Chronic anatabine administration attenuates cardiovascular activity by targeting NF-κB/caspase-1/NLRP3-dependent pyroptosis and oxidative stress in paraventricular nucleus of hypertensive rat

Chronic anatabine administration attenuates cardiovascular activity by targeting NF-κB/caspase-1/NLRP3-dependent pyroptosis and oxidative stress in paraventricular nucleus of hypertensive rat | 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 Chronic anatabine administration attenuates cardiovascular activity by targeting NF-κB/caspase-1/NLRP3-dependent pyroptosis and oxidative stress in paraventricular nucleus of hypertensive rat Qing Su, Shao-Jun Li, Jin-Bao Yang, Fang Zhao, Guo-Quan Zou, Jia-Xuan Ma, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6152686/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Jul, 2025 Read the published version in Cardiovascular Toxicology → Version 1 posted 18 You are reading this latest preprint version Abstract Objectives : The hypertensive process is a chronic low-grade inflammation. Anatabine, a natural alkaloid with anti-inflammatory properties, can modulate inflammatory pathways. Therefore, this study sought to explore the impact of anatabine on cardiovascular activity in hypertensive rats, focusing on mechanisms associated with inflammation and oxidative stress. Method : We collected fecal samples from male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (300-350g), and performed untargeted metabolomics analysis. Anatabine was identified as the potential metabolite, and anatabine dicitrate (20 mg/kg) within mini-pump was subcutaneously implanted in SHR or WKY for 12- week. Systolic pressure was recorded weekly and cardiovascular events were detected at terminated animal study. Angiotensin II induced microglia (HMC3) was treated with anatabine and PapRIV (NF-κB activator) to explore the molecular mechanism. Results : High blood pressure significantly triggered nucleotide-binding domain, leucine-rich-containing family pyrin domain containing 3 (NLRP3)-dependent inflammasome assembly (ASC, Caspase-1, and NLRP3) and pyroptosis (GSDMD) in the hypothalamic paraventricular nucleus (PVN), which evoked massive inflammatory cytokine production (IL-1β, TNF-α, IL-10, IL-18, and MCP-1) and oxidative stress responses (Cu/Zn-SOD activity, GSH-PX, and MDA) in the SHR group. Notably, anatabine not only improved cardiac function and attenuated sympathetic activation, but also reduced the intensity of inflammatory reaction from the NLRP3-dependent inflammasome and pyroptosis, and decreased reactive oxygen species (ROS) overproduction in the PVN of hypertensive rats. Furthermore, microglia stimulated inflammation after adding Ang II; oxidative stress responses were activated, while the inflammasome compounds and cytokines were overexpressed. The anatabine inhibited NLRP3-mediated pyroptosis and oxidative stress in Ang II-induced microglia. However, those responses were aggravating after the NF-κB activator. Conclusion : Chronic hypertension activated the NLRP3 inflammasome and pyroptosis-driven inflammatory responses, triggering oxidative stress in the PVN. Anatabine, a natural alkaloid with anti-inflammatory properties, has shown potential capability for inhibition of inflammation. Sustained adminstration anatabine cross the blood-brain barrier arriving the PVN and effectively lowed blood pressure, reduced sympathetic drive, and improved cardiac function, by suppressing the NF-κB/caspase- 1/NLRP3-dependent pyroptosis pathway in microglia, curbing excessive ROS generation in paraventricular nucleus of hypertensive rat Caspase-1 Inflammation Paraventricular nucleus Hypertension Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 21 Jul, 2025 Read the published version in Cardiovascular Toxicology → Version 1 posted Editorial decision: Revision requested 10 Apr, 2025 Reviews received at journal 08 Apr, 2025 Reviews received at journal 07 Apr, 2025 Reviews received at journal 26 Mar, 2025 Reviews received at journal 26 Mar, 2025 Reviewers agreed at journal 25 Mar, 2025 Reviewers agreed at journal 24 Mar, 2025 Reviewers agreed at journal 24 Mar, 2025 Reviews received at journal 23 Mar, 2025 Reviewers agreed at journal 22 Mar, 2025 Reviewers agreed at journal 21 Mar, 2025 Reviewers agreed at journal 21 Mar, 2025 Reviewers agreed at journal 20 Mar, 2025 Reviewers agreed at journal 17 Mar, 2025 Reviewers invited by journal 17 Mar, 2025 Editor assigned by journal 15 Mar, 2025 Submission checks completed at journal 05 Mar, 2025 First submitted to journal 04 Mar, 2025 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-6152686","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":424315397,"identity":"f9f9236a-89af-4ce1-a454-6a7428707325","order_by":0,"name":"Qing Su","email":"","orcid":"","institution":"Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Su","suffix":""},{"id":424315399,"identity":"4ac76868-9a77-48e6-9944-28f4207f9f70","order_by":1,"name":"Shao-Jun 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Anatabine, a natural alkaloid with anti-inflammatory properties, can modulate inflammatory pathways. Therefore, this study sought to explore the impact of anatabine on cardiovascular activity in hypertensive rats, focusing on mechanisms associated with inflammation and oxidative stress.