权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

New drug therapy for retinal degeneration using calcium channel blockers

使用钙通道阻滞剂治疗视网膜变性的新药物疗法

基本信息

批准号：
15390523
负责人：
OHGURO Hiroshi
金额：
$ 8.06万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

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

视网膜色素变性（RP）是一种遗传性视网膜变性疾病，其特征是夜盲症、环形暗点和骨针色素沉着。迄今为止，RP尚无有效的治疗方法。本研究采用多种不同病因的动物模型，包括1）RCS大鼠视网膜色素上皮（retinal pigment epithelium，RPE）功能缺陷，2）P23 H，S334ter和光应激致视紫红质功能障碍模型、磷酸二酯酶（PDE）功能障碍模型和癌相关视网膜病变（CAR）恢复依赖性光感受器适应功能障碍模型，观察视网膜电图（ERG）视网膜功能、视网膜形态、3）类视色素分析，4）视紫红质再生，5）视紫红质磷酸化 ...更多信息去磷酸化和去磷酸化以及6）胞质cGMP水平，以阐明这些模型中的共同病理机制。结果发现，视紫红质磷酸化和去磷酸化失衡引起的光感受器适应过程的失调导致视网膜功能障碍，导致光感受器细胞死亡，作为使这些视网膜功能障碍正常化并阻止进一步视网膜变性的可能候选药物，尼伐地平，一种Ca通道阻断剂，选择类维生素A衍生物和蒽酮，并测试它们对上述几种视网膜变性动物模型的作用。尼伐地平在所有测试模型中显示出对视网膜变性的有益作用，但类维生素A衍生物和蒽酮仅在一些模型中显示出这些作用。因此，我们目前的数据使我们能够测试尼伐地平人类RP患者。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患者相比，使用尼伐地平的RP患者在静态视野分析中显示出显著较低的进展。结论尼伐地平是一种很有前途的预防RP患者视网膜变性的药物。少