The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke.
The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke.
复制标题
超氧化物歧化酶模拟tempol的神经保护特性与在啮齿动物模型中减少病理谷氨酸释放的能力相关。
DOI：
10.1016/j.freeradbiomed.2014.08.029
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发表时间：
2014-12
影响因子：
7.4
通讯作者：
Mongin, Alexander A.
中科院分区：
文献类型：
--
作者：
Dohare, Preeti;Hyzinski-Garcia, Maria C.;Vipani, Aarshi;Bowens, Nicole H.;Nalwalk, Julia W.;Feustel, Paul J.;Keller, Richard W., Jr.;Jourd'heuil, David;Mongin, Alexander A.
关键词：
氧化应激在缺血性脑损伤中的作用是公认的。然而，由于未知的原因，几种经过临床测试的抗氧化剂疗法未能显示出对人类中风的益处。基于我们以前的体外工作，我们假设抗氧化剂的神经保护作用与其限制兴奋性毒性氨基酸谷氨酸和天冬氨酸的释放有关。在大鼠大脑中动脉短暂性闭塞(MCAO)模型上，我们探讨了两种抗氧化剂坦普尔和依达拉奉对大脑皮层氨基酸释放的影响。用微透析法量化氨基酸水平，通过激光多普勒技术证实探头位于缺血半暗带。大脑中动脉阻塞2小时后，谷氨酸、天冬氨酸、牛磺酸和丙氨酸水平显著升高。10 mM坦普尔的微透析液可使氨基酸释放量减少60%-80%，而匹配剂量的依达拉奉则无影响。与后一项数据一致的是，侧脑室注射temol而不是依达拉奉(每次500nmol，MCAO前15分钟)可使脑梗塞体积减少约50%，并改善神经行为结果。体外实验表明，坦普尔对超氧阴离子的清除能力优于依达拉奉，而依达拉奉对过氧化氢、羟基自由基和过氧亚硝酸根的清除能力较强。总体而言，我们的数据表明，temol的神经保护特性可能与其降低组织超氧阴离子水平和病理性谷氨酸释放的能力有关，并通过这种方式限制缺血半暗带内脑梗塞的进展。这些新发现可能有助于开发新的抗氧化剂疗法来治疗中风。
The contribution of oxidative stress to ischemic brain damage is well established. Nevertheless, for unknown reasons, several clinically tested antioxidant therapies failed to show benefits in human stroke. Based on our previous in vitro work, we hypothesized that the neuroprotective potency of antioxidants is related to their ability to limit release of the excitotoxic amino acids, glutamate and aspartate. We explored the effects of two antioxidants, tempol and edaravone, on amino acid release in the brain cortex, in a rat model of transient occlusion of the middle cerebral artery (MCAo). Amino acid levels were quantified using a microdialysis approach, with the probe positioned in the ischemic penumbra as verified by a laser Doppler technique. Two-hour MCAo triggered a dramatic increase in the levels of glutamate, aspartate, taurine and alanine. Microdialysate delivery of 10 mM tempol reduced the amino acid release by 60–80%, while matching levels of edaravone had no effect. In line with these latter data, an intracerebroventri-cular injection of tempol but not edaravone (500 nmols each, 15 minutes prior to MCAo) reduced infarction volumes by ~50% and improved neurobehavioral outcomes. In vitro assays showed that tempol was superior in removing superoxide anion, whereas edaravone was more potent in scavenging hydrogen peroxide, hydroxyl radical, and peroxynitrite. Overall, our data suggests that the neuroprotective properties of tempol are likely related to its ability to reduce tissue levels of the superoxide anion and pathological glutamate release, and, in such a way, limit progression of brain infarction within ischemic penumbra. These new findings may be instrumental in developing new antioxidant therapies for treatment of stroke.
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