Protective Effects of Trimetazidine in Retarding Selenite-Induced Lens Opacification

ABSTRACT

Purpose: Cataracts are the leading cause of vision loss worldwide, and the over-production of reactive oxygen species (ROS) is the foremost underlying cause of cataracts. Reducing ROS levels can efficiently prevent lens opacification, as evidenced by many studies. Here, we inhibited ROS overproduction with trimetazidine (TMZ), which is an antioxidant, to explore the therapeutic effects of TMZ and the mechanism of lens opacification.

Materials and methods: Sodium selenite-induced cataract formation resulted in a significant loss of lens transparency. This effect could be efficiently rescued by TMZ, which was further found to be an inhibitor of ROS production, as determined by assaying oxidative stress-related parameters (SOD activity, MDA, ·OH and H₂O₂ levels) during cataract formation. The experimental protocols involving animal research were approved by the Animal Care and Ethics Committee of Wenzhou Medical University and conducted according to the Association for Research in Vision and Ophthalmology under the guidelines of the Animal Welfare Act (SYXK 2015–0009).

Results: Our study found that TMZ can retard the onset and progression of lens opacification in vivo in experiments using Sprague-Dawley (SD) suckling rats and can rescue the morphology of HLEB₃ cells in vitro. The flow cytometry and DNA fragmentation assays showed that TMZ could prevent sodium selenite-induced apoptosis. The western blot analysing showed that the levels of apoptosis-associated Bcl-2 and Nrf2 were dramatically decreased following the sodium selenite treatment. In addition, the bisulfate DNA sequencing revealed that the demethylation of CpGs in the promoter region of Keap1 was stimulated, and that this demethylation could be inhibited by TMZ by rescuing the Nrf2 expression level.

Conclusions: Our findings indicate that the antioxidant TMZ strongly reduces ROS production, which ultimately delays the progression of cataract formation, suggesting that treatment with TMZ represents a novel, promising antioxidant protection to retard cataract formation.

KEYWORDS:

• Cataract
• Trimetazidine (TMZ)
• reactive oxygen species
• Keap1/Nrf2 pathway

Acknowledgments

We thank Bang Wang (School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University), Yufei Wang (School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University), Fanfan Li, and Jie Liu(School of The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou Medical University).

Author Contributions

Conceptualization: Feng Gu and, Yihua Zhu.

Data curation: Feng Gu.

Formal analysis: Feng Gu and, Yihua Zhu.

Funding acquisition: Feng Gu and, Yihua Zhu.

Investigation: Weifang Fang, Qin Ye, Yihua Yao, Feng Gu, and Yihua Zhu.

Methodology: Weifang Fang, Qin Ye, Yihua Yao, Feng Gu, and Yihua Zhu.

Project administration: Feng Gu and, Yihua Zhu

Resources: Feng Gu and, Yihua Zhu.

Software: Weifang Fang.

Supervision: Feng Gu and, Yihua Zhu.

Validation: Weifang Fang, Qin Ye, and Yihua Yao.

Visualization: Weifang Fang.

Writing – original draft: Weifang Fang, Feng Gu, and Yihua Zhu.

Writing – review and editing: Weifang Fang, Feng Gu, and Yihua Zhu.

Declaration of interest

The authors have no conflicts of interest to report. The authors alone are responsible for the content and writing of the paper.

Supplementary material

Supplymental data for this article can be accessed here.

Additional information

Funding

This work was supported by grants from the Natural Science Foundation of China [81270999/H1204, YHZ, http://www.nsfc.gov.cn/]; the Professor Academic Development Fund of Fujian Medical University [JS14019, YHZ, http://www.nsfc.gov.cn/]; the Chinese National Program on Key Basic Research Project [973 Program, 2013CB967502,FG, http://program.most.gov.cn/]; the Natural Science Foundation of China [81201181/H1818, FG, http://www.nsfc.gov.cn/]; Zhejiang Provincial and Ministry of Health research fund for medical sciences [201339279, FG, http://www.zjkjt.gov.cn/]; and Wenzhou Medical University PI Start-Up Grant [QTJ12011, FG, http://www.wmu.edu.cn/].