The 5HT1a receptor agonist 8-Oh DPAT induces protection from lipofuscin accumulation and oxidative stress in the retinal pigment epithelium.
The 5HT1a receptor agonist 8-Oh DPAT induces protection from lipofuscin accumulation and oxidative stress in the retinal pigment epithelium.
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5HT1A受体激动剂8-OH DPAT诱导视网膜色素上皮中脂肪霉素积累和氧化应激的保护。
DOI：
10.1371/journal.pone.0034468
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Boulton ME
中科院分区：
文献类型：
--
作者：
Thampi P;Rao HV;Mitter SK;Cai J;Mao H;Li H;Seo S;Qi X;Lewin AS;Romano C;Boulton ME
老年性黄斑变性(AMD)是老年人失明的主要原因之一，与氧化应激、脂褐素积聚和视网膜变性有关。本研究的目的是确定5-HT1A受体激动剂在体外和体内是否能够减少脂褐素的积累，减少氧化损伤和防止视网膜细胞的丢失。用流式细胞仪分析和共聚焦显微镜观察5-HT1a受体激动剂8-OH DPAT对培养的视网膜色素上皮(RPE)细胞自噬和光感受器外节(POS)来源的脂褐素形成的影响。与对照组相比，8-OHDPAT处理导致自噬和POS来源的脂褐素均呈剂量依赖性减少。停药后，自噬诱导的脂褐素的减少持续了4周。评估了8-羟基DPAT在200微米H_2O_2中减少氧化损伤的能力。与对照组相比，8-OHDPAT减少了超氧化物歧化产物的产生，提高了线粒体超氧化物歧化酶(MnSOD)水平和还原型谷胱甘肽与氧化型谷胱甘肽的比率，并保护细胞免受过氧化氢引发的脂质过氧化、硝基酪氨酸水平和线粒体损伤。Sod2基因敲除小鼠具有类似AMD的表型，每天皮下注射生理盐水、0.5或5.0 mg/kg 8-OH DPAT，并每隔一个月进行评估。与接受载体控制的被击倒的小鼠相比，系统注射8-OH DPAT改善了SOD2被击倒的小鼠眼睛的视网膜电信号反应。在MnSOD基因敲除后4个月，接受8-OH DPAT治疗的小鼠的ONL厚度与未治疗的对照组相比显著增加，同时RPE脂褐素减少了60%。这些数据表明，5-HT1A激动剂可以减少脂褐素的积聚，保护视网膜免受氧化损伤和线粒体功能障碍的影响。5-HT1a受体激动剂有可能作为治疗视网膜退行性疾病的药物。
Age-related macular degeneration (AMD), a major cause of blindness in the elderly, is associated with oxidative stress, lipofuscin accumulation and retinal degeneration. The aim of this study was to determine if a 5-HT1A receptor agonist can reduce lipofuscin accumulation, reduce oxidative damage and prevent retinal cell loss both in vitro and in vivo. Autophagy-derived and photoreceptor outer segment (POS)-derived lipofuscin formation was assessed using FACS analysis and confocal microscopy in cultured retinal pigment epithelial (RPE) cells in the presence or absence of the 5-HT1A receptor agonist, 8-OH DPAT. 8-OH DPAT treatment resulted in a dose-dependent reduction in both autophagy- and POS-derived lipofuscin compared to control. Reduction in autophagy-induced lipofuscin was sustained for 4 weeks following removal of the drug. The ability of 8-OH DPAT to reduce oxidative damage following exposure to 200 µM H2O2 was assessed. 8-OH DPAT reduced superoxide generation and increased mitochondrial superoxide dismutase (MnSOD) levels and the ratio of reduced glutathione to the oxidized form of glutathione in H2O2-treated cells compared to controls and protected against H2O2-initiated lipid peroxidation, nitrotyrosine levels and mitochondrial damage. SOD2 knockdown mice, which have an AMD-like phenotype, received daily subcutaneous injections of either saline, 0.5 or 5.0 mg/kg 8-OH DPAT and were evaluated at monthly intervals. Systemic administration of 8-OH DPAT improved the electroretinogram response in SOD2 knockdown eyes of mice compared to knockdown eyes receiving vehicle control. There was a significant increase in the ONL thickness in mice treated with 8-OH DPAT at 4 months past the time of MnSOD knockdown compared to untreated controls together with a 60% reduction in RPE lipofuscin. The data indicate that 5-HT1A agonists can reduce lipofuscin accumulation and protect the retina from oxidative damage and mitochondrial dysfunction. 5-HT1A receptor agonists may have potential as therapeutic agents in the treatment of retinal degenerative disease.
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影响因子：
4.4
作者：
Justilien, Verline;Pang, Ji-Jing;Lewin, Alfred S.
通讯作者：
Lewin, Alfred S.
影响因子：
3.1
作者：
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