Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa
Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa
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DOI：
10.1073/pnas.1007644107
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发表时间：
2010-10-26
影响因子：
11.1
通讯作者：
Ghidoni, Riccardo
中科院分区：
文献类型：
--
作者：
Strettoi, Enrica;Gargini, Claudia;Ghidoni, Riccardo
视网膜色素变性（RP）是一种遗传性疾病，导致光感受器进行性凋亡死亡，最终导致无法治愈的失明。使用视网膜变性10（rd 10）RP小鼠模型，我们研究了神经酰胺，一种促凋亡鞘脂，在视网膜变性中的作用。我们还测试了通过干扰体内细胞凋亡的神经酰胺信号通路可以减缓或阻断感光细胞损失的可能性。视网膜神经酰胺水平增加，在rd 10小鼠感光细胞死亡的最大时期。单次眼内注射多球壳菌素（一种丝氨酸棕榈酰辅酶A转移酶（神经酰胺生物合成的限速酶）的强效抑制剂）可将视网膜神经酰胺水平降低至正常值，并将光感受器从凋亡死亡中拯救出来。非侵入性治疗是通过滴眼液实现的，滴眼液由装载有多球霉素的固体脂质纳米颗粒的悬浮液组成。短期非侵入性治疗以类似于眼内注射的方式降低视网膜神经酰胺，表明纳米颗粒作为载体允许经角膜给药。延长治疗（10-20天）与固体脂质纳米粒子增加感光细胞的生存，保存感光细胞形态，并延长视网膜的能力，以响应光通过视网膜电图评估。总之，神经酰胺生物合成的药理学靶向减缓了RP在小鼠模型中的进展，因此可能代表了治疗人类这种疾病的治疗方法。如本研究中所试验的，固体脂质纳米粒中携带的药物的经角膜给药可能有助于RP和其他视网膜病变患者的连续、非侵入性治疗。
Retinitis pigmentosa (RP) is a genetic disease causing progressive apoptotic death of photoreceptors and, ultimately, incurable blindness. Using the retinal degeneration 10 (rd10) mouse model of RP, we investigated the role of ceramide, a proapoptotic sphingolipid, in retinal degeneration. We also tested the possibility that photoreceptor loss can be slowed or blocked by interfering with the ceramide signaling pathway of apoptosis in vivo. Retinal ceramide levels increased in rd10 mice during the period of maximum photoreceptor death. Single intraocular injections of myriocin, a powerful inhibitor of serine palmitoyl-CoA transferase, the rate-limiting enzyme of ceramide biosynthesis, lowered retinal ceramide levels to normal values and rescued photoreceptors from apoptotic death. Noninvasive treatment was achieved using eye drops consisting of a suspension of solid lipid nanoparticles loaded with myriocin. Short-term noninvasive treatment lowered retinal ceramide in a manner similar to intraocular injections, indicating that nanoparticles functioned as a vector permitting transcorneal drug administration. Prolonged treatment (10-20 d) with solid lipid nanoparticles increased photoreceptor survival, preserved photoreceptor morphology, and extended the ability of the retina to respond to light as assessed by electroretinography. In conclusion, pharmacological targeting of ceramide biosynthesis slowed the progression of RP in a mouse model, and therefore may represent a therapeutic approach to treating this disease in humans. Transcorneal administration of drugs carried in solid lipid nanoparticles, as experimented in this study, may facilitate continuous, noninvasive treatment of patients with RP and other retinal pathologies.