Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
Microvasc Res. 2012 Nov;84(3):278-85. doi: 10.1016/j.mvr.2012.08.004. Epub 2012 Aug 27.
As the population ages, the need for effective methods to maintain brain function in older adults is increasingly pressing. Vascular disease and neurodegenerative disorders commonly co-occur in older persons. Cerebrovascular products contribute to the neuronal milieu and have important consequences for neuronal viability. In this regard vascular derived neuroprotective proteins, Such as vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), and pituitary adenylate cyclase activating peptide (PACAP) are important for maintaining neuronal viability, especially in the face of injury and disease. The objective of this study is to measure and compare levels of VEGF, PEDF and PACAP released from isolated brain microvessels of Fischer 344 rats at 6, 12, 18, and 24 months of age. Addition of acetaminophen to isolated brain microvessels is employed to determine whether this drug affects vascular expression of these neuroprotective proteins. Experiments on cultured brain endothelial cells are performed to explore the mechanisms/mediators that regulate the effect of acetaminophen on endothelial cells. The data indicate cerebrovascular expression of VEGF, PEDF and PACAP significantly decreases with age. The age-associated decrease in VEGF and PEDF is ameliorated by addition of acetaminophen to isolated brain microvessels. Also, release of VEGF, PEDF, and PACAP from cultured brain endothelial cells decreases with exposure to the oxidant stressor menadione. Acetaminophen treatment upregulates VEGF, PEDF and PACAP in brain endothelial cells exposed to oxidative stress. The effect of acetaminophen on cultured endothelial cells is in part inhibited by the selective thrombin inhibitor hirudin. The results of this study suggest that acetaminophen may be a useful agent for preserving cerebrovascular function. If a low dose of acetaminophen can counteract the decrease in vascular-derived neurotrophic factors evoked by age and oxidative stress, this drug might be useful for improving brain function in the elderly.
随着人口老龄化，对于有效方法来维持老年人大脑功能的需求日益迫切。血管疾病和神经退行性疾病在老年人中常同时发生。脑血管产物有助于神经元环境，并对神经元活力有重要影响。在这方面，血管衍生的神经营养蛋白，如血管内皮生长因子（VEGF）、色素上皮衍生因子（PEDF）和垂体腺苷酸环化酶激活肽（PACAP），对于维持神经元活力非常重要，特别是在面对损伤和疾病时。本研究的目的是测量和比较来自 Fischer 344 大鼠 6、12、18 和 24 个月龄的分离脑微血管中释放的 VEGF、PEDF 和 PACAP 的水平。将对乙酰氨基酚添加到分离的脑微血管中，以确定这种药物是否会影响这些神经营养蛋白的血管表达。在培养的脑内皮细胞上进行实验，以探索调节对乙酰氨基酚对内皮细胞影响的机制/介质。数据表明，VEGF、PEDF 和 PACAP 的脑血管表达随年龄显著下降。向分离的脑微血管中添加对乙酰氨基酚可改善与年龄相关的 VEGF 和 PEDF 减少。此外，暴露于氧化剂应激剂 menadione 可使培养的脑内皮细胞中 VEGF、PEDF 和 PACAP 的释放减少。在暴露于氧化应激的脑内皮细胞中，对乙酰氨基酚处理可上调 VEGF、PEDF 和 PACAP。乙酰氨基酚对培养的内皮细胞的作用部分被选择性凝血酶抑制剂水蛭素抑制。本研究结果表明，对乙酰氨基酚可能是一种有用的维持脑血管功能的药物。如果低剂量的对乙酰氨基酚可以抵消因年龄和氧化应激引起的血管源性神经营养因子减少，那么这种药物可能有助于改善老年人的大脑功能。
