Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin

Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin | 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 Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin Akiko Ohashi, Eiko Nakamaru-Ogiso, Hiroshi Matsuoka, Shin Aizawa, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4111864/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Tetrahydrobiopterin (BH4) is an essential coenzyme for tryptophan and tyrosine hydroxylases, making brain monoamine biosynthesis BH4-dependent. Peripheral administration of BH4 successfully replenishes hepatic BH4 in hereditary BH4 deficiency and enables the function of another BH4-dependent enzyme, phenylalanine hydroxylase. However, brain BH4 replenishment has been unsuccessful for decades because BH4 cannot effectively cross the blood–brain barrier (BBB). Sepiapterin, a highly membrane-permeable precursor of BH4, has been tested but abandoned due to extensive conversion to BH4 before reaching the brain. This study re-examines whether peripherally administered sepiapterin can (i) reach the brain, (ii) cross the BBB, (iii) be taken up by brain cells, and (iv) increase brain BH4 levels. As a result, peripherally administered sepiapterin reached the brain when the dose was above a threshold. All subsequent steps were positive. Sepiapterin administration dose-dependently increased brain BH4 levels, reaching 3–4 times baseline levels for over 6 hours at practical doses. In addition, we quantified and analyzed sepiapterin permeability across potential barriers using knowledge of the transporters responsible for sepiapterin and BH4 permeation across cell membranes and confirmed that these results were theoretically consistent. This suggests that sepiapterin administration may be a promising treatment to increase monoamine synthesis in various neurotransmitter deficiencies. General Biochemistry Cellular & Molecular Neuroscience Cellular Metabolism Drug Delivery Blood–brain barrier Cerebral monoamine Permeability Transporter Replenishment Sepiapterin Tetrahydrobiopterin Full Text Additional Declarations The authors declare potential competing interests as follows: HH provided Shiratori Pharmaceutical Co., Ltd. with advice regarding the potential use of sepiapterin (2013). HH was an advisory board member (2016–2021) and holds stock options in Censa Pharmaceuticals Inc (acquired by PTC Therapeutics). Intellectual property rights in PCT application (WO2011/132435) invented by HH and SA were assigned to Censa Pharmaceuticals Inc (acquired by PTC Therapeutics). Supplementary Files Hasegawasuppl241002.docx Supplementary Information for Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-4111864","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":280973416,"identity":"a0a4a8cd-a262-4313-bef1-9aae9583c48a","order_by":0,"name":"Akiko Ohashi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIie2QsUoDQRCGZwl4zR7bbojkXmGOQKII+iqRK2x8gICiJwtXbXqF4GMEy4QF00zOVsFOsLIw5WHjcGAE2QuxE9mvGdiZj/lnAQKBP4kEELnmKgzACCR+t2bbKLS9UtcWiAIAG+bWqGg8X1V3e6CsM7i6fd4dRONZS8JhAmLpXdO2ZdaJSYNeXpnjm+mr3LflkJUszaEc+hR8PMWOKPiWB2FcPHWSXwYfnJLHyRuSB3pVxUpSK5NaQd5yuUnp65gV5GBZnK8V16i0LfUPWJEpzU16fc8KEYoJLtKi4RYV2d5TVVx0u3Tyot/P3REuLMLb6CxR2v9jX8ifgQF2NG0yvCj7ayUQCAT+JZ/QaVrgV1tt+QAAAABJRU5ErkJggg==","orcid":"","institution":"Nihon University School of Dentistry","correspondingAuthor":true,"prefix":"","firstName":"Akiko","middleName":"","lastName":"Ohashi","suffix":""},{"id":280973417,"identity":"b331cbf4-8bb2-4eca-80b4-81580fc87a14","order_by":1,"name":"Eiko Nakamaru-Ogiso","email":"","orcid":"","institution":"The Children’s Hospital of Philadelphia","correspondingAuthor":false,"prefix":"","firstName":"Eiko","middleName":"","lastName":"Nakamaru-Ogiso","suffix":""},{"id":280973418,"identity":"df99195f-25ad-4c32-8c18-e2b0201c3d2f","order_by":2,"name":"Hiroshi Matsuoka","email":"","orcid":"","institution":"Teikyo University of Science","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Matsuoka","suffix":""},{"id":280973419,"identity":"b22b662e-43de-4bc5-a3aa-b0a0683f1848","order_by":3,"name":"Shin