{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:14:42Z","timestamp":1791360882082,"version":"4.3.1"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Council of Science and Technology (NST), Republic of Korea","award":["GTL24022-000"],"award-info":[{"award-number":["GTL24022-000"]}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2022R1C1C1006068"],"award-info":[{"award-number":["NRF-2022R1C1C1006068"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Soonchunhyang University research fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Autophagy is a fundamental catabolic process that degrades and recycles intracellular components, serving as a key survival mechanism in neurons. In glaucomatous optic neuropathy, autophagy has been linked to both protection of retinal ganglion cells (RGCs) and their accelerated loss, yet its precise impact remains unresolved. In this study, we established and validated a straightforward rat model of retinal ischemia\/reperfusion (I\/R) using double circumlimbal sutures, which reliably produced RGC apoptosis, retinal thinning, and axonal degeneration compared with controls. Early after reperfusion (1\u20136 h), robust induction of the autophagy marker LC3B was observed, but this activation diminished within 48 h. Other autophagy-related proteins, including ATG4, ATG7, Beclin-1, and p62, followed similar temporal patterns, while components of the mammalian target of rapamycin (mTOR) pathway displayed an inverse time course. Pharmacologic suppression of mTOR with intravitreal rapamycin administered prior to ischemia provided the most significant neuroprotection, whereas post-injury treatment yielded minimal benefit. Collectively, these findings indicate that timely stimulation of autophagy before retinal ischemic injury can enhance RGC survival and may represent a therapeutic potential for glaucoma management.<\/jats:p>","DOI":"10.3390\/ijms27021031","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T14:57:58Z","timestamp":1768921078000},"page":"1031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enhanced Retinal Ganglion Cell Survival via Autophagy Activation in a Novel Retinal Ischemia\/Reperfusion Rat Model"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6383-4673","authenticated-orcid":false,"given":"Si Hyung","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, College of Medicine, Soonchunhyang University, 31, Suncheonhyang 6-gil, Dongnam-gu, Cheonan 33151, Republic of Korea"},{"name":"Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, 170, Jomaru-ro, Bucheon 14584, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Woo","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, College of Medicine, Soonchunhyang University, 31, Suncheonhyang 6-gil, Dongnam-gu, Cheonan 33151, Republic of Korea"},{"name":"Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, 170, Jomaru-ro, Bucheon 14584, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5355-7465","authenticated-orcid":false,"given":"Su-ah","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, 170, Jomaru-ro, Bucheon 14584, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4025-4182","authenticated-orcid":false,"given":"Hun Soo","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Program in Biomedical Science, Soonchunhyang Graduate School, Soonchunhyang University Hospital Bucheon, Bucheon 14584, Republic of Korea"},{"name":"Department of Microbiology, Soonchunhyang University College of Medicine, Cheonan 31151, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9689-4384","authenticated-orcid":false,"given":"Tae Kwann","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, College of Medicine, Soonchunhyang University, 31, Suncheonhyang 6-gil, Dongnam-gu, Cheonan 33151, Republic of Korea"},{"name":"Department of Ophthalmology, Soonchunhyang University Hospital Bucheon, 170, Jomaru-ro, Bucheon 14584, Republic of Korea"},{"name":"Laboratory of Molecular Therapy for Retinal Degeneration, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon 14584, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/ncb2788","article-title":"Emerging regulation and functions of autophagy","volume":"15","author":"Boya","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1172\/JCI73944","article-title":"Autophagy and neurodegeneration","volume":"125","author":"Frake","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4401","DOI":"10.1113\/jphysiol.2008.156695","article-title":"Retinal ganglion cells in diabetes","volume":"586","author":"Kern","year":"2008","journal-title":"J. