Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury.
Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury.
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DOI：
10.1371/journal.pone.0047098
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ju WK
中科院分区：
文献类型：
--
作者：
Lee D;Kim KY;Noh YH;Chai S;Lindsey JD;Ellisman MH;Weinreb RN;Ju WK
谷氨酸兴奋性毒性诱导的氧化应激与视网膜缺血和视神经病变（包括青光眼）中的线粒体功能障碍有关。溴莫尼定（Brimonindine，BMD）是一种α 2-肾上腺素能受体激动剂，可保护视网膜神经节细胞（retinal ganglion cells，RGC）免受谷氨酸兴奋毒性或氧化应激的损伤。然而，在视网膜缺血损伤后，BMD相关的线粒体保护RGC免受谷氨酸兴奋性毒性诱导的氧化应激的分子机制仍然很大程度上未知。在这里，我们测试是否激活α 2肾上腺素能受体的全身BMD治疗阻断谷氨酸兴奋性毒性诱导的氧化应激，并保留线粒体转录因子A（Tfam）和氧化磷酸化（OXPHOS）复合物在缺血性视网膜的表达。Sprague-Dawley大鼠全身接受BMD（1 mg/kg/天）或溶剂（0.9%盐水），然后通过急性眼内压升高诱导短暂缺血。全身BMD治疗显著增加缺血后4周RGC存活率。在24小时，BMD显著降低缺血视网膜中Bax的表达，但增加Bcl-xL和磷酸化Bad蛋白的表达。重要的是。BMD在24小时显著阻断缺血视网膜中N-甲基-D-天冬氨酸受体1和2A蛋白表达以及SOD 2蛋白表达的上调。在缺血性损伤后的早期神经变性（12-72小时）期间，在溶剂处理的视网膜中Tfam和OXPHOS复合物蛋白表达显著增加。缺血24 h，Tfam免疫反应在外丛状层、内核层、内丛状层和神经节细胞层增强。此外，Tfam蛋白主要在RGC中表达。最后，BMD保留了RGC中的Tfam免疫反应性以及视网膜提取物中的Tfam/OXPHOS复合物蛋白表达以对抗缺血性损伤。我们的研究结果表明，全身BMD治疗保护视网膜节细胞的谷氨酸兴奋性毒性诱导的氧化应激和随后的保护Tfam/OXPHOS复合物在缺血性视网膜表达的封锁。
Glutamate excitotoxicity-induced oxidative stress have been linked to mitochondrial dysfunction in retinal ischemia and optic neuropathies including glaucoma. Brimonindine (BMD), an alpha 2-adrenergic receptor agonist, contributes to the neuroprotection of retinal ganglion cells (RGCs) against glutamate excitotoxicity or oxidative stress. However, the molecular mechanisms of BMD-associated mitochondrial preservation in RGC protection against glutamate excitotoxicity-induced oxidative stress following retinal ischemic injury remain largely unknown. Here, we tested whether activation of alpha 2 adrenergic receptor by systemic BMD treatment blocks glutamate excitotoxicity-induced oxidative stress, and preserves the expression of mitochondrial transcription factor A (Tfam) and oxidative phosphorylation (OXPHOS) complex in ischemic retina. Sprague-Dawley rats received BMD (1 mg/kg/day) or vehicle (0.9% saline) systemically and then transient ischemia was induced by acute intraocular pressure elevation. Systemic BMD treatment significantly increased RGC survival at 4 weeks after ischemia. At 24 hours, BMD significantly decreased Bax expression but increased Bcl-xL and phosphorylated Bad protein expression in ischemic retina. Importantly. BMD significantly blocked the upregulations of N-methyl-D-aspartate receptors 1 and 2A protein expression, as well as of SOD2 protein expression in ischemic retina at 24 hours. During the early neurodegeneration following ischemic injury (12–72 hours), Tfam and OXPHOS complex protein expression were significantly increased in vehicle-treated retina. At 24 hours after ischemia, Tfam immunoreactivity was increased in the outer plexiform layer, inner nuclear layer, inner plexiform layer and ganglion cell layer. Further, Tfam protein was expressed predominantly in RGCs. Finally, BMD preserved Tfam immunoreactivity in RGCs as well as Tfam/OXPHOS complex protein expression in the retinal extracts against ischemic injury. Our findings suggest that systemic BMD treatment protects RGCs by blockade of glutamate excitotoxicity-induced oxidative stress and subsequent preservation of Tfam/OXPHOS complex expression in ischemic retina.
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