Ucf-101 Alleviates Ischaemia/Reperfusion Induced Retinal Inflammation and Injury Via Suppressing Oxidative Damage

Overview

Journal J Mol Histol

Specialty Biochemistry

Date 2024 Jun 14

PMID 38877338

Authors

Yuan-Jun Qin

Guangyi Huang

Jing Liao

Li Jiang

Fen Tang

Ningning Tang

Yiyi Hong

Chaolan Shen

Qianqian Lan

Fan Xu

Lifei Chen

Affiliations

Soon will be listed here.

Abstract

The Omi/HtrA2 inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (Ucf-101) has shown neuroprotective effects in the central nervous system. However, whether Ucf-101 can protect retinal ganglion cells (RGCs) after retinal ischemia/reperfusion (IR) has not been investigated. We aimed to investigate the effects of Ucf-101 on RGCs apoptosis and inflammation after IR-induced retinal injury in mice. We injected Ucf-101 into the mouse vitreous body immediately after IR injury. After 7 days, hematoxylin and eosin staining was conducted to assess retinal tissue damage. Next, retrograde labeling with FluoroGold, counting of RGCs and TUNEL staining were conducted to evaluate apoptosis. Immunohistochemistry, immunofluorescence staining, and western blotting were conducted to analyze protein levels. IR injury-induced retinal tissue damage could be prevented by Ucf-101 treatment. The number of TUNEL-positive RGCs was reduced by Ucf-101 treatment in mice with IR injury. Ucf-101 treatment inhibited the upregulation of Bax, cleaved caspase-3 and cleaved caspase-9 and activated the JNK/ERK/P38 signaling pathway. Furthermore, Ucf-101 treatment inhibited the upregulation of glial fibrillary acidic protein (GFAP), vimentin, Iba1 and CD68 in mice with IR injury. Ucf-101 prevents retinal tissue damage, improves the survival of RGCs, and suppresses microglial overactivation after IR injury. Ucf-101 might be a potential target to prevent RGCs apoptosis and inflammation in neurodegenerative eye diseases.

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References

Almasieh M, Wilson A, Morquette B, Cueva Vargas J, Di Polo A . The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res. 2011; 31(2):152-81. DOI: 10.1016/j.preteyeres.2011.11.002. View

Chu X, Wang C, Wu Z, Fan L, Tao C, Lin J . JNK/c-Jun-driven NLRP3 inflammasome activation in microglia contributed to retinal ganglion cells degeneration induced by indirect traumatic optic neuropathy. Exp Eye Res. 2020; 202:108335. DOI: 10.1016/j.exer.2020.108335. View

Davies M, Eubanks J, Powers M . Microglia and macrophages are increased in response to ischemia-induced retinopathy in the mouse retina. Mol Vis. 2006; 12:467-77. View

Ding X, Patel M, Shen D, Herzlich A, Cao X, Villasmil R . Enhanced HtrA2/Omi expression in oxidative injury to retinal pigment epithelial cells and murine models of neurodegeneration. Invest Ophthalmol Vis Sci. 2009; 50(10):4957-66. PMC: 2903625. DOI: 10.1167/iovs.09-3381. View

Du Y, Yang D, Dong X, Du Q, Wang D, Shen Y . Omi inhibition ameliorates neuron apoptosis and neurological deficit after subarachnoid hemorrhage in rats. Genes Genomics. 2021; 43(12):1423-1432. PMC: 8606397. DOI: 10.1007/s13258-021-01176-y. View

Dvoriantchikova G, Ivanov D . Tumor necrosis factor-alpha mediates activation of NF-κB and JNK signaling cascades in retinal ganglion cells and astrocytes in opposite ways. Eur J Neurosci. 2014; 40(8):3171-8. PMC: 4205188. DOI: 10.1111/ejn.12710. View

Hu Y, Bi Y, Yao D, Wang P, Li Y . Omi/HtrA2 Protease Associated Cell Apoptosis Participates in Blood-Brain Barrier Dysfunction. Front Mol Neurosci. 2019; 12:48. PMC: 6395387. DOI: 10.3389/fnmol.2019.00048. View