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1167\/iovs.06-0510","article-title":"Retinal ischemia and reperfusion causes capillary degeneration: Similarities to diabetes","volume":"48","author":"Zheng","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/path.2858","article-title":"Retinal ganglion cell death is induced by microglia derived pro-inflammatory cytokines in the hypoxic neonatal retina","volume":"224","author":"Sivakumar","year":"2011","journal-title":"J. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/jpi.12016","article-title":"Neuroprotective effect of melatonin against hypoxia-induced retinal ganglion cell death in neonatal rats","volume":"54","author":"Kaur","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/S0140-6736(10)61423-7","article-title":"Glaucoma","volume":"377","author":"Quigley","year":"2011","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S1350-9462(02)00008-3","article-title":"The impact of ocular blood flow in glaucoma","volume":"21","author":"Flammer","year":"2002","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/s41419-018-1044-5","article-title":"Rapamycin and fasting sustain autophagy response activated by ischemia\/reperfusion injury and promote retinal ganglion cell survival","volume":"9","author":"Russo","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Su, W., Li, Z., Jia, Y., and Zhuo, Y. (2014). Rapamycin is neuroprotective in a rat chronic hypertensive glaucoma model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099719"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/cdd.2011.88","article-title":"Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice","volume":"19","author":"Germain","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1002\/jnr.21738","article-title":"Activation of autophagy in retinal ganglion cells","volume":"86","author":"Kim","year":"2008","journal-title":"J. Neurosci. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e290","DOI":"10.1038\/cddis.2012.26","article-title":"Activation of autophagy induces retinal ganglion cell death in a chronic hypertensive glaucoma model","volume":"3","author":"Park","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Piras, A., Gianetto, D., Conte, D., Bosone, A., and Vercelli, A. (2011). Activation of autophagy in a rat model of retinal ischemia following high intraocular pressure. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022514"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"476","DOI":"10.3892\/etm.2014.2084","article-title":"Activation of autophagy and paraptosis in retinal ganglion cells after retinal ischemia and reperfusion injury in rats","volume":"9","author":"Wei","year":"2015","journal-title":"Exp. Ther. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5767","DOI":"10.1038\/s41598-021-85181-x","article-title":"Characterization of the role of autophagy in retinal ganglion cell survival over time using a rat model of chronic ocular hypertension","volume":"11","author":"Lee","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3860","DOI":"10.1167\/iovs.08-3267","article-title":"Brn3a as a marker of retinal ganglion cells: Qualitative and quantitative time course studies in naive and optic nerve-injured retinas","volume":"50","author":"Agudo","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","first-page":"1387","article-title":"Evaluation of the percentage of ganglion cells in the ganglion cell layer of the rodent retina","volume":"19","author":"Schlamp","year":"2013","journal-title":"Mol. Vis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1167\/iovs.14-16009","article-title":"Chronic ocular hypertension induced by circumlimbal suture in rats","volume":"56","author":"Liu","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"He, Z., Zhao, D., van Koeverden, A.K., Nguyen, C.T., Lim, J.K.H., Wong, V.H.Y., Vingrys, A.J., and Bui, B.V. (2018). A Model of Glaucoma Induced by Circumlimbal Suture in Rats and Mice. J. Vis. Exp., 58287.","DOI":"10.3791\/58287-v"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Renner, M., Stute, G., Alzureiqi, M., Reinhard, J., Wiemann, S., Schmid, H., Faissner, A., Dick, H.B., and Joachim, S.C. (2017). Optic Nerve Degeneration after Retinal Ischemia\/Reperfusion in a Rodent Model. Front. Cell. Neurosci., 11.","DOI":"10.3389\/fncel.2017.00254"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhao, D., Nguyen, C.T., Wong, V.H., Lim, J.K., He, Z., Jobling, A.I., Fletcher, E.L., Chinnery, H.R., Vingrys, A.J., and Bui, B.V. (2017). Characterization of the Circumlimbal Suture Model of Chronic IOP Elevation in Mice and Assessment of Changes in Gene Expression of Stretch Sensitive Channels. