Studies on neuroprotective strategies in retinal ischemia and reperfusion injury

Abstract

Retinal ischemia and reperfusion (RIR) injury, characterized by an insufficient supply or blockage of blood flow followed by subsequent reperfusion to the retina, is a common pathological process involved in various ocular diseases. RIR injury induces neuronal degeneration, leading to irreversible visual impairment and blindness. To date, the therapeutic strategies to RIR induced retinal degeneration are limited. Either anti-vascular endothelial growth factor or laser photocoagulation, acts on the complications of angiogenesis which develop at the late-stage of the injury. However, the irreversible neuron damage occurs as early as the RIR injury initiates. Therefore, the researchers are seeking to explore ideal strategies to halt or reverse the retinal neurodenegeration in the early stage of the injury. This study focused on two candidate therapies, physical exercise and resveratrol, which have been suggested to have protective effects in multiple neurodegenerative diseases. A well-established animal model, acute intraocular hypertension, was conducted to mimic the pathological process of RIR injury.

In the investigation of physical exercise, the voluntary exercise was conducted by separately housing the rat in a cage with free access to a voluntary running wheel. The rats were pre-treated with voluntary exercise for 30 days and post-treated for 14 days after RIR injury. However, voluntary exercise did not suggest any benefits in retinal ganglion cells (RGCs) density, retinal thickness as well as retinal function after RIR injury.

In the part of resveratrol treatment, daily intraperitoneal injection of resveratrol for 1 week and 4 weeks was found to alleviate RGCs loss caused by RIR injury, but had no effect in microglia activation, retinal thickness as well as retinal function. Resveratrol is an activator of sirtuin (SIRT1), which is a protein deacetylase that regulates a variety of molecular processes of stress response. The results from the protein expression level suggested that the protective effect of resveratrol treatment on RGCs at 4 weeks might be mediated by activation of SIRT1, which thereby induced anti-inflammatory effect through the inhibition of cyclooxygenase-2 and interleukin 6. Although the resveratrol was deemed as the activator of SIRT1, it took time to accumulate in the body to an effective dose to exert effects as no activation of SIRT1 was found after daily resveratrol treatment for 1 week. This result indicated that the protective effect of resveratrol on RGCs at 1 week after injury might be mediated by targets other than SIRT1.

In conclusion, for the two candidate therapies, our study demonstrated that only resveratrol has the potential to meet the clinical needs in RGCs loss induced by RIR injury. In the future work, more investigations on molecular levels, including the exercise-induced protein changes, and other targets of resveratrol at 1 week after RIR injury, are required.