Therapeutic Potential of a Novel Spirocyclic Molecule in a Murine Model of Peripheral Nerve Injury Mediated via Anti-inflammatory and Neuroprotective Properties

Therapeutic Potential of a Novel Spirocyclic Molecule in a Murine Model of Peripheral Nerve Injury Mediated via Anti-inflammatory and Neuroprotective Properties | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Therapeutic Potential of a Novel Spirocyclic Molecule in a Murine Model of Peripheral Nerve Injury Mediated via Anti-inflammatory and Neuroprotective Properties Soumya Ghosh, Papia Basuthakur, Vincy Vijay, Joachyutharayalu Oja, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9110922/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Apr, 2026 Read the published version in Molecular Biology Reports → Version 1 posted 15 You are reading this latest preprint version Abstract Background Peripheral nervous system injury (PNI) is a leading cause of long-term disability worldwide, with traumatic damage to major nerves such as the sciatic nerve, facial nerve, and brachial plexus severely impairing motor function, reducing life expectancy, and predisposing to mood disorders, thereby imposing a substantial socioeconomic burden. Effective therapies to limit PNI-induced neural damage, particularly in sciatic nerve injury (SNI), remain inadequate, largely due to an incomplete understanding of the underlying molecular mechanisms. Objective To evaluate the efficacy of the CNS-active Spiro tricyclic compound IM-1725-RS-109a in improving motor deficits and modulating injury-related molecular markers in a mouse model of SNI. Methods Sciatic nerve injury was induced in C57BL/6NCrl mice using a standardized crush-force technique. The spiro compound IM-1725-RS-109a, previously shown to be effective in an ischemic stroke mouse model, was administered intraperitoneally at a daily dose of 5 mg/kg for 5 days following injury. Results Treatment with IM-1725-RS-109a significantly restored motor behavioral performance in OFT, rotarod, and pole tests in SNI mice compared with untreated controls. Marked differences were observed between groups receiving treatment initiated at different post-injury time points. qRT-PCR and Western Blot analysis revealed significant increases in neurogenesis and reductions in inflammation in the treatment groups. Conclusion IM-1725-RS-109a confers functional and molecular neuroprotection in a mouse model of sciatic nerve injury, supporting the peripheral neuroprotective and anti-inflammatory potential of CNS-active spiro tricyclic compounds. These findings suggest that the compound may be a promising candidate for further development as a therapeutic strategy for PNI. Sciatic nerve injury Crush force model Motor function Gastrocnemius muscle Dentate gyrus Neurogenesis Full Text Additional Declarations No competing interests reported. Supplementary Files SupplimentaryDoc.docx Cite Share Download PDF Status: Published Journal Publication published 28 Apr, 2026 Read the published version in Molecular Biology Reports → Version 1 posted Editorial decision: Revision requested 24 Mar, 2026 Reviews received at journal 24 Mar, 2026 Reviewers agreed at journal 23 Mar, 2026 Reviews received at journal 21 Mar, 2026 Reviewers agreed at journal 21 Mar, 2026 Reviewers agreed at journal 20 Mar, 2026 Reviewers agreed at journal 20 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers agreed at journal 19 Mar, 2026 Reviewers invited by journal 19 Mar, 2026 Editor assigned by journal 14 Mar, 2026 Submission checks completed at journal 14 Mar, 2026 First submitted to journal 13 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9110922","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":610018651,"identity":"5322a675-9feb-4770-966b-cddee3fa1c16","order_by":0,"name":"Soumya Ghosh","email":"","orcid":"","institution":"CSIR-Indian Institute of Chemical Technology","correspondingAuthor":false,"prefix":"","firstName":"Soumya","middleName":"","lastName":"Ghosh","suffix":""},{"id":610018652,"identity":"8de4bd55-bec0-4465-9fc8-41d2017d9170","order_by":1,"name":"Papia Basuthakur","email":"","orcid":"","institution":"CSIR-Indian Institute of Chemical 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Properties","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-biology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mole","sideBox":"Learn more about [Molecular Biology Reports](https://www.springer.com/journal/11033)","snPcode":"11033","submissionUrl":"https://submission.nature.com/new-submission/11033/3","title":"Molecular Biology Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Sciatic nerve injury, Crush force model, Motor function, Gastrocnemius muscle, Dentate gyrus, Neurogenesis","lastPublishedDoi":"10.21203/rs.3.rs-9110922/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9110922/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePeripheral nervous system injury (PNI) is a leading cause of long-term disability worldwide, with traumatic damage to major nerves such as the sciatic nerve, facial nerve, and brachial plexus severely impairing motor function, reducing life expectancy, and predisposing to mood disorders, thereby imposing a substantial socioeconomic burden. Effective therapies to limit PNI-induced neural damage, particularly in sciatic nerve injury (SNI), remain inadequate, largely due to an incomplete understanding of the underlying molecular mechanisms.