Uz T, Pesold C, Longone P, Manev H
The Psychiatric Institute, University of Illinois at Chicago, 60612, USA.
FASEB J. 1998 Apr;12(6):439-49. doi: 10.1096/fasebj.12.6.439.
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.
衰老与神经退行性过程相关。5-脂氧合酶（5-LO）也在神经元中表达，是白三烯合成的关键酶，白三烯是一类炎症类二十碳烷酸，能够促进神经退行性变。我们推测，在衰老过程中神经元5-LO的表达可能会上调，这可能会增加大脑对神经退行性变的易感性。我们观察了成年年轻（2个月大）和老年（24个月大）雄性大鼠不同脑区中5-LO样免疫反应性的分布差异。与年轻大鼠相比，老年大鼠中5-LO样免疫反应性更强，特别是在边缘结构（包括海马体）的锥体细胞树突中，以及额顶叶皮层的V层锥体细胞及其顶端树突中。神经元5-LO蛋白随衰老增加的表达似乎是由于5-LO基因表达增加所致。使用定量逆转录/聚合酶链反应分析以及5-LO特异性寡核苷酸引物及其突变的内标，我们观察到老年大鼠海马体中5-LO mRNA含量大约高2.5倍。在谷氨酸脱羧酶或胶质纤维酸性蛋白呈阳性的小的非锥体细胞中也观察到了5-LO样免疫反应性。老年大鼠中这种类型的5-LO免疫染色没有增加。全身注射红藻氨酸诱导的海马兴奋性毒性损伤在老年大鼠中更严重。使用5-LO抑制剂咖啡酸可观察到神经保护作用。总之，这些结果表明衰老会增加神经元5-LO的表达以及神经元对5-LO抑制剂敏感的兴奋性毒性的易感性，并表明5-LO系统可能在衰老相关神经退行性疾病的病理生物学中起重要作用。
