Agonists at the Serotonin Receptor (5-HT1A) Protect the Retina from Severe Photo-Oxidative Stress
Agonists at the Serotonin Receptor (5-HT1A) Protect the Retina from Severe Photo-Oxidative Stress
复制标题
DOI：
10.1167/iovs.10-6304
复制
发表时间：
2011-04-01
影响因子：
4.4
通讯作者：
Romano, Carmelo
中科院分区：
文献类型：
--
作者：
Collier, Robert J.;Patel, Yamini;Romano, Carmelo
目的。5-HT1A激动剂对中枢神经系统损伤模型具有神经保护作用。作者评价了5-HT1A激动剂保护视网膜免受严重蓝光诱导的光氧化损伤的疗效。在蓝光照射6小时前，给白化大鼠皮下注射AL8309A、8-OH DPAT或丁螺环酮1次或3次。视网膜电图（ERGs）评估视网膜功能，光学显微镜评估视网膜损伤。还评估了1.75% AL-8309B局部眼剂量。给大鼠注射5-HT1A拮抗剂WAY-100635，以确定保护是否需要激活5-HT1A受体。光暴露后，车辆给药大鼠ERG反应幅度明显下降（P < 0.05） 66%以上。AL-8309A （0.1-30 mg/kg）、8-OH DPAT （0.1-1 mg/kg）、丁螺环酮（5-20 mg/kg）或1.75% AL-8309B局部眼用药组大鼠egg显著升高。AL-8309A和8-OH dpat处理的大鼠视网膜无组织学病变。在光照射前0、24或48小时给药一次的大鼠测量了显著的保护作用。给药AL-8309B或8-OH DPAT对way -100635大鼠的保护作用被抑制。5-HT1A激动剂提供了有效和完整的功能和结构保护。用WAY-100635处理后，保护作用被抑制，这证实了激活5-HT1A受体是启动这一生存途径的必要条件。AL-8309A单剂量实验表明，保护机制迅速激活，保护持续48小时。AL-8309B（1.75%）在眼部局部给药后有效。AL-8309B正在临床评估中，可能对治疗老年性黄斑变性有用。（Invest Ophthalmol Vis Sci. 2011;52:2118-2126） DOI:10.1167/iovs.106304
PURPOSE. 5-HT1A agonists are neuroprotective in CNS injury models. The authors evaluated the efficacy of 5-HT1A agonists to protect the retina from severe blue light-induced photooxidative damage.METHODS. Albino rats were dosed (subcutaneously) with AL8309A, 8-OH DPAT, or buspirone once or three times before 6-hour exposure to blue light. Electroretinograms (ERGs) were measured to assess retinal function, and retinal damage was evaluated by light microscopy. Topical ocular dosing with 1.75% AL-8309B was also evaluated. Rats were dosed with WAY-100635, a 5-HT1A antagonist, to determine whether protection required activation of the 5-HT1A receptor.RESULTS. ERG response amplitudes were significantly (P < 0.05) depressed more than 66% in vehicle-dosed rats after light exposure. ERGs were significantly higher in rats treated with AL-8309A (0.1-30 mg/kg), 8-OH DPAT (0.1-1 mg/kg), buspirone (5-20 mg/kg) or topical ocular with 1.75% AL-8309B. Retinas from AL-8309A and 8-OH DPAT-treated rats were devoid of histologic lesions. Significant protection was measured in rats dosed once 0, 24, or 48 hours before light exposure. Protection provided by dosing with AL-8309B or 8-OH DPAT was inhibited in rats predosed with WAY-100635.CONCLUSIONS. 5-HT1A agonists provided potent and complete functional and structural protection. Protection was inhibited by treatment with WAY-100635, confirming the requirement for activating the 5-HT1A receptor in initiating this survival pathway. Single-dose experiments with AL-8309A suggest that the mechanism of protection is rapidly activated and protection persists for 48 hours. AL-8309B (1.75%) was effective after topical ocular dosing. AL-8309B is under evaluation in the clinic and may be useful in treating age-related macular degeneration. (Invest Ophthalmol Vis Sci. 2011;52:2118-2126) DOI:10.1167/iovs.106304