Neuroprotection of the retina through application of carbon monoxide releasing molecules (CO-RM) after retinal ischemia and reperfusion injury.

在视网膜缺血和再灌注损伤后应用一氧化碳释放分子（CO-RM）对视网膜进行神经保护。

• 批准号: 240808643
• 负责人: Privatdozentin Dr. Julia Biermann
• 金额: --
• 依托单位: St. Franziskus-Hospital Münster
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/240808643?language=en
• 关键词: Neuroprotection; retina; through; application; carbon

One fundamental reason of postoperative cognitive dysfunction and neurological conspicuousness is most often presumed to cerebral ischemia- and reperfusion (I/R) injuries, occurring during anesthesia or due to surgical interventions in patients of all ages. We chose the eye as a neuronal organ, which in function is partly comparable to the brain, to analyze and counteract I/R related neuronal damage. Ocular I/R injuries due to diseases such as central retinal artery occlusion or diabetic retinopathy ultimately result in neuronal destruction of the retina, most often leading to visual impairment. Because of their high specialization neuronal cells in the retina react most sensitive regarding dysbalance of ocular homeostasis. Any form of regeneration of these highly specialized neuronal cells seemed almost impossible, so far. Our lab has recently shown that preconditioning with inhalative carbon monoxide (CO) exerts protective effects in a retinal I/R model. Seven days after I/R injury, retinal ganglion cell (RGC) death decreased by 52% in the CO-preconditioning group compared with controls receiving room air. CO inhalation after 0-3h after I/R injury likewise attenuated RGC loss. In preliminary experiments, we have shown that the inflammatory response is inhibited by CO combined with an attenuation of caspase-3 activity. By contrast, the absence of CO before/after I/R injury led to significantly higher expression of inflammatory proteins and to a tremendous activation and proliferation of retinal glia cells. Despite this description, the molecular etiologies of these effects remain poorly understood. It is assumed that responsible pathways include the activation of the soluble guanylyl cyclase (sGC) and the mitogen activated protein kinases (MAPK). Apart from the inhalative application of CO, which still triggers reservations about its clinical application due to its potential toxic side effects, carbon monoxide releasing molecules (CO-RM) seem to exert cytoprotective effects as well, thus gaining increasingly attention.Furthermore, new CO-RM - like ALF-186 - are now water-soluble and show longstanding effectiveness in vivo. The advantages of topic (intravitreally) and systemic administration of the CO-RM ALF186 after retinal I/R injury and its neuroprotective properties on retinal neurons have not been investigated so far.Based on these facts, we will investigate the following hypotheses:Hypothesis 1: The systemic application of ALF186 leads to a reduction in neuronal cell death and inflammation in a postconditioning retinal I/R rat model. Hypothesis 2: The protective properties of ALF186 are mediated by the MAPK, the sGC and by its potential to suppress neuroinflammation in the retina. Hypothesis 3: Topical application of ALF186 (intravitreally) is able to reduce neuronal cell death and retinal inflammation in a postconditioning retinal I/R rat model.

术后认知功能障碍和神经系统显着性的根本原因之一最常被认为是麻醉期间或由于所有年龄段患者的手术干预而发生的脑缺血和再灌注（I/R）损伤。我们选择眼睛作为神经器官，其功能在一定程度上与大脑相当，来分析和抵消 I/R 相关的神经元损伤。视网膜中央动脉闭塞或糖尿病视网膜病变等疾病引起的眼 I/R 损伤最终会导致视网膜神经元破坏，最常导致视力障碍。由于视网膜中神经元细胞的高度专业化，它们对眼稳态失衡的反应最为敏感。到目前为止，这些高度特化的神经元细胞的任何形式的再生似乎几乎是不可能的。我们的实验室最近表明，吸入一氧化碳 (CO) 预处理对视网膜 I/R 模型具有保护作用。 I/R 损伤后 7 天，与接受室内空气的对照组相比，CO 预处理组的视网膜神经节细胞 (RGC) 死亡减少了 52%。 I/R 损伤后 0-3 小时吸入 CO 同样可以减轻 RGC 损失。在初步实验中，我们已经证明 CO 可以抑制炎症反应，并减弱 caspase-3 活性。相比之下，I/R损伤前后缺乏CO会导致炎症蛋白的表达显着升高，并导致视网膜神经胶质细胞的巨大活化和增殖。尽管有这样的描述，但这些效应的分子病因学仍然知之甚少。据推测，相关途径包括可溶性鸟苷酸环化酶 (sGC) 和丝裂原激活蛋白激酶 (MAPK) 的激活。除了吸入式CO因其潜在的毒副作用仍对其临床应用持保留态度外，一氧化碳释放分子（CO-RM）似乎也发挥着细胞保护作用，因此受到越来越多的关注。此外，新的CO-RM（如ALF-186）现在是水溶性的，并在体内显示出长期有效性。视网膜 I/R 损伤后局部（玻璃体内）和全身施用 CO-RM ALF186 的优点及其对视网膜神经元的神经保护特性尚未得到研究。基于这些事实，我们将研究以下假设：假设 1：ALF186 的全身应用导致视网膜后处理中神经元细胞死亡和炎症的减少 I/R 大鼠模型。假设 2：ALF186 的保护特性由 MAPK、sGC 及其抑制视网膜神经炎症的潜力介导。假设 3：在后处理视网膜 I/R 大鼠模型中，局部应用 ALF186（玻璃体内）能够减少神经元细胞死亡和视网膜炎症。

项目成果

Carbon monoxide treatment reduces microglial activation in the ischemic rat retina

• DOI: 10.1007/s00417-016-3435-6
• 发表时间: 2016-07
• 期刊: Graefe's Archive for Clinical and Experimental Ophthalmology
• 作者: Felix Ulbrich;U. Goebel;D. Böhringer;P. Charalambous;W. Lagrèze;J. Biermann