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e: We collected fecal samples from male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (300-350g), and performed untargeted metabolomics analysis. Anatabine was identified as the potential metabolite, and anatabine dicitrate (20 mg/kg) within mini-pump was subcutaneously implanted in SHR or WKY for 12- week. Systolic pressure was recorded weekly and cardiovascular events were detected at terminated animal study. Angiotensin II induced microglia (HMC3) was treated with anatabine and PapRIV (NF-κB activator) to explore the molecular mechanism.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: High blood pressure significantly triggered nucleotide-binding domain, leucine-rich-containing family pyrin domain containing 3 (NLRP3)-dependent inflammasome assembly (ASC, Caspase-1, and NLRP3) and pyroptosis (GSDMD) in the hypothalamic paraventricular nucleus (PVN), which evoked massive inflammatory cytokine production (IL-1β, TNF-α, IL-10, IL-18, and MCP-1) and oxidative stress responses (Cu/Zn-SOD activity, GSH-PX, and MDA) in the SHR group. Notably, anatabine not only improved cardiac function and attenuated sympathetic activation, but also reduced the intensity of inflammatory reaction from the NLRP3-dependent inflammasome and pyroptosis, and decreased reactive oxygen species (ROS) overproduction in the PVN of hypertensive rats. Furthermore, microglia stimulated inflammation after adding Ang II; oxidative stress responses were activated, while the inflammasome compounds and cytokines were overexpressed. The anatabine inhibited NLRP3-mediated pyroptosis and oxidative stress in Ang II-induced microglia. However, those responses were aggravating after the NF-κB activator.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Chronic hypertension activated the NLRP3 inflammasome and pyroptosis-driven inflammatory responses, triggering oxidative stress in the PVN. Anatabine, a natural alkaloid with anti-inflammatory properties, has shown potential capability for inhibition of inflammation. Sustained adminstration anatabine cross the blood-brain barrier arriving the PVN and effectively lowed blood pressure, reduced sympathetic drive, and improved cardiac function, by suppressing the NF-κB/caspase- 1/NLRP3-dependent pyroptosis pathway in microglia, curbing excessive ROS generation in paraventricular nucleus of hypertensive rat\u003c/p\u003e","manuscriptTitle":"Chronic anatabine administration attenuates cardiovascular activity by targeting NF-κB/caspase-1/NLRP3-dependent pyroptosis and oxidative stress in paraventricular nucleus of hypertensive rat","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-07 02:34:02","doi":"10.21203/rs.3.rs-6152686/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-10T21:10:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-09T01:58:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-07T18:20:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-26T16:53:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-26T15:45:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"170373514222595882527693131452096579831","date":"2025-03-26T00:30:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"241652822207998730866462640470181341336","date":"2025-03-24T13:01:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187968358213035292397492982612507293033","date":"2025-03-24T05:03:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-24T01:22:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187456946841191172564568678069908525720","date":"2025-03-22T11:27:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146569585326297514992300524411679757735","date":"2025-03-21T17:22:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197309805972253379963066055168015037932","date":"2025-03-21T06:23:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37039159601179339214159583283345970429","date":"2025-03-20T11:14:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"40189872986566445221632588431701034678","date":"2025-03-17T15:39:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-17T08:00:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-15T20:31:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-05T06:13:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardiovascular Toxicology","date":"2025-03-04T08:46:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cato","sideBox":"Learn more about [Cardiovascular Toxicology](http://link.springer.com/journal/12012)","snPcode":"12012","submissionUrl":"https://submission.nature.com/new-submission/12012/3","title":"Cardiovascular Toxicology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d8cbc8aa-c4d1-4548-b907-2a6f97663efa","owner":[],"postedDate":"March 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T16:04:04+00:00","versionOfRecord":{"articleIdentity":"rs-6152686","link":"https://doi.org/10.1007/s12012-025-10034-2","journal":{"identity":"cardiovascular-toxicology","isVorOnly":false,"title":"Cardiovascular Toxicology"},"publishedOn":"2025-07-21 15:56:57","publishedOnDateReadable":"July 21st, 2025"},"versionCreatedAt":"2025-03-07 02:34:02","video":"","vorDoi":"10.1007/s12012-025-10034-2","vorDoiUrl":"https://doi.org/10.1007/s12012-025-10034-2","workflowStages":[]},"version":"v1","identity":"rs-6152686","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6152686","identity":"rs-6152686","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}