大，用5-LO抑制剂咖啡酸观察到神经保护作用，这些结果表明老化增加了神经元5-LO表达和神经元对5-LO递质敏感性兴奋毒性的脆弱性，提示5-LO系统可能在衰老相关的神经退行性疾病的病理生物学中起重要作用。
Aging is associated with neurodegenerative processes, 5-Lipoxygenase (5-LO), which is also expressed in neurons, is the key enzyme in the synthesis of leukotrienes, inflammatory eicosanoids that are capable of promoting neurodegeneration, We hypothesized that neuronal 5-LO expression can be up-regulated in aging and that this may increase the brain's vulnerability to neurodegeneration. We observed differences in the distribution of 5-LO-like immunoreactivity in various brain areas of adult young (2-month-old) vs, old (24-month-old) male rats, Greater 5-LO-like immunoreactivity was found in old vs, young rats, in particular in the dendrites of pyramidal neurons in limbic structures, including the hippocampus, and in layer V pyramidal cells of the frontoparietal cortex and their apical dendrites, The aging-increased expression of neuronal 5-LO protein appears to be due to increased 5-LO gene expression, Using a quantitative reverse transcription/polymerase chain reaction assay and 5-LO-specific oligonucleotide primers and their mutated internal standards, we observed about a 2.5-fold greater hippocampal 5-LO mRNA content in old rats, 5-LO-like immunoreactivity was also observed in small, nonpyramidal cells, which were positive for glutamic acid decarboxylase or glial fibrillary acid protein, This type of 5-LO immunostaining did not increase in the old rats, Hippocampal excitotoxic injury induced by systemic injection of kainate was greater in old rats, Neuroprotection was observed with the 5-LO inhibitor, caffeic acid, Together, these results suggest that aging increases both neuronal 5-LO expression and neuronal vulnerability to 5-LO inhibitor-sensitive excitotoxicity, and indicate that the 5-LO system might play a significant role in the pathobiology of aging-associated neurodegenerative diseases.