2,3,5,6-Tetramethylpyrazine protects retinal photoreceptors against endoplasmic reticulum stress by modulating ATF4-mediated inhibition of PRP aggregation
2,3,5,6-Tetramethylpyrazine protects retinal photoreceptors against endoplasmic reticulum stress by modulating ATF4-mediated inhibition of PRP aggregation
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2,3,5,6-Tetramethylpyrazine 通过调节 ATF4 介导的 PRP 聚集抑制来保护视网膜感光细胞免受内质网应激
DOI：
10.1007/s00109-020-02017-3
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Huangxuan Shen
中科院分区：
文献类型：
--
作者：
Hao Huang;Xiaobo Zhu;Hao Cheng;Xielan Kuang;Chongde Long;Xizhi Deng;Yuxiu Zou;Han Zhang;Yue Xing;Xiangtian Ling;Renchun Wang;Han Tang;Han Du;Kangpei Shi;Lei Wang;Jianhua Yan;Huangxuan Shen
Endoplasmic reticulum (ER) stress is a common threat to photoreceptors during the pathogenesis of chronic retinopathies and often results in irreversible visual impairment. 2,3,5,6-Tetramethylpyrazine (TMP), which possesses many beneficial pharmacological activities, is a potential drug that could be used to protect photoreceptors. In the present study, we found that the cellular growth rate of 661 W cells cultured under low glucose conditions was lower than that of control cells, while the G2/M phase of the cell cycle was longer. We further found that the mitochondrial membrane potential (ΔΨm) was lower and that ER stress factor expression was increased in 661 W cells cultured under low glucose conditions. TMP reversed these trends. Visual function and cell counts in the outer nuclear layer (ONL) were low and the TUNEL-positive rate in the ONL was high in a C3H mouse model of spontaneous retinal degeneration. Similarly, visual function was decreased, and the TUNEL-positive rate in the ONL was increased in fasted C57/BL6j mice compared with control mice. On the other hand, ER stress factor expression was found to be increased in the retinas of both mouse models, as shown by reverse transcription real-time PCR (RT-qPCR) and western blotting. TMP reversed the physiological and molecular biological variations observed in both mouse models, and ATF4 expression was enhanced again. Further investigation by using western blotting illustrated that the proportion of insoluble prion protein (PRP) versus soluble PRP was reduced both in vitro and in vivo. Taken together, these results suggest that TMP increased the functions of photoreceptors by alleviating ER stress in vitro and in vivo, and the intrinsic mechanism was the ATF4-mediated inhibition of PRP aggregation. TMP may potentially be used clinically as a therapeutic agent to attenuate the functional loss of photoreceptors during the pathogenesis of chronic retinopathies. KEY MESSAGES: • Already known: TMP is a beneficial drug mainly used in clinic to enhance organ functions, and the intrinsic mechanism is still worthy of exploring. • New in the study: We discovered that TMP ameliorated retinal photoreceptors function via ER stress alleviation, which was promoted by ATF4-mediated inhibition of PRP aggregation. • Application prospect: In prospective clinical practices, TMP may potentially be used in the clinic as a therapeutic agent to attenuate the photoreceptors functional reduction in chronic retinopathies.
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DOI：
10.1136/bmj.323.7318.879
发表时间：
2001-10
期刊：
BMJ : British Medical Journal
影响因子：
--
作者：
R. Kale
通讯作者：
R. Kale
影响因子：
5.6
作者：
Zhu X;Wang K;Zhang K;Tan X;Wu Z;Sun S;Zhou F;Zhu L
通讯作者：
Zhu L
影响因子：
17.8
作者：
Organisciak, Daniel T.;Vaughan, Dana K.
通讯作者：
Vaughan, Dana K.
全反式视网膜通过氧化应激和内质网应激途径诱导人视网膜色素上皮细胞自噬细胞死亡
影响因子：
3.5
作者：
Zhang Lingmin;Zhou Yingying;Xia Qingqing;Chen Ying;Li Jie
通讯作者：
Li Jie
影响因子：
17.8
作者：
Zhang, Sarah X.;Ma, Jacey H.;Bhatta, Maulasri;Fliesler, Steven J.;Wang, Joshua J.
通讯作者：
Wang, Joshua J.