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首页> 外文期刊>Journal of neuroinflammation >The Carbon monoxide releasing molecule ALF-186 mediates anti-inflammatory and neuroprotective effects via the soluble guanylate cyclase ?1 in rats’ retinal ganglion cells after ischemia and reperfusion injury
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The Carbon monoxide releasing molecule ALF-186 mediates anti-inflammatory and neuroprotective effects via the soluble guanylate cyclase ?1 in rats’ retinal ganglion cells after ischemia and reperfusion injury

机译：一氧化碳释放分子ALF-186通过可溶性鸟苷酸环化酶β1介导缺血和再灌注损伤后大鼠视网膜神经节细胞的抗炎和神经保护作用

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BackgroundThe endogenously produced gaseous molecule carbon monoxide is able to promote organ protection after ischemia-reperfusion injuries (IRI). The impact of carbon monoxide releasing molecules (CORM) regarding inflammation in neuronal tissues has not been studied in detail. In this investigation, we aimed to analyze the effects of the CORM ALF-186 on neuro-inflammation and hypothesized that the soluble guanylate cyclase (sGC) is playing a decisive role. MethodsRetinal ischemia-reperfusion injury was performed for 60?min in Sprague-Dawley rats. Thereafter, the CORM ALF-186 (10?mg/kg) in the presence or absence of the sGC inhibitor ODQ was injected via a tail vein. Retinal tissue was harvested 24?h later to analyze mRNA or protein expression of sGC-β1 subunit, transcription factors NF-κB and CREB, the inflammatory cytokines TNF-α and IL-6, as well as the heat shock proteins (HSP) HSP-70 and HSP-90. Immunohistochemistry was performed on frozen sections of the retina. The overall neuroprotective effect of ALF-186 was assessed by counting fluorogold-pre-labeled retinal ganglion cells (RGC) 7?days after IRI. ResultsIschemia-reperfusion mediated loss of vital RGC was attenuated by the administration of ALF-186 after injury. ALF-186 treatment after IRI induced sGC-?1 leading to a decreased NF-κB and CREB phosphorylation. Consecutively, ALF-186 mitigated IRI induced TNF-α and IL-6 expression in the retina and in the rats’ serum. Moreover, ALF-186 attenuated heat shock protein 70 (Hsp-70) while increasing Hsp-90. The sGC-inhibitor ODQ attenuated the anti-inflammatory effects of ALF-186 and increased retinal loss of ganglion cells. These results were confirmed by immunohistochemistry. ConclusionThe CORM ALF-186 protected RGC from IRI induced loss. Furthermore, ALF-186 reduced IRI mediated neuroinflammation in the retina and in the serum by activating sGC. Inhibition of sGC stopped the beneficial and protective effects of ALF-186. ALF-186 may present a promising therapeutic alternative in treating inflammation after neuronal IRI.
机译：背景内源性气态分子一氧化碳能够促进缺血再灌注损伤（IRI）后的器官保护。尚未详细研究一氧化碳释放分子（CORM）对神经元组织炎症的影响。在这项调查中，我们旨在分析CORM ALF-186对神经炎症的影响，并假设可溶性鸟苷酸环化酶（sGC）起着决定性作用。方法对Sprague-Dawley大鼠进行视网膜缺血再灌注损伤60分钟。此后，通过尾静脉注射在存在或不存在sGC抑制剂ODQ的情况下的CORM ALF-186（10？mg / kg）。 24小时后收获视网膜组织，以分析sGC-β1亚基，转录因子NF-κB和CREB，炎性细胞因子TNF-α和IL-6以及热休克蛋白（HSP）HSP的mRNA或蛋白表达-70和HSP-90。在视网膜的冷冻切片上进行免疫组织化学。在IRI后7天，通过计数氟金预标记的视网膜神经节细胞（RGC）评估ALF-186的总体神经保护作用。结果损伤后给予ALF-186可减轻缺血再灌注介导的重要RGC的丧失。 IRI诱导sGC-α 1 后ALF-186治疗导致NF-κB和CREB磷酸化降低。连续地，ALF-186减轻了IRI诱导的视网膜和大鼠血清中TNF-α和IL-6的表达。此外，ALF-186减弱了热激蛋白70（Hsp-70），同时增加了Hsp-90。 sGC抑制剂ODQ减弱了ALF-186的抗炎作用并增加了神经节细胞的视网膜损失。免疫组织化学证实了这些结果。结论CORM ALF-186可保护RGC免受IRI引起的损失。此外，ALF-186通过激活sGC减少了视网膜和血清中IRI介导的神经炎症。抑制sGC停止了ALF-186的有益和保护作用。 ALF-186在治疗神经元IRI后的炎症中可能提供有希望的治疗选择。

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