Alcon Research, Ltd., Fort Worth, Texas 76134-2099, USA.
Invest Ophthalmol Vis Sci. 2011 Apr 4;52(5):2118-26. doi: 10.1167/iovs.10-6304.
5-HT(1A) agonists are neuroprotective in CNS injury models. The authors evaluated the efficacy of 5-HT(1A) agonists to protect the retina from severe blue light-induced photo-oxidative damage.
Albino rats were dosed (subcutaneously) with AL-8309A, 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-HT(1A) antagonist, to determine whether protection required activation of the 5-HT(1A) receptor.
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.
5-HT(1A) agonists provided potent and complete functional and structural protection. Protection was inhibited by treatment with WAY-100635, confirming the requirement for activating the 5-HT(1A) 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.
5-HT（1A）激动剂在中枢神经系统损伤模型中具有神经保护作用。作者评估了 5-HT（1A）激动剂保护视网膜免受严重蓝光诱导的光氧化损伤的功效。
白化大鼠在暴露于蓝光前 6 小时，单次或三次皮下给予 AL-8309A、8-OH DPAT 或丁螺环酮。通过视网膜电图（ERG）评估视网膜功能，并通过光镜评估视网膜损伤。还评估了眼部局部滴注 1.75%AL-8309B 的效果。大鼠给予 WAY-100635，一种 5-HT（1A）拮抗剂，以确定保护是否需要激活 5-HT（1A）受体。
与暴露于蓝光的载体处理大鼠相比，ERG 反应幅度显著（P<0.05）降低了 66%以上。AL-8309A（0.1-30mg/kg）、8-OH DPAT（0.1-1mg/kg）、丁螺环酮（5-20mg/kg）或局部眼部滴注 1.75%AL-8309B 处理的大鼠的 ERG 显著升高。AL-8309A 和 8-OH DPAT 处理的大鼠的视网膜没有组织学病变。在暴露于蓝光前 0、24 或 48 小时单次给药的大鼠中测量到显著的保护作用。在用 WAY-100635 预给药的大鼠中，AL-8309B 或 8-OH DPAT 给药提供的保护作用被抑制。
5-HT（1A）激动剂提供了强大而完全的功能和结构保护。用 WAY-100635 治疗抑制了保护作用，证实了在启动这种存活途径时激活 5-HT（1A）受体的必要性。AL-8309A 的单次剂量实验表明，保护机制迅速激活，保护作用持续 48 小时。局部眼部滴注 1.75%AL-8309B 有效。AL-8309B 正在临床评估中，可能对治疗年龄相关性黄斑变性有用。
