[Comprehensive strategy for retinal neuroprotection. Challenging the clinical application]

The retina is the most critical tissue for visual function. The death of retinal neuronal cells results in a loss of visual acuity. A report in 2006 shows that Japan's top 5 ranking diseases leading to visual loss were related to the death of either retinal photoreceptor cells or retinal ganglion cells. This analysis suggests that neuroprotective strategy is one significant treatment for retinal disorders. In this review, we introduce four strategies for retinal neuroprotection: I. Direct Neuroprotection, II. Indirect Neuroprotection, ll. Neuroprotection for Surgical Stress, and IV. Minimally Invasive Equipment for Retinal Examination. I. Direct neuroprotection. Recently, apoptosis is reported to be an important factor in various ocular disorders. In this study, we focused on the apoptosis-inducing factor (AIF) as a target for retinal diseases. Our data indicate that AIF could contribute to photoreceptor apoptosis in retinal detachment, and that an AIF inhibitor, Nelfinavir, could prevent apoptotic change. We also clarified the essential role of AIF and oxidative damage in retinal photoreceptor death in retinal pigmentosa. Because clinical trials have shown that a neuroprotective factor, pigment epithelium-derived factor (PEDF), could inhibit cell death in retinitis pigmentosa, we applied neuroprotective gene therapy using PEDF in a clinical setting. II. Indirect neuroprotection. Fibrovascular membranes (FVMs) in diabetic retinopathy often induce tractional retinal detachment, causing decreased vision and blindness. To regulate the FVM, we performed global gene expression profiling of human FVMs associated with PDR and found that periostin was expressed more strongly in FVMs than in idiopathic epiretinal membranes. In this study, immunohistochemical analysis showed colocalization of periostin and α-smooth muscle actin (α-SMA) in FVM cells. Our data also indicate that the FVM contained several splicing variants of periostin and that variant-specific inhibition could be a therapeutic target for FVM. III. Neuroprotection for surgical stress. Brilliant blue G (BBG) is a triphenylmethane dye approved for intraoperative use in ocular surgery, in the context of chromovitrectomy, which involves the use of vital dyes to improve the visualization of intraocular tissues during vitrectomy. Following the recent characterization of BBG as a P2RX7 antagonist, we decided to investigate the pathogenic implications of P2RX7 in pathologic photoreceptor loss, as well as the therapeutic utility of BBG in this context. The resulting data show that increased extracellular ATP levels contribute to pathologic photoreceptor loss and that BBG efficiently prevents photoreceptor cell death. IV. Minimally invasive equipment for retinal examination. Reduced oxygen saturation in the retina can cause retinal neuronal damage. Therefore, measuring the oxygen saturation mapping is important in the diagno sis of patients with retinal disorders. Recently, we developed a system to measure retinal oxygen saturation by using a spectroscopic technique with two different absorption spectra, morphological processing (closing) and a line convergence index filter. We would like to propose the concept of "comprehensive strategy for retinal neuroprotection" for the future treatment of retinal diseases.