The impact of muscarinic or mGlu activators on some NO-dependent biochemical pathways in MK-801 animal model

The impact of muscarinic or mGlu activators on some NO-dependent biochemical pathways in MK-801 animal model | 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 The impact of muscarinic or mGlu activators on some NO-dependent biochemical pathways in MK-801 animal model Grzegorz Burnat, Michał Santocki, Leszek Kalinowski, Joanna M. Wierońska This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6287635/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jun, 2025 Read the published version in Pharmacological Reports → Version 1 posted 13 You are reading this latest preprint version Abstract Cognitive impairment and dementia significantly affect life quality, with conditions like Alzheimer’s, dementia, and Parkinsonian dementia posing treatment difficulties. Nitric oxide (NO﮲) is crucial for brain function, yet its imbalance contributes to neurodegeneration. Typically, NO﮲ supports synaptic activity, but under pathological conditions, oxidative stress triggers harmful peroxynitrite formation. Excessive NO﮲ disrupts protein function, aggravating CNS disorders. Recent studies investigate mGlu and muscarinic receptor modulators as potential treatments targeting NO﮲ pathways. However, clinical breakthroughs remain unattained despite ongoing research, highlighting the need for further exploration. The study examined NO֗-related biochemical pathways in reversing schizophrenia-related deficits using mGlu and muscarinic ligands. We analyzed cGMP levels, oxidative stress, and s-nitrosylation in mouse brain samples. Additionally, some aspects of MK-801 and mGlu as well as muscarinic ligands administration on oxidative burst ware analyzed in in vitro study on C8D1a and 1231N1 cells lines. MK-801, a schizophrenia model compound, disrupted NO֗ signaling, impairing neurovascular stability. The tested ligands mitigated oxidative stress and prevented harmful NO֗ derivatives. Increased SOD activity suggested prior oxidative stress, with the compounds acting as antioxidants. MK-801 altered glutamate uptake, aligning with schizophrenia’s glutamatergic theory. Findings indicate that mGlu and muscarinic receptor activators may counteract schizophrenia-related dysfunctions through NO-dependent pathways, offering potential therapeutic benefits in neurovascular regulation. mGlu receptors muscaynic receptors Schizophrenia reactive oxygen species Full Text Additional Declarations No competing interests reported. Supplementary Files supplementary.pptx Cite Share Download PDF Status: Published Journal Publication published 24 Jun, 2025 Read the published version in Pharmacological Reports → Version 1 posted Editorial decision: Revision requested 11 Apr, 2025 Reviews received at journal 07 Apr, 2025 Reviews received at journal 06 Apr, 2025 Reviewers agreed at journal 30 Mar, 2025 Reviewers agreed at journal 30 Mar, 2025 Reviews received at journal 28 Mar, 2025 Reviewers agreed at journal 27 Mar, 2025 Reviewers agreed at journal 25 Mar, 2025 Reviewers agreed at journal 25 Mar, 2025 Reviewers invited by journal 25 Mar, 2025 Editor assigned by journal 25 Mar, 2025 Submission checks completed at journal 25 Mar, 2025 First submitted to journal 23 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6287635","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":436906378,"identity":"754ec8d6-7d9b-4b3a-9f70-8b5734bf74c4","order_by":0,"name":"Grzegorz Burnat","email":"","orcid":"","institution":"Maj Institute of Pharmacology Polish Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Grzegorz","middleName":"","lastName":"Burnat","suffix":""},{"id":436906379,"identity":"b2dd0b99-355c-4280-97c9-2dcc1a8234ae","order_by":1,"name":"Michał Santocki","email":"","orcid":"","institution":"Maj Institute of Pharmacology Polish Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Michał","middleName":"","lastName":"Santocki","suffix":""},{"id":436906384,"identity":"0503c508-4273-4345-8b6f-9b62b76f83ae","order_by":2,"name":"Leszek Kalinowski","email":"","orcid":"","institution":"Medical University of Gdansk","correspondingAuthor":false,"prefix":"","firstName":"Leszek","middleName":"","lastName":"Kalinowski","suffix":""},{"id":436906388,"identity":"49e722b8-6e6e-49ee-bdbc-1e9849a3961d","order_by":3,"name":"Joanna M. Wierońska","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIie3Rv2vCQBTA8VcOXpeTrCdJzb+QcJAugv9KJJAsdXcKTq9T62r+E8fAQbrkT3BQBJ0ERSgUFExshnbIj7HQ+y73lg93xwPQ6f5i7PsYIEvvgwOA98FqIxLR/01422XjWWfifLDseFrG0TsCrr+WIJ9fs/GWw6qeKAySJFcTQnh033LwrDxUksOulniKS9ajdEL2/FP0CIYCIjJfQDUQ41yQOMLiYf1rSYx9G+GsIMwviVnc4gkRZo1kpFA+JKTc8i/yiYQUYhfIi1P/l/5cbeFEsW0T4OZAQ3dhhO5mMV0N6sjPyn2IanbSLqJaYVU3otPpdP+iGyf8RxOzBTGVAAAAAElFTkSuQmCC","orcid":"","institution":"Maj Institute of Pharmacology Polish Academy of Sciences","correspondingAuthor":true,"prefix":"","firstName":"Joanna","middleName":"M.","lastName":"Wierońska","suffix":""}],"badges":[],"createdAt":"2025-03-23 10:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6287635/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6287635/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s43440-025-00752-3","type":"published","date":"2025-06-24T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85686164,"identity":"241b6c7a-edc8-4ae0-a027-e6ba81126ead","added_by":"auto","created_at":"2025-06-30 16:04:08","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":688848,"visible":true,"origin":"","legend":"","description":"","filename":"14.03.25PharmacologicalReports.