PMID- 37019993 OWN - NLM STAT- MEDLINE DCOM- 20230407 LR - 20230420 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 13 IP - 1 DP - 2023 Apr 5 TI - Aldose reductase inhibition decelerates optic nerve degeneration by alleviating retinal microglia activation. PG - 5592 LID - 10.1038/s41598-023-32702-5 [doi] LID - 5592 AB - As part of the central nervous system (CNS), retinal ganglion cells (RGCs) and their axons are the only neurons in the retina that transmit visual signals from the eye to the brain via the optic nerve (ON). Unfortunately, they do not regenerate upon injury in mammals. In ON trauma, retinal microglia (RMG) become activated, inducing inflammatory responses and resulting in axon degeneration and RGC loss. Since aldose reductase (AR) is an inflammatory response mediator highly expressed in RMG, we investigated if pharmacological inhibition of AR can attenuate ocular inflammation and thereby promote RGC survival and axon regeneration after ON crush (ONC). In vitro, we discovered that Sorbinil, an AR inhibitor, attenuates BV2 microglia activation and migration in the lipopolysaccharide (LPS) and monocyte chemoattractant protein-1 (MCP-1) treatments. In vivo, Sorbinil suppressed ONC-induced Iba1 + microglia/macrophage infiltration in the retina and ON and promoted RGC survival. Moreover, Sorbinil restored RGC function and delayed axon degeneration one week after ONC. RNA sequencing data revealed that Sorbinil protects the retina from ONC-induced degeneration by suppressing inflammatory signaling. In summary, we report the first study demonstrating that AR inhibition transiently protects RGC and axon from degeneration, providing a potential therapeutic strategy for optic neuropathies. CI - (c) 2023. The Author(s). FAU - Rao, Mishal AU - Rao M AD - Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, 203 Lothrop, Pittsburgh, PA, 15213, USA. FAU - Huang, Yu-Kai AU - Huang YK AD - Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. AD - Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan. AD - Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, 80145, Taiwan. FAU - Liu, Chia-Chun AU - Liu CC AD - Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, 203 Lothrop, Pittsburgh, PA, 15213, USA. FAU - Meadows, Chandler AU - Meadows C AD - Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, 203 Lothrop, Pittsburgh, PA, 15213, USA. FAU - Cheng, Hui-Chun AU - Cheng HC AD - Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, 203 Lothrop, Pittsburgh, PA, 15213, USA. FAU - Zhou, Mengli AU - Zhou M AD - Department of Computational and Systems Biology, Hillman Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15260, USA. FAU - Chen, Yu-Chih AU - Chen YC AD - Department of Computational and Systems Biology, Hillman Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15260, USA. FAU - Xia, Xin AU - Xia X AD - Spencer Center for Vision Research, Byers Eye Institute, School of Medicine, Stanford University, Palo Alto, CA, 94304, USA. FAU - Goldberg, Jeffrey L AU - Goldberg JL AD - Spencer Center for Vision Research, Byers Eye Institute, School of Medicine, Stanford University, Palo Alto, CA, 94304, USA. FAU - Williams, Andrew M AU - Williams AM AD - Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, 203 Lothrop, Pittsburgh, PA, 15213, USA. FAU - Kuwajima, Takaaki AU - Kuwajima T AD - Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, 203 Lothrop, Pittsburgh, PA, 15213, USA. FAU - Chang, Kun-Che AU - Chang KC AD - Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, 203 Lothrop, Pittsburgh, PA, 15213, USA. kcchang@pitt.edu. AD - Department of Neurobiology, Center of Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. kcchang@pitt.edu. AD - Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. kcchang@pitt.edu. LA - eng GR - P30 EY026877/EY/NEI NIH HHS/United States GR - R01 EY032416/EY/NEI NIH HHS/United States GR - P30 EY008098/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230405 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - EC 1.1.1.21 (Aldehyde Reductase) SB - IM MH - Animals MH - Microglia MH - Axons/physiology MH - Aldehyde Reductase MH - Nerve Regeneration MH - Retina MH - *Optic Nerve Injuries/pathology MH - *Optic Atrophy/pathology MH - Nerve Degeneration/pathology MH - Mammals PMC - PMC10076364 COIS- The authors declare no competing interests. EDAT- 2023/04/06 06:00 MHDA- 2023/04/07 06:42 PMCR- 2023/04/05 CRDT- 2023/04/05 23:20 PHST- 2022/11/22 00:00 [received] PHST- 2023/03/31 00:00 [accepted] PHST- 2023/04/07 06:42 [medline] PHST- 2023/04/05 23:20 [entrez] PHST- 2023/04/06 06:00 [pubmed] PHST- 2023/04/05 00:00 [pmc-release] AID - 10.1038/s41598-023-32702-5 [pii] AID - 32702 [pii] AID - 10.1038/s41598-023-32702-5 [doi] PST - epublish SO - Sci Rep. 2023 Apr 5;13(1):5592. doi: 10.1038/s41598-023-32702-5.