New drug therapy for retinal degeneration using calcium channel blockers

色素性视网膜炎（RP）是一种遗传性视网膜变性疾病，其特征是视网膜夜盲症、环状暗斑和骨针状色素沉着。到目前为止，还没有有效的治疗RP的方法。视网膜特异性基因缺陷最有可能是RP的分子病因，但在翻译后水平导致视网膜感光细胞死亡的细胞内机制方面很少被确定。本研究采用1)视网膜色素上皮（RPE）功能缺损的RCS大鼠，2)视紫红质功能缺损的P23H、S334ter和光应激模型，3)磷酸二酯酶（PDE）功能缺损的rd小鼠，4)恢复依赖性光受体适应功能缺损的癌症相关性视网膜病变（CAR）模型，采用视网膜电图（ERG）观察其视网膜功能，2)视网膜形态学，3)类维生素a分析，4)视紫红质再生，5)视紫红质磷酸化，更多的磷酸化和去磷酸化，6)细胞质cGMP水平，以阐明这些模型的共同病理机制。因此，我们发现由视紫红质磷酸化和去磷酸化失衡引起的光受体适应过程失调导致视网膜功能障碍导致光受体细胞死亡。作为可能的候选药物，我们选择了尼伐地平、钙通道阻滞剂、类维甲酸衍生物和花青素，并对上述几种视网膜变性动物模型进行了效果测试。尼伐地平对所有模型的视网膜变性均有有益作用，但类维甲酸衍生物和花青素仅在某些模型中有这种作用。因此，我们目前的数据允许我们测试尼伐地平对人类RP患者的作用。使用尼伐地平1.5年的前瞻性研究显示，与未使用尼伐地平的RP患者相比，使用尼伐地平的RP患者在静态周长分析中表现出明显较低的进展。总之，尼伐地平是一种很有希望预防RP患者视网膜变性的药物。少

Retinitis pigmentosa (RP) is a disease of inherited retinal degeneration characterized by nyctalopia, ring-scotoma and bone-spicule pigmentation of the retina. So far, no effective therapy has been available for RP. As possible molecular etiology of RP, retina specific gene deficits are most likely involved but little has been identified in terms of intracellular mechanisms leading to retinal photoreceptor cell death at post translational levels.In the present study, several animal models with different causes including 1)RCS rat with deficit of retinal pigment epithelium (RPE) function, 2)P23H,S334ter and photo-stress model with deficit of rhodopsin function, 3)rd mouse with deficit of phosphodiesterase (PDE) function and 4)cancer-associated retinopathy (CAR) model with deficit of recoverin-dependent photoreceptor adaptation function were studied their 1)retinal function by electroretinogram (ERG), 2)retinal morphology, 3)retinoid analysis, 4)rhodopsin regeneration, 5)rhodopsin phosph … More orylation and dephosphorylation and 6)cytosolic cGMP levels in order to elucidate common pathological mechanisms among these models. As a result, we found that misregulation of photoreceptor adaptation processes caused by imbalance of rhodopsin phosphorylation and dephosphorylation caused retinal dysfunction leading to photoreceptor cell death.As possible candidate drugs normalizing these retinal dysfunction and stop further retinal degeneration, nilvadipine, a Ca channel blocker, retinoid derivatives and anthocyanine were choose and tested to their effect toward several animal models with retinal degeneration as above. Nilvadipine showed beneficial effects toward retinal degeneration in all models tested, but retinoid derivatives and anthocyanine showed these effects in only some models. Thus our present data allowed us to test nilvadipine to human RP patients. Prospective study using nilvadipine for 1.5 years revealed RP patients used nilvadipine administration showed significant lower progression in static perimetric analysis as compared to those without nilvadipine administration. In conclusion, nilvadipine is one of promising drug for preventing retinal degeneration RP patients. Less