Dept. of Biomedical Sciences, Atlantic Veterinary College, Univ. of Prince Edward Island, Charlottetown, P.E.I., Canada.
Am J Physiol Regul Integr Comp Physiol. 2012 Apr;302(7):R886-95. doi: 10.1152/ajpregu.00644.2011. Epub 2012 Jan 25.
Previous work in our laboratory has provided evidence that preadministration of apocynin and lipoic acid at subthreshold levels for neuroprotection enhanced the neuroprotective capacity when injected in combination. Therefore, the present investigation was designed to determine whether a co-drug consisting of lipoic acid and apocynin functional groups bound by a covalent bond, named UPEI-100, is capable of similar efficacy using a rodent model of stroke. Male rats were anesthetized with Inactin (100 mg/kg iv), and the middle cerebral artery was occluded for 6 h or allowed to reperfuse for 5.5 h following a 30-min occlusion (ischemia/reperfusion, I/R). Preadministration of UPEI-100 dose-dependently decreased infarct volume in the I/R model (P < 0.05), but not in the middle cerebral artery occlusion model of stroke. Using the optimal dose, we then injected UPEI-100 during the stroke or at several time points during reperfusion, and significant neuroprotection was observed when UPEI-100 was administered up to 90 min following the start of reperfusion (P < 0.05). A time course for this neuroprotective effect showed that UPEI-100 resulted in a decrease in infarct volume following 2 h of reperfusion compared with vehicle. The time course of this neuroprotective effect was also used to study several mediators along the antioxidant pathway and showed that UPEI-100 increased the level of mitochondrial superoxide dismutase and oxidized glutathione and decreased a marker of lipid peroxidation due to oxidative stress (HNE-His adduct formation). Taken together, the data suggest that UPEI-100 may utilize similar pathways to those observed for the two parent compounds; however, it may also act through a different mechanism of action.
先前在我们实验室的工作已经提供了证据，即在亚治疗水平下预先给予白藜芦醇和硫辛酸以增强神经保护作用，然后联合注射时可增强神经保护能力。因此，本研究旨在确定一种由白藜芦醇和硫辛酸功能基团通过共价键结合而成的药物，命名为 UPEI-100，是否可以在中风的啮齿动物模型中发挥类似的功效。雄性大鼠用 Inactin（100mg/kgiv）麻醉，在 30 分钟闭塞后，大脑中动脉闭塞 6 小时或允许再灌注 5.5 小时（缺血/再灌注，I/R）。预先给予 UPEI-100 剂量依赖性地降低 I/R 模型中的梗塞体积（P<0.05），但在中风的大脑中动脉闭塞模型中则不然。使用最佳剂量，我们在中风期间或再灌注期间的多个时间点注射 UPEI-100，当在再灌注开始后 90 分钟内给予 UPEI-100 时观察到显著的神经保护作用（P<0.05）。该神经保护作用的时间过程表明，与载体相比，UPEI-100 在再灌注 2 小时后可减少梗塞体积。该神经保护作用的时间过程也用于研究抗氧化途径中的几种介质，结果表明 UPEI-100 增加了线粒体超氧化物歧化酶和氧化型谷胱甘肽的水平，并降低了氧化应激的脂质过氧化标志物（HNE-His 加合物形成）。综上所述，数据表明 UPEI-100 可能利用与两种母体化合物相同的途径；然而，它也可能通过不同的作用机制发挥作用。
