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

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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.