Gastrodin Mitigates Vascular Dementia via SIRT1-Mediated eIF2α Deacetylation and ER Stress Reduction

Gastrodin Mitigates Vascular Dementia via SIRT1-Mediated eIF2α Deacetylation and ER Stress Reduction | 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 Gastrodin Mitigates Vascular Dementia via SIRT1-Mediated eIF2α Deacetylation and ER Stress Reduction Yini Xu, Yang Cui, Xueting Wang, Tingting Chen, Chunen Jiao, Chunqiang Zhang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9393315/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Background Gastrodin (GAS), the primary bioactive constituent of Gastrodia elata , exhibits significant neuroprotective activity and is clinically used for neurological cardio- and cerebrovascular disorders, but its mechanism against vascular dementia (VaD) related cognitive deficits is unclear. Purpose To elucidate the therapeutic effects of GAS and the underlying mechanism in VaD. Methods VaD was induced in rats by permanent bilateral common carotid artery occlusion (2-VO). Cognitive performance, hippocampal neuronal injury, oxidative stress, endoplasmic reticulum stress (ERS), and apoptosis were evaluated. In vitro , HT22 neurons were exposed to hypoxia to assess mitochondrial dysfunction and apoptotic signaling. The GAS-SIRT1 interaction was examined by molecular docking and surface plasmon resonance (SPR). To verify SIRT1-dependent ERS modulation, 4-PBA, RES, and SIRT1-RNAi were applied. Protein interactions and post-translational regulation were analyzed by co-immunoprecipitation (Co-IP) and immunoblotting. Results GAS significantly improved learning and memory, attenuated hippocampal neuronal loss, and reduced oxidative stress and apoptosis in 2-VO rats. GAS suppressed ERS activation, decreasing GRP78, p-PERK, p-eIF2α, and ATF4, and downregulated the pro-apoptotic effector CHOP. In hypoxic HT22 cells, GAS alleviated mitochondrial impairment and inhibited apoptosis. SIRT1 knockdown abolished GAS-mediated ERS inhibition and anti-apoptotic protection, indicating an essential role for SIRT1. Docking and SPR demonstrated direct binding of GAS to SIRT1, accompanied by increased SIRT1 expression. Co-IP further supported a mechanistic link whereby SIRT1 promoted eIF2α deacetylation, dampening ERS signaling and its downstream apoptotic program. Conclusion GAS mitigates VaD-associated cognitive impairment and hippocampal damage by binding and activating SIRT1, enhancing eIF2α deacetylation, and thereby suppressing ERS-induced apoptosis. The SIRT1/eIF2α axis represents a potential therapeutic target for vascular cognitive impairment. Gastrodin Vascular dementia SIRT1 Endoplasmic reticulum stress eIF2α Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 15 May, 2026 Reviews received at journal 14 May, 2026 Reviews received at journal 13 May, 2026 Reviewers agreed at journal 05 May, 2026 Reviews received at journal 02 May, 2026 Reviewers agreed at journal 30 Apr, 2026 Reviewers agreed at journal 17 Apr, 2026 Reviewers invited by journal 17 Apr, 2026 Editor assigned by journal 13 Apr, 2026 Submission checks completed at journal 13 Apr, 2026 First submitted to journal 12 Apr, 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-9393315","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":628106364,"identity":"c4e058ac-0169-4e22-abe2-a3fecfcaf791","order_by":0,"name":"Yini Xu","email":"","orcid":"","institution":"Guizhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yini","middleName":"","lastName":"Xu","suffix":""},{"id":628106365,"identity":"3f8fae55-37b4-4632-85d9-595e119d266a","order_by":1,"name":"Yang Cui","email":"","orcid":"","institution":"Guizhou Medical 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Reduction","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"chinese-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmed","sideBox":"Learn more about [Chinese Medicine](http://cmjournal.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/cmed/default.aspx","title":"Chinese Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gastrodin, Vascular dementia, SIRT1, Endoplasmic reticulum stress, eIF2α","lastPublishedDoi":"10.21203/rs.3.rs-9393315/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9393315/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eGastrodin (GAS), the primary bioactive constituent of \u003cem\u003eGastrodia elata\u003c/em\u003e, exhibits significant neuroprotective activity and is clinically used for neurological cardio- and cerebrovascular disorders, but its mechanism against vascular dementia (VaD) related cognitive deficits is unclear.