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Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg\/kg twice a day or 7.5 mg\/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death.<\/jats:p>","DOI":"10.3390\/cells13110911","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:27:59Z","timestamp":1716805679000},"page":"911","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cytoprotective Small Compound M109S Attenuated Retinal Ganglion Cell Degeneration Induced by Optic Nerve Crush in Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Jonah J.","family":"Scott-McKean","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mieko","family":"Matsuyama","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0822-0240","authenticated-orcid":false,"given":"Charles W.","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8997-1941","authenticated-orcid":false,"given":"Lin","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon","family":"Sassouni","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-7118","authenticated-orcid":false,"given":"Shree","family":"Kurup","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Nickells","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, School of Medicine, University of Wisconsin (Madison), Madison, WI 53706, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigemi","family":"Matsuyama","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Division of Hematology and Oncology, Departments of Medicine, Pharmacology and Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Case Comprehensive Cancer Center, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101225","DOI":"10.1016\/j.mam.2023.101225","article-title":"Novel frontiers in neuroprotective therapies in glaucoma: Molecular and clinical aspects","volume":"94","author":"Boccaccini","year":"2023","journal-title":"Mol. Aspects Med."},{"key":"ref_2","first-page":"774","article-title":"Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis","volume":"36","author":"Quigley","year":"1995","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1007\/s12035-019-01783-7","article-title":"BAX-Depleted Retinal Ganglion Cells Survive and Become Quiescent Following Optic Nerve Damage","volume":"57","author":"Donahue","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1126\/science.1059108","article-title":"Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death","volume":"292","author":"Wei","year":"2001","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1006\/exer.2000.0873","article-title":"Bax-dependent and independent pathways of retinal ganglion cell death induced by different damaging stimuli","volume":"71","author":"Li","year":"2000","journal-title":"Exp. Eye Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1371\/journal.pgen.0010004","article-title":"Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage","volume":"1","author":"Libby","year":"2005","journal-title":"PLoS Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00032","DOI":"10.1042\/AN20100003","article-title":"A single nucleotide polymorphism in the Bax gene promoter affects transcription and influences retinal ganglion cell death","volume":"2","author":"Semaan","year":"2010","journal-title":"ASN Neuro"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41580-018-0089-8","article-title":"Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins","volume":"20","author":"Singh","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13024-023-00659-8","article-title":"BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps","volume":"18","author":"Maes","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2017.01.002","article-title":"BAX to basics: How the BCL2 gene family controls the death of retinal ganglion cells","volume":"57","author":"Maes","year":"2017","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1007\/s12035-021-02675-5","article-title":"Bax Contributes to Retinal Ganglion Cell Dendritic Degeneration During Glaucoma","volume":"59","author":"Risner","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107916","DOI":"10.1016\/j.isci.2023.107916","article-title":"Development of novel cytoprotective small compounds inhibiting mitochondria-dependent cell death","volume":"26","author":"Matsuyama","year":"2023","journal-title":"iScience"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Cameron, E.G., Xia, X., Galvao, J., Ashouri, M., Kapiloff, M.S., and Goldberg, J.L. (2020). Optic Nerve Crush in Mice to Study Retinal Ganglion Cell Survival and Regeneration. Bio Protoc., 10.","DOI":"10.21769\/BioProtoc.3559"},{"key":"ref_14","first-page":"1004","article-title":"Experimental induction of retinal ganglion cell death in adult mice","volume":"40","author":"Li","year":"1999","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_15","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":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17032","DOI":"10.1038\/cddiscovery.2017.32","article-title":"Caspases in retinal ganglion cell death and axon regeneration","volume":"3","author":"Thomas","year":"2017","journal-title":"Cell Death Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/sj.ki.5002256","article-title":"The pathological role of Bax in cisplatin nephrotoxicity","volume":"72","author":"Wei","year":"2007","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1172\/JCI111524","article-title":"Oxygen free radicals in ischemic acute renal failure in the rat","volume":"74","author":"Paller","year":"1984","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1706","DOI":"10.1038\/cddis.2015.11","article-title":"Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases","volume":"6","author":"Ngo","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5229","DOI":"10.1073\/pnas.0608557104","article-title":"Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice","volume":"104","author":"Perez","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mead, B., Thompson, A., Scheven, B.A., Logan, A., Berry, M., and Leadbeater, W. (2014). Comparative evaluation of methods for estimating retinal ganglion cell loss in retinal sections and wholemounts. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110612"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nadal-Nicolas, F.M., Jimenez-Lopez, M., Salinas-Navarro, M., Sobrado-Calvo, P., Alburquerque-Bejar, J.J., Vidal-Sanz, M., and Agudo-Barriuso, M. (2012). Whole number, distribution and co-expression of brn3 transcription factors in retinal ganglion cells of adult albino and pigmented rats. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049830"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"970","DOI":"10.3389\/fnins.2018.00970","article-title":"Retinal Neuroprotection From Optic Nerve Trauma by Deletion of Arginase 2","volume":"12","author":"Xu","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_24","first-page":"643","article-title":"beta-III-Tubulin: A reliable marker for retinal ganglion cell labeling in experimental models of glaucoma","volume":"8","author":"Jiang","year":"2015","journal-title":"Int. J. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.exer.2016.08.006","article-title":"Evaluating retinal ganglion cell loss and dysfunction","volume":"151","author":"Mead","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2121273119","DOI":"10.1073\/pnas.2121273119","article-title":"A small molecule M1 promotes optic nerve regeneration to restore target-specific neural activity and visual function","volume":"119","author":"Au","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.ymthe.2004.11.014","article-title":"Long-term in vivo inhibition of CNS neurodegeneration by Bcl-XL gene transfer","volume":"11","author":"Malik","year":"2005","journal-title":"Mol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hardwick, J.M., and Soane, L. (2013). Multiple functions of BCL-2 family proteins. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a008722"},{"key":"ref_29","first-page":"108","article-title":"Caspases as therapeutic targets in Alzheimer\u2019s disease: Is it time to \u201ccut\u201d to the chase?","volume":"2","author":"Rohn","year":"2009","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8161","DOI":"10.1073\/pnas.0609874104","article-title":"Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson\u2019s disease","volume":"104","author":"Perier","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8774","DOI":"10.1523\/JNEUROSCI.2315-06.2006","article-title":"Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS","volume":"26","author":"Gould","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1172\/JCI42986","article-title":"Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis","volume":"120","author":"Reyes","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12849","DOI":"10.1523\/JNEUROSCI.4086-06.2006","article-title":"Neuromuscular denervation: Bax up against the wall in amyotrophic lateral sclerosis","volume":"26","author":"Steele","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0278-5846(03)00021-6","article-title":"Apoptosis in Huntington\u2019s disease","volume":"27","author":"Hickey","year":"2003","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nature03579","article-title":"An inhibitor of Bcl-2 family proteins induces regression of solid tumours","volume":"435","author":"Oltersdorf","year":"2005","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1089\/neu.2000.17.927","article-title":"Apoptosis after traumatic brain injury","volume":"17","author":"Raghupathi","year":"2000","journal-title":"J. Neurotrauma"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/11\/911\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:48:32Z","timestamp":1760107712000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/11\/911"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,25]]},"references-count":36,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["cells13110911"],"URL":"https:\/\/doi.org\/10.3390\/cells13110911","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,25]]}}}