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo evaluate the efficacy of the CNS-active Spiro tricyclic compound IM-1725-RS-109a in improving motor deficits and modulating injury-related molecular markers in a mouse model of SNI.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSciatic nerve injury was induced in C57BL/6NCrl mice using a standardized crush-force technique. The spiro compound IM-1725-RS-109a, previously shown to be effective in an ischemic stroke mouse model, was administered intraperitoneally at a daily dose of 5 mg/kg for 5 days following injury.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTreatment with IM-1725-RS-109a significantly restored motor behavioral performance in OFT, rotarod, and pole tests in SNI mice compared with untreated controls. Marked differences were observed between groups receiving treatment initiated at different post-injury time points. qRT-PCR and Western Blot analysis revealed significant increases in neurogenesis and reductions in inflammation in the treatment groups.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIM-1725-RS-109a confers functional and molecular neuroprotection in a mouse model of sciatic nerve injury, supporting the peripheral neuroprotective and anti-inflammatory potential of CNS-active spiro tricyclic compounds. These findings suggest that the compound may be a promising candidate for further development as a therapeutic strategy for PNI.\u003c/p\u003e","manuscriptTitle":"Therapeutic Potential of a Novel Spirocyclic Molecule in a Murine Model of Peripheral Nerve Injury Mediated via Anti-inflammatory and Neuroprotective Properties","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-23 22:04:48","doi":"10.21203/rs.3.rs-9110922/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-24T09:28:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-24T05:39:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58807624472917907049074895468403422997","date":"2026-03-23T20:40:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-22T02:34:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158301681724146176067176494285951475168","date":"2026-03-21T09:46:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"239798020160843498153969634676564093091","date":"2026-03-20T07:56:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"208318564781662164261825242118952612762","date":"2026-03-20T06:44:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4817086666432148874281585319306234351","date":"2026-03-19T18:10:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332330178213013146250011322222883136628","date":"2026-03-19T17:38:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79071958792979050718106835251140924536","date":"2026-03-19T14:18:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"156141317721648533280154105062956400506","date":"2026-03-19T12:56:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-19T12:41:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-14T05:22:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-14T05:21:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Biology Reports","date":"2026-03-13T06:19:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-biology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mole","sideBox":"Learn more about [Molecular Biology Reports](https://www.springer.com/journal/11033)","snPcode":"11033","submissionUrl":"https://submission.nature.com/new-submission/11033/3","title":"Molecular Biology Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"101e0ae9-3018-4a15-8669-4351612b7383","owner":[],"postedDate":"March 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T16:48:59+00:00","versionOfRecord":{"articleIdentity":"rs-9110922","link":"https://doi.org/10.1007/s11033-026-11843-6","journal":{"identity":"molecular-biology-reports","isVorOnly":false,"title":"Molecular Biology Reports"},"publishedOn":"2026-04-28 15:57:18","publishedOnDateReadable":"April 28th, 2026"},"versionCreatedAt":"2026-03-23 22:04:48","video":"","vorDoi":"10.1007/s11033-026-11843-6","vorDoiUrl":"https://doi.org/10.1007/s11033-026-11843-6","workflowStages":[]},"version":"v1","identity":"rs-9110922","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9110922","identity":"rs-9110922","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}