{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T02:47:52Z","timestamp":1788662872920,"version":"build-2803163510"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,1,12]],"date-time":"2016-01-12T00:00:00Z","timestamp":1452556800000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004435","name":"Universidad de Navarra","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004435","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001570","name":"CS Fund","doi-asserted-by":"publisher","award":["PTQ\u201012\u201005641"],"award-info":[{"award-number":["PTQ\u201012\u201005641"]}],"id":[{"id":"10.13039\/100001570","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Sildenafil (Viagra) is a selective inhibitor of phosphodiesterase type 5 (<jats:styled-content style=\"fixed-case\">PDE<\/jats:styled-content>5), which degrades cyclic guanosine monophosphate to the linear nucleotide. Sildenafil is acutely used in erectile dysfunction and chronically in pulmonary hypertension. Evidence in the last decade shows that sildenafil may have potential as a therapeutic option for Alzheimer's disease or other neurodegenerative disorders. The purpose of this work was to explore whether sildenafil crosses the blood\u2013brain barrier. Pharmacokinetic properties of sildenafil in rodents were investigated using <jats:sup>11<\/jats:sup>C\u2010radiolabeling followed by <jats:italic>in\u00a0vivo<\/jats:italic> positron emission tomography (<jats:styled-content style=\"fixed-case\">PET<\/jats:styled-content>) and <jats:italic>ex\u00a0vivo<\/jats:italic> tissue dissection and gamma counting. <jats:styled-content style=\"fixed-case\">