Nuclear factor erythroid 2-related factor 2 agonist protects retinal ganglion cells in glutamate excitotoxicity retinas

Yaqiong An; Haibo Li; Mengxiao Wang; Zhaohua Xia; Lexi Ding; Xiaobo Xia

doi:10.1016/j.biopha.2022.113378

Nuclear factor erythroid 2-related factor 2 agonist protects retinal ganglion cells in glutamate excitotoxicity retinas

Biomed Pharmacother. 2022 Sep:153:113378. doi: 10.1016/j.biopha.2022.113378. Epub 2022 Jul 13.

Authors

Yaqiong An¹, Haibo Li¹, Mengxiao Wang¹, Zhaohua Xia¹, Lexi Ding², Xiaobo Xia³

Affiliations

¹ Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
² Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: lexiding@csu.edu.cn.
³ Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: xbxia21@csu.edu.cn.

PMID: 36076474
DOI: 10.1016/j.biopha.2022.113378

Abstract

Objective: To investigate whether tert-Butylhydroquinone (TBHQ) can ameliorate oxidative stress and inflammation induced by glutamate excitotoxicity, and mediate retinal ganglion cell (RGC) damage by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and inhibiting the nuclear factor kappa B (NF-κB) signaling pathway.

Materials and methods: TBHQ was used to treat a glutamate excitotoxicity model of retinal cell line 28 and C57 mice. Damage to RGCs and visual function were assessed using flash visual evoked potential (FVEP), immunofluorescence, propidium iodide staining, and hematoxylin and eosin staining. Knockdown of Nrf2 used Nrf2 shRNA. The expression levels of related proteins were detected using western blot and immunofluorescence.

Results: Glutamate excitotoxicity down-regulated Nrf2 expression in vitro and in vivo. Nuclear factor erythroid2-related factor 2 activation by TBHQ reduced the damage to retinal ganglion cells, reduced the thinning of the whole retina and the ganglion cell complex, and shortened the latency of the FVEP forward wave after injury. In addition, the levels of NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase 1 (HO-1), and Nrf2 increased significantly, and those of cyclooxygenase-2 (COX2) and NF-κB decreased significantly, after TBHQ treatment. Compared with TBHQ treatment group, the expression level of p-p65 in shRNA transfected group was increased, but still lower than that in Glu group.

Conclusion: The protective effect of TBHQ on RGC loss under glutamate excitotoxicity might be related to the activation of the Nrf2 signaling pathway, anti-oxidative stress, inhibition of NF-κB activation, and inhibition of retinal inflammation. Thus, TBHQ might be used to treat glutamate excitotoxicity -related retinopathy.

Keywords: Glutamate excitotoxicity; NF-κB; Neuroprotection; Nrf2; Retinal ganglion cell; TBHQ.

MeSH terms

Animals
Evoked Potentials, Visual
Glutamic Acid / toxicity
Heme Oxygenase-1 / metabolism
Inflammation
Mice
NF-E2-Related Factor 2* / metabolism
NF-kappa B
RNA, Small Interfering
Retinal Ganglion Cells* / metabolism

Substances

NF-E2-Related Factor 2
NF-kappa B
Nfe2l2 protein, mouse
RNA, Small Interfering
Glutamic Acid
Heme Oxygenase-1