Department of Ophthalmology and Vision Science, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China.
NHC Key Laboratory of Myopia (Fudan University), Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.
Invest Ophthalmol Vis Sci. 2019 Jan 2;60(1):407-419. doi: 10.1167/iovs.18-25572.
Our study aimed to evaluate the side effects of selective serotonin reuptake inhibitors (SSRIs) on the ocular surface.
Twenty patients with depression and dry eye disease (DED) were randomly picked to receive SSRI treatment, whereas another 20 patients received placebo treatment. The serotonin, inflammatory cytokine, and proapoptotic protein levels were determined by using protein chip, qRT-PCR, and ELISA analyses. A rat depression model was established, and SSRIs were applied for 3 or 6 weeks. Tear production and corneal epithelial barrier function were evaluated. The serotonin and inflammatory cytokine levels were analyzed by qRT-PCR, immunohistochemical staining, and ELISA. Human corneal epithelial cells were subjected to serotonin, a HTR antagonist, and/or an NF-κB signaling inhibitor. The inflammatory cytokine and proapoptotic protein levels were determined by qRT-PCR, Western blot analysis, and ELISA. The cell apoptosis rate was assessed by using flow cytometry.
The SSRI group had higher tear serotonin levels and more serious inflammation and cell apoptosis on the ocular surface. In the rat depression model, depression decreased tear secretion and increased IL-1β and TNF-α production, whereas the serotonin, TLR2, and TLR4 levels were not increased. SSRI aggravated DED, disrupted the corneal epithelial barrier, and promoted an inflammatory response on the ocular surface by increasing the tear serotonin levels. In addition, serotonin induced an inflammatory response and cell apoptosis in corneal epithelial cells by activating NF-κB signaling.
SSRIs aggravate depression-associated DED via activating the NF-κB pathway. The antagonist of HTRs or the inhibitor of NF-κB signaling presents a potential therapeutic strategy for depression-associated DED. (Trial registration number, ChiCTR1800015592).
本研究旨在评估选择性 5-羟色胺再摄取抑制剂（SSRIs）对眼表的副作用。
随机抽取 20 例抑郁症合并干眼症（DED）患者接受 SSRIs 治疗，另 20 例患者接受安慰剂治疗。采用蛋白芯片、qRT-PCR 和 ELISA 分析检测血清素、炎症细胞因子和促凋亡蛋白水平。建立大鼠抑郁模型，应用 SSRIs 治疗 3 或 6 周。评估泪液生成和角膜上皮屏障功能。通过 qRT-PCR、免疫组化染色和 ELISA 分析血清素和炎症细胞因子水平。将人角膜上皮细胞暴露于血清素、5-羟色胺受体拮抗剂和/或 NF-κB 信号通路抑制剂。通过 qRT-PCR、Western blot 分析和 ELISA 测定炎症细胞因子和促凋亡蛋白水平。采用流式细胞术评估细胞凋亡率。
SSRI 组眼表泪液中血清素水平较高，炎症和细胞凋亡更为严重。在大鼠抑郁模型中，抑郁导致泪液分泌减少，IL-1β和 TNF-α生成增加，而血清素、TLR2 和 TLR4 水平没有增加。SSRI 通过增加泪液中血清素水平加重 DED，破坏角膜上皮屏障，并在眼表引发炎症反应。此外，血清素通过激活 NF-κB 信号通路诱导角膜上皮细胞炎症反应和细胞凋亡。
SSRIs 通过激活 NF-κB 通路加重与抑郁相关的 DED。5-羟色胺受体拮抗剂或 NF-κB 信号通路抑制剂可能为与抑郁相关的 DED 提供潜在的治疗策略。（注册号，ChiCTR1800015592）。
