Tao Ye, Hu Bang, Ma Zhao, Li Haijun, Du Enming, Wang Gang, Xing Biao, Ma Jie, Song Zongming
Department of Ophthalmology, People's hospital of Zhengzhou University, Zhengzhou, PR China.
Department of physiology and neuroscience, Basic college of medicine, Zhengzhou University Zhengzhou, PR China.
Drug Deliv. 2020 Dec;27(1):1386-1396. doi: 10.1080/10717544.2020.1818882.
Intravitreal delivery can maximize the intensity of therapeutic agents and extend their residence time within ocular tissue. Melatonin is a lipophilic molecule that crosses freely biological barriers and cell membranes. This study intends to investigate the effects of intravitreally delivered melatonin on mouse retina. The visual function of administered mice is assessed by electrophysiological and behavior examinations three weeks after intravitreal delivery. Moreover, multi-electrode array (MEA) was used to assess the electrical activities of retinal ganglion cells (RGCs). We found that intravitreal delivery of high dosage melatonin (400-500 µg/kg) destroyed the retinal architecture and impaired the visual function of mice. Conversely, the melatonin administration at low dose (100-300 µg/kg) did not have any significant effects on the photoreceptor survival or visual function. As shown in the MEA recording, the photoreceptors activity of the central region was more severely disturbed by the high dose melatonin. A pronounced augment of the spontaneous firing frequency was recorded in these mice received high dosage melatonin, indicating that intravitreal delivery of high dosage melatonin would affect the electrical activity of RGCs. Immunostaining assay showed that the vitality of cone photoreceptor was impaired by high dose melatonin. These findings suggest that intravitreal melatonin is not always beneficial for ocular tissues, especially when it is administered at high dosage. These data add new perspectives to current knowledge about melatonin delivery at the ocular level. Further therapeutic strategies should take into consideration of these risks that caused by delivery approach.
玻璃体内给药可使治疗药物的浓度最大化，并延长其在眼组织内的停留时间。褪黑素是一种亲脂性分子，可自由穿过生物屏障和细胞膜。本研究旨在探讨玻璃体内注射褪黑素对小鼠视网膜的影响。在玻璃体内给药三周后，通过电生理和行为学检查评估给药小鼠的视觉功能。此外，使用多电极阵列（MEA）评估视网膜神经节细胞（RGC）的电活动。我们发现，玻璃体内注射高剂量褪黑素（400 - 500μg/kg）会破坏视网膜结构并损害小鼠的视觉功能。相反，低剂量（100 - 300μg/kg）的褪黑素给药对光感受器存活或视觉功能没有任何显著影响。如MEA记录所示，高剂量褪黑素对中央区域的光感受器活动干扰更严重。在接受高剂量褪黑素的这些小鼠中记录到自发放电频率明显增加，表明玻璃体内注射高剂量褪黑素会影响RGC的电活动。免疫染色分析表明，高剂量褪黑素会损害视锥光感受器的活力。这些发现表明，玻璃体内注射褪黑素对眼组织并非总是有益的，尤其是在高剂量给药时。这些数据为当前关于眼内褪黑素给药的知识增添了新的视角。进一步的治疗策略应考虑到给药方式所带来的这些风险。