Aizawa","email":"","orcid":"","institution":"Nihon University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shin","middleName":"","lastName":"Aizawa","suffix":""},{"id":280973420,"identity":"0e4c823f-f929-4650-aa45-c6e729f8dbbb","order_by":4,"name":"Hiroyuki Hasegawa","email":"data:image/png;base64,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","orcid":"","institution":"No affiliation","correspondingAuthor":true,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Hasegawa","suffix":""}],"badges":[],"createdAt":"2024-03-16 07:38:52","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true},"doi":"10.21203/rs.3.rs-4111864/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-4111864/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66197494,"identity":"0bbdb83c-6a0c-43ed-bba9-97172e37bc91","added_by":"auto","created_at":"2024-10-08 14:57:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1072066,"visible":true,"origin":"","legend":"","description":"","filename":"Hasegawamaintext241002.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4111864/v2_covered_47047905-e77c-4a42-aecd-ed4d292d4587.pdf"},{"id":66195437,"identity":"159a314a-d8cb-40a8-bc8b-36ed284bea8f","added_by":"auto","created_at":"2024-10-08 14:40:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":191179,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Information for\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePeripheral administration of sepiapterin replenishes brain tetrahydrobiopterin\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Hasegawasuppl241002.docx","url":"https://assets-eu.researchsquare.com/files/rs-4111864/v2/3689b7d9fb7b55fab14fcb63.docx"}],"financialInterests":"The authors declare potential competing interests as follows: HH provided Shiratori Pharmaceutical Co., Ltd. with advice regarding the potential use of sepiapterin (2013). 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Intellectual property rights in PCT application (WO2011/132435) invented by HH and SA were assigned to Censa Pharmaceuticals Inc (acquired by PTC Therapeutics).","formattedTitle":"\u003cp\u003ePeripheral administration of sepiapterin replenishes brain tetrahydrobiopterin\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Nihon University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Blood–brain barrier, Cerebral monoamine, Permeability, Transporter, Replenishment, Sepiapterin, Tetrahydrobiopterin","lastPublishedDoi":"10.21203/rs.3.rs-4111864/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4111864/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTetrahydrobiopterin (BH4) is an essential coenzyme for tryptophan and tyrosine hydroxylases, making brain monoamine biosynthesis BH4-dependent. Peripheral administration of BH4 successfully replenishes hepatic BH4 in hereditary BH4 deficiency and enables the function of another BH4-dependent enzyme, phenylalanine hydroxylase. However, brain BH4 replenishment has been unsuccessful for decades because BH4 cannot effectively cross the blood\u0026ndash;brain barrier (BBB). Sepiapterin, a highly membrane-permeable precursor of BH4, has been tested but abandoned due to extensive conversion to BH4 before reaching the brain. This study re-examines whether peripherally administered sepiapterin can (i) reach the brain, (ii) cross the BBB, (iii) be taken up by brain cells, and (iv) increase brain BH4 levels. As a result, peripherally administered sepiapterin reached the brain when the dose was above a threshold. All subsequent steps were positive. Sepiapterin administration dose-dependently increased brain BH4 levels, reaching 3\u0026ndash;4 times baseline levels for over 6 hours at practical doses. In addition, we quantified and analyzed sepiapterin permeability across potential barriers using knowledge of the transporters responsible for sepiapterin and BH4 permeation across cell membranes and confirmed that these results were theoretically consistent. 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