Kilic E, Hermann D, Isenmann S, Bahr M . Effects of pinealectomy and melatonin on the retrograde degeneration of retinal ganglion cells in a novel model of intraorbital optic nerve transection in mice. J Pineal Res. 2002; 32(2):106-11. DOI: 10.1034/j.1600-079x.2002.1823.x. View

Li N, Li Y, Duan X . Heat shock protein 72 confers protection in retinal ganglion cells and lateral geniculate nucleus neurons via blockade of the SAPK/JNK pathway in a chronic ocular-hypertensive rat model. Neural Regen Res. 2014; 9(14):1395-401. PMC: 4160872. DOI: 10.4103/1673-5374.137595. View

10.

Lucotte B, Tajhizi M, Alkhatib D, Samuelsson E, Wiehager B, Schedin-Weiss S . Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells. Mol Neurobiol. 2014; 52(3):1077-1092. DOI: 10.1007/s12035-014-8906-3. View

11.

Luo H, Zhuang J, Hu P, Ye W, Chen S, Pang Y . Resveratrol Delays Retinal Ganglion Cell Loss and Attenuates Gliosis-Related Inflammation From Ischemia-Reperfusion Injury. Invest Ophthalmol Vis Sci. 2018; 59(10):3879-3888. DOI: 10.1167/iovs.18-23806. View

12.

Ma Q, Hu Q, Xu R, Zhen X, Wang G . Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1. Acta Pharmacol Sin. 2015; 36(8):966-75. PMC: 4564885. DOI: 10.1038/aps.2015.48. View

13.

Matei N, Leahy S, Blair N, Shahidi M . Assessment of retinal oxygen metabolism, visual function, thickness and degeneration markers after variable ischemia/reperfusion in rats. Exp Eye Res. 2021; 213:108838. PMC: 8665131. DOI: 10.1016/j.exer.2021.108838. View

14.

Nakano Y, Hirooka K, Chiba Y, Ueno M, Ojima D, Hossain M . Retinal ganglion cell loss in kinesin-1 cargo Alcadein α deficient mice. Cell Death Dis. 2020; 11(3):166. PMC: 7054276. DOI: 10.1038/s41419-020-2363-x. View

15.

Nakka V, Gusain A, Mehta S, Raghubir R . Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. Mol Neurobiol. 2007; 37(1):7-38. DOI: 10.1007/s12035-007-8013-9. View

16.

Pang I, Clark A . Inducible rodent models of glaucoma. Prog Retin Eye Res. 2019; 75:100799. PMC: 7085984. DOI: 10.1016/j.preteyeres.2019.100799. View

17.

Qin Y, Xiao K, Zhong Z, Zhao Y, Zhang Y, Sun X . Markers of the sympathetic, parasympathetic and sensory nervous system are altered in the human diabetic choroid. Peptides. 2021; 146:170661. DOI: 10.1016/j.peptides.2021.170661. View

18.

Qin Y, Xiao K, Zhong Z, Zhao Y, Yu T, Sun X . LECT2 Ameliorates Blood-Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway. Invest Ophthalmol Vis Sci. 2022; 63(3):7. PMC: 8934553. DOI: 10.1167/iovs.63.3.7. View

19.

Renner M, Stute G, Alzureiqi M, Reinhard J, Wiemann S, Schmid H . Optic Nerve Degeneration after Retinal Ischemia/Reperfusion in a Rodent Model. Front Cell Neurosci. 2017; 11:254. PMC: 5572359. DOI: 10.3389/fncel.2017.00254. View

20.

Risner M, Pasini S, McGrady N, Calkins D . Bax Contributes to Retinal Ganglion Cell Dendritic Degeneration During Glaucoma. Mol Neurobiol. 2022; 59(3):1366-1380. PMC: 8882107. DOI: 10.1007/s12035-021-02675-5. View