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6287635/v1_covered_18472121-18ef-46c6-9c6b-8b235cb45be5.pdf"},{"id":79751667,"identity":"8ac394b1-8050-42ff-9d30-00da03b15293","added_by":"auto","created_at":"2025-04-02 09:25:16","extension":"pptx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":4892567,"visible":true,"origin":"","legend":"","description":"","filename":"supplementary.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6287635/v1/a5c7c37b32cfa8c850e35227.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The impact of muscarinic or mGlu activators on some NO-dependent biochemical pathways in MK-801 animal model","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":"pharmacological-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prep","sideBox":"Learn more about [Pharmacological Reports](https://link.springer.com/journal/43440)","snPcode":"43440","submissionUrl":"https://submission.springernature.com/new-submission/43440/3","title":"Pharmacological Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"mGlu receptors, muscaynic receptors, Schizophrenia, reactive oxygen species","lastPublishedDoi":"10.21203/rs.3.rs-6287635/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6287635/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Cognitive impairment and dementia significantly affect life quality, with conditions like Alzheimer’s, dementia, and Parkinsonian dementia posing treatment difficulties. Nitric oxide (NO﮲) is crucial for brain function, yet its imbalance contributes to neurodegeneration. Typically, NO﮲ supports synaptic activity, but under pathological conditions, oxidative stress triggers harmful peroxynitrite formation. Excessive NO﮲ disrupts protein function, aggravating CNS disorders. Recent studies investigate mGlu and muscarinic receptor modulators as potential treatments targeting NO﮲ pathways. However, clinical breakthroughs remain unattained despite ongoing research, highlighting the need for further exploration.\nThe study examined NO֗-related biochemical pathways in reversing schizophrenia-related deficits using mGlu and muscarinic ligands. We analyzed cGMP levels, oxidative stress, and s-nitrosylation in mouse brain samples. Additionally, some aspects of MK-801 and mGlu as well as muscarinic ligands administration on oxidative burst ware analyzed in in vitro study on C8D1a and 1231N1 cells lines. MK-801, a schizophrenia model compound, disrupted NO֗ signaling, impairing neurovascular stability. The tested ligands mitigated oxidative stress and prevented harmful NO֗ derivatives. Increased SOD activity suggested prior oxidative stress, with the compounds acting as antioxidants. MK-801 altered glutamate uptake, aligning with schizophrenia’s glutamatergic theory. Findings indicate that mGlu and muscarinic receptor activators may counteract schizophrenia-related dysfunctions through NO-dependent pathways, offering potential therapeutic benefits in neurovascular regulation.","manuscriptTitle":"The impact of muscarinic or mGlu activators on some NO-dependent biochemical pathways in MK-801 animal model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-02 09:17:12","doi":"10.21203/rs.3.rs-6287635/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-11T14:15:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-07T08:05:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-06T15:05:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9091106032555111794151084840625402806","date":"2025-03-30T16:34:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"297905908623338756896314417649308951534","date":"2025-03-30T15:49:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-28T17:40:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"274985208595515131357567489279651718746","date":"2025-03-27T09:23:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67939245335862443881426953278797278101","date":"2025-03-25T11:49:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"77764354368860897729694729152464920387","date":"2025-03-25T11:37:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-25T11:27:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-25T08:03:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-25T05:48:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pharmacological Reports","date":"2025-03-23T09:58:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pharmacological-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prep","sideBox":"Learn more about [Pharmacological Reports](https://link.springer.com/journal/43440)","snPcode":"43440","submissionUrl":"https://submission.springernature.com/new-submission/43440/3","title":"Pharmacological Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8825ae13-696b-4fef-ad3c-ff5b57e564ab","owner":[],"postedDate":"April 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-30T16:00:49+00:00","versionOfRecord":{"articleIdentity":"rs-6287635","link":"https://doi.org/10.1007/s43440-025-00752-3","journal":{"identity":"pharmacological-reports","isVorOnly":false,"title":"Pharmacological Reports"},"publishedOn":"2025-06-24 15:57:34","publishedOnDateReadable":"June 24th, 2025"},"versionCreatedAt":"2025-04-02 09:17:12","video":"","vorDoi":"10.1007/s43440-025-00752-3","vorDoiUrl":"https://doi.org/10.1007/s43440-025-00752-3","workflowStages":[]},"version":"v1","identity":"rs-6287635","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6287635","identity":"rs-6287635","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}