\u003c/p\u003e\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo elucidate the therapeutic effects of GAS and the underlying mechanism in VaD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eVaD was induced in rats by permanent bilateral common carotid artery occlusion (2-VO). Cognitive performance, hippocampal neuronal injury, oxidative stress, endoplasmic reticulum stress (ERS), and apoptosis were evaluated. \u003cem\u003eIn vitro\u003c/em\u003e, HT22 neurons were exposed to hypoxia to assess mitochondrial dysfunction and apoptotic signaling. The GAS-SIRT1 interaction was examined by molecular docking and surface plasmon resonance (SPR). To verify SIRT1-dependent ERS modulation, 4-PBA, RES, and SIRT1-RNAi were applied. Protein interactions and post-translational regulation were analyzed by co-immunoprecipitation (Co-IP) and immunoblotting.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eGAS significantly improved learning and memory, attenuated hippocampal neuronal loss, and reduced oxidative stress and apoptosis in 2-VO rats. GAS suppressed ERS activation, decreasing GRP78, p-PERK, p-eIF2α, and ATF4, and downregulated the pro-apoptotic effector CHOP. In hypoxic HT22 cells, GAS alleviated mitochondrial impairment and inhibited apoptosis. SIRT1 knockdown abolished GAS-mediated ERS inhibition and anti-apoptotic protection, indicating an essential role for SIRT1. Docking and SPR demonstrated direct binding of GAS to SIRT1, accompanied by increased SIRT1 expression. Co-IP further supported a mechanistic link whereby SIRT1 promoted eIF2α deacetylation, dampening ERS signaling and its downstream apoptotic program.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eGAS mitigates VaD-associated cognitive impairment and hippocampal damage by binding and activating SIRT1, enhancing eIF2α deacetylation, and thereby suppressing ERS-induced apoptosis. The SIRT1/eIF2α axis represents a potential therapeutic target for vascular cognitive impairment.\u003c/p\u003e","manuscriptTitle":"Gastrodin Mitigates Vascular Dementia via SIRT1-Mediated eIF2α Deacetylation and ER Stress Reduction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-24 06:47:21","doi":"10.21203/rs.3.rs-9393315/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-15T05:53:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-14T11:47:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-14T03:07:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196837883071856503194868380801306890758","date":"2026-05-05T11:48:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T11:02:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73574737861020797577940943527819262878","date":"2026-05-01T01:43:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180359089466757099538778538170871424033","date":"2026-04-17T06:55:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-17T04:17:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-13T15:05:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-13T15:04:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Chinese Medicine","date":"2026-04-12T09:51:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"chinese-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmed","sideBox":"Learn more about [Chinese Medicine](http://cmjournal.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/cmed/default.aspx","title":"Chinese Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"69587054-3aae-47e4-b805-06ff5a0c717e","owner":[],"postedDate":"April 24th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-15T05:53:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-14T11:47:04+00:00","index":76,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-14T03:07:58+00:00","index":75,"fulltext":""},{"type":"reviewerAgreed","content":"196837883071856503194868380801306890758","date":"2026-05-05T11:48:09+00:00","index":74,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T11:02:40+00:00","index":72,"fulltext":""},{"type":"reviewerAgreed","content":"73574737861020797577940943527819262878","date":"2026-05-01T01:43:23+00:00","index":71,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T06:09:23+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-24 06:47:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9393315","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9393315","identity":"rs-9393315","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}