{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:54:39Z","timestamp":1791222879088,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T00:00:00Z","timestamp":1724371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Rotenone is a mitochondrial complex I inhibitor that causes retinal degeneration. A study of a rat model of rotenone-induced retinal degeneration suggested that this model is caused by indirect postsynaptic N-methyl-D-aspartate (NMDA) stimulation triggered by oxidative stress-mediated presynaptic intracellular calcium signaling. To elucidate the mechanisms by which rotenone causes axonal degeneration, we investigated morphological changes in optic nerves and the change in retinal ganglion cell (RGC) number in rats. Optic nerves and retinas were collected 3 and 7 days after the intravitreal injection of rotenone. The cross-sections of the optic nerves were subjected to a morphological analysis with axon quantification. The axons and somas of RGCs were analyzed immunohistochemically in retinal flatmounts. In the optic nerve, rotenone induced axonal swelling and degeneration with the incidence of reactive gliosis. Rotenone also significantly reduced axon numbers in the optic nerve. Furthermore, rotenone caused axonal thinning, fragmentation, and beading in RGCs on flatmounts and decreased the number of RGC soma. In conclusion, the intravitreal injection of rotenone in rats induced morphological abnormities with a reduced number of optic nerve axons and RGC axons when the RGC somas were degenerated. These findings help elucidate the pathogenesis of optic neuropathy induced by mitochondrial dysfunction.<\/jats:p>","DOI":"10.3390\/biom14091047","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T12:53:19Z","timestamp":1724417599000},"page":"1047","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rotenone-Induced Optic Nerve Damage and Retinal Ganglion Cell Loss in Rats"],"prefix":"10.3390","volume":"14","author":[{"given":"Yasuko","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Product Development Division, Santen Pharmaceutical Co., Ltd., Nara 630-0101, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takazumi","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Ophthalmology Innovation Center, Santen Pharmaceutical Co., Ltd., Nara 630-0101, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Shimazaki","sequence":"additional","affiliation":[{"name":"Product Development Division, Santen Pharmaceutical Co., Ltd., Nara 630-0101, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1146\/annurev-pharmtox-010716-104908","article-title":"Repairing Mitochondrial Dysfunction in Disease","volume":"58","author":"Sorrentino","year":"2018","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/cns.12655","article-title":"Mitochondrial Dysfunction and Biogenesis in Neurodegenerative Diseases: Pathogenesis and Treatment","volume":"23","author":"Golpich","year":"2017","journal-title":"CNS Neurosci. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.bbabio.2004.05.009","article-title":"Bioenergetics Shapes Cellular Death Pathways in Leber\u2019s Hereditary Optic Neuropathy: A Model of Mitochondrial Neurodegeneration","volume":"1658","author":"Carelli","year":"2004","journal-title":"Biochim. Biophys. Acta\u2014Bioenerg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.bbabio.2018.05.019","article-title":"Mitochondrial Uncoupling, ROS Generation and Cardioprotection","volume":"1859","author":"Cadenas","year":"2018","journal-title":"Biochim. Biophys. Acta\u2014Bioenerg."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Heitz, F.D., Erb, M., Anklin, C., Robay, D., Pernet, V., and Gueven, N. (2012). Idebenone Protects against Retinal Damage and Loss of Vision in a Mouse Model of Leber\u2019s Hereditary Optic Neuropathy. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045182"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.neulet.2014.12.004","article-title":"Long-Term Evaluation of Leber\u2019s Hereditary Optic Neuropathy-like Symptoms in Rotenone Administered Rats","volume":"585","author":"Zhang","year":"2015","journal-title":"Neurosci. Lett."},{"key":"ref_7","first-page":"379","article-title":"Mechanisms of Retinal Ganglion Specific-Cell Death in Leber Hereditary Optic Neuropathy","volume":"105","author":"Levin","year":"2007","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.4103\/ijo.IJO_358_17","article-title":"Mitochondrial Genetics and Therapeutic Overview of Leber\u2019s Hereditary Optic Neuropathy","volume":"65","author":"Manickam","year":"2017","journal-title":"Indian J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"461","DOI":"10.5301\/ejo.5000055","article-title":"Meta-Analysis of the Prevalence of Leber Hereditary Optic Neuropathy MtDNA Mutations in Europe","volume":"22","author":"Mascialino","year":"2012","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Finnegan, L.K., Chadderton, N., Kenna, P.F., Palfi, A., Carty, M., Bowie, A.G., Millington-Ward, S., and Farrar, G.J. (2022). SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031606"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jphs.2021.07.003","article-title":"Involvement of Endoplasmic Reticulum Stress in Rotenone-Induced Leber Hereditary Optic Neuropathy Model and the Discovery of New Therapeutic Agents","volume":"147","author":"Aoyama","year":"2021","journal-title":"J. Pharmacol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sasaoka, M., Ota, T., and Kageyama, M. (2020). Rotenone-Induced Inner Retinal Degeneration via Presynaptic Activation of Voltage-Dependent Sodium and L-Type Calcium Channels in Rats. