Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
Invest Ophthalmol Vis Sci. 2019 Jul 1;60(8):3046-3053. doi: 10.1167/iovs.19-27241.
Accumulation of lysosomal waste is linked to neurodegeneration in multiple diseases, and pharmacologic enhancement of lysosomal activity is hypothesized to reduce pathology. An excessive accumulation of lysosomal-associated lipofuscin waste and an elevated lysosomal pH occur in retinal pigment epithelial cells of the ABCA4-/- mouse model of Stargardt's retinal degeneration. As treatment with the P2Y12 receptor antagonist ticagrelor was previously shown to lower lysosomal pH and lipofuscin-like autofluorescence in these cells, we asked whether oral delivery of ticagrelor also prevented photoreceptor loss.
Moderate light exposure was used to accelerate photoreceptor loss in albino ABCA4-/- mice as compared to BALB/c controls. Ticagrelor (0.1%-0.15%) was added to mouse chow for between 1 and 10 months. Photoreceptor function was determined with electroretinograms, while cell survival was determined using optical coherence tomography and histology.
Protection by ticagrelor was demonstrated functionally by using the electroretinogram, as ticagrelor-treated ABCA4-/- mice had increased a- and b-waves compared to untreated mice. Mice receiving ticagrelor treatment had a thicker outer nuclear layer, as measured with both optical coherence tomography and histologic sections. Ticagrelor decreased expression of LAMP1, implicating enhanced lysosomal function. No signs of retinal bleeding were observed after prolonged treatment with ticagrelor.
Oral treatment with ticagrelor protected photoreceptors in the ABCA4-/- mouse, which is consistent with enhanced lysosomal function. As mouse ticagrelor exposure levels were clinically relevant, the drug may be of benefit in preventing the loss of photoreceptors in Stargardt's disease and other neurodegenerations associated with lysosomal dysfunction.
溶酶体废物的积累与多种疾病的神经退行性变有关，人们假设通过药理学增强溶酶体活性可以减少病变。在 ABCA4-/- 型斯塔加特氏视网膜变性的小鼠模型的视网膜色素上皮细胞中，会出现溶酶体相关脂褐素废物的过度积累和溶酶体 pH 值升高。先前的研究表明，P2Y12 受体拮抗剂替卡格雷洛可以降低这些细胞中的溶酶体 pH 值和脂褐素样自发荧光，因此我们想知道替卡格雷洛的口服给药是否也能防止光感受器的丧失。
与 BALB/c 对照相比，中度光暴露用于加速白化 ABCA4-/- 小鼠的光感受器丧失。替卡格雷洛（0.1%-0.15%）被添加到老鼠的饲料中，持续 1 到 10 个月。使用视网膜电图来确定光感受器的功能，而使用光学相干断层扫描和组织学来确定细胞存活。
替卡格雷洛通过使用视网膜电图来证明其保护作用，因为与未治疗的小鼠相比，替卡格雷洛治疗的 ABCA4-/- 小鼠的 a-和 b-波增加。接受替卡格雷洛治疗的小鼠的外核层较厚，这一点通过光学相干断层扫描和组织学切片都可以测量到。替卡格雷洛降低了 LAMP1 的表达，暗示了增强的溶酶体功能。在长期使用替卡格雷洛治疗后，没有观察到视网膜出血的迹象。
替卡格雷洛的口服治疗保护了 ABCA4-/- 小鼠的光感受器，这与增强的溶酶体功能一致。由于替卡格雷洛在小鼠体内的暴露水平与临床相关，因此该药物可能有助于预防斯塔加特氏病和其他与溶酶体功能障碍相关的神经退行性疾病中光感受器的丧失。