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00041"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1167\/iovs.16-20576","article-title":"A Mouse Model of Chronic Ocular Hypertension Induced by Circumlimbal Suture","volume":"58","author":"Liu","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"108348","DOI":"10.1016\/j.exer.2020.108348","article-title":"Increased episcleral venous pressure in a mouse model of circumlimbal suture induced ocular hypertension","volume":"202","author":"Wong","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5466","DOI":"10.1167\/iovs.14-14380","article-title":"Retinal ischemia\/reperfusion injury is mediated by Toll-like receptor 4 activation of NLRP3 inflammasomes","volume":"55","author":"Qi","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Palmhof, M., Frank, V., Rappard, P., Kortenhorn, E., Demuth, J., Biert, N., Stute, G., Dick, H.B., and Joachim, S.C. (2019). From Ganglion Cell to Photoreceptor Layer: Timeline of Deterioration in a Rat Ischemia\/Reperfusion Model. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00174"},{"key":"ref_28","first-page":"2190","article-title":"The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice","volume":"118","author":"Pickford","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/jnen\/64.2.113","article-title":"Extensive involvement of autophagy in Alzheimer disease: An immuno-electron microscopy study","volume":"64","author":"Nixon","year":"2005","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17071","DOI":"10.1073\/pnas.1315110110","article-title":"Adaptor complex AP2\/PICALM, through interaction with LC3, targets Alzheimer\u2019s APP-CTF for terminal degradation via autophagy","volume":"110","author":"Tian","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1093\/brain\/awm318","article-title":"The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson\u2019s disease","volume":"131","author":"Pan","year":"2008","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1083\/jcb.201003122","article-title":"\u03b1-Synuclein impairs macroautophagy: Implications for Parkinson\u2019s disease","volume":"190","author":"Winslow","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_33","first-page":"1574","article-title":"The altered autophagy mediated by TFEB in animal and cell models of amyotrophic lateral sclerosis","volume":"7","author":"Chen","year":"2015","journal-title":"Am. J. Transl. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00401-013-1090-0","article-title":"Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: Genetics and neuropathology","volume":"125","author":"Teyssou","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.4161\/auto.7.12.18051","article-title":"Macroautophagy-generated increase of lysosomal amyloid \u03b2-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells","volume":"7","author":"Zheng","year":"2011","journal-title":"Autophagy"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.celrep.2013.08.042","article-title":"A\u03b2 secretion and plaque formation depend on autophagy","volume":"5","author":"Nilsson","year":"2013","journal-title":"Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"173369","DOI":"10.1016\/j.ejphar.2020.173369","article-title":"Topical administration of rapamycin promotes retinal ganglion cell survival and reduces intraocular pressure in a rat glaucoma model","volume":"884","author":"Wang","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/s42003-025-08314-2","article-title":"Differential regulation of mTOR activity in retinal ganglion cells underlies their distinct susceptibility to ischemia\/reperfusion","volume":"8","author":"Zhu","year":"2025","journal-title":"Commun. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.molcel.2010.09.026","article-title":"Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress","volume":"40","author":"Sengupta","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.3341\/jkos.2012.53.8.1150","article-title":"Neuroprotective Effect of Rapamycin in Optic Nerve Transection Model","volume":"53","author":"Kim","year":"2012","journal-title":"J. Korean Ophthalmol. Soc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1089\/hgtb.2013.089","article-title":"Laser photocoagulation enhances adeno-associated viral vector transduction of mouse retina","volume":"25","author":"Lee","year":"2014","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.omtm.2018.01.008","article-title":"Transduction Patterns of Adeno-associated Viral Vectors in a Laser-Induced Choroidal Neovascularization Mouse Model","volume":"9","author":"Lee","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/1031\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T05:12:40Z","timestamp":1769058760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/1031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27021031"],"URL":"https:\/\/doi.org\/10.3390\/ijms27021031","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}