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-57638-y"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/0014-4835(75)90125-6","article-title":"A Light and Transmission Electron-Microscopic Study of the Rat Iris in Pupillary Dilation and Constriction","volume":"21","author":"Lim","year":"1975","journal-title":"Exp. Eye Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.exer.2016.04.012","article-title":"An Open-Source Computational Tool to Automatically Quantify Immunolabeled Retinal Ganglion Cells","volume":"147","author":"Gregory","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ghnenis, A.B., Czaikowski, R.E., Zhang, Z.J., and Bushman, J.S. (2018). Toluidine Blue Staining of Resin-Embedded Sections for Evaluation of Peripheral Nerve Morphology. J. Vis. Exp., 58031.","DOI":"10.3791\/58031-v"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ritch, M.D., Hannon, B.G., Read, A.T., Feola, A.J., Cull, G.A., Reynaud, J., Morrison, J.C., Burgoyne, C.F., Pardue, M.T., and Ethier, C.R. (2020). AxoNet: A Deep Learning-Based Tool to Count Retinal Ganglion Cell Axons. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-64898-1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/S0165-0173(00)00038-2","article-title":"CNS Energy Metabolism as Related to Function","volume":"34","author":"Ames","year":"2000","journal-title":"Brain Res. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1139\/y92-257","article-title":"Energy Requirements of CNS Cells as Related to Their Function and to Their Vulnerability to Ischemia: A Commentary Based on Studies on Retina","volume":"70","author":"Ames","year":"1992","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mito.2019.07.003","article-title":"Mitochondrial Dysfunction in Neurodegenerative Diseases and Drug Targets via Apoptotic Signaling","volume":"49","author":"Wu","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1002\/1873-3468.13013","article-title":"Mitochondrial Dysfunction and Axon Degeneration in Progressive Multiple Sclerosis","volume":"592","author":"Campbell","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8516","DOI":"10.1074\/jbc.M210432200","article-title":"Mitochondrial Complex I Inhibitor Rotenone Induces Apoptosis through Enhancing Mitochondrial Reactive Oxygen Species Production","volume":"278","author":"Li","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0304-3940(02)00327-0","article-title":"Mouse Model of Optic Neuropathy Caused by Mitochondrial Complex I Dysfunction","volume":"326","author":"Zhang","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Zhou, J., Shen, M., Xu, H., Yu, S., Cheng, Q., and Ding, F. (2020). Pyrroloquinoline Quinone Inhibits Rotenone-Induced Microglia Inflammation by Enhancing Autophagy. Molecules, 25.","DOI":"10.3390\/molecules25194359"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tawarayama, H., Inoue-Yanagimachi, M., Himori, N., and Nakazawa, T. (2021). Glial Cells Modulate Retinal Cell Survival in Rotenone-Induced Neural Degeneration. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-90604-w"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1097\/BRS.0b013e31820cd2d8","article-title":"Annulus Fibrosus Cells Interact with Neuron-like Cells to Modulate Production of Growth Factors and Cytokines in Symptomatic Disc Degeneration","volume":"37","author":"Moon","year":"2012","journal-title":"Spine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1167\/iovs.05-0299","article-title":"TNF-Alpha-Induced Optic Nerve Degeneration and Nuclear Factor-KappaB P65","volume":"47","author":"Kitaoka","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.bbadis.2015.11.014","article-title":"Reactive Gliosis in the Pathogenesis of CNS Diseases","volume":"1862","author":"Pekny","year":"2016","journal-title":"Biochim. Biophys. Acta\u2014Mol. Basis Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10444","DOI":"10.1074\/jbc.M413863200","article-title":"Neuritic Beading Induced by Activated Microglia Is an Early Feature of Neuronal Dysfunction toward Neuronal Death by Inhibition of Mitochondrial Respiration and Axonal Transport","volume":"280","author":"Takeuchi","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.bpj.2019.07.046","article-title":"The Roles of Microtubules and Membrane Tension in Axonal Beading, Retraction, and Atrophy","volume":"117","author":"Datar","year":"2019","journal-title":"Biophys. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1146\/annurev.neuro.28.061604.135632","article-title":"Axon Retraction and Degeneration in Development and Disease","volume":"28","author":"Luo","year":"2005","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0896-6273(03)00429-X","article-title":"Involvement of the Ubiquitin-Proteasome System in the Early Stages of Wallerian Degeneration","volume":"39","author":"Zhai","year":"2003","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/jnc.15493","article-title":"MEC17-Induced \u03b1-Tubulin Acetylation Restores Mitochondrial Transport Function and Alleviates Axonal Injury after Intracerebral Hemorrhage in Mice","volume":"160","author":"Yang","year":"2022","journal-title":"J. Neurochem."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/9\/1047\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:42:11Z","timestamp":1760110931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/9\/1047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,23]]},"references-count":32,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["biom14091047"],"URL":"https:\/\/doi.org\/10.3390\/biom14091047","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,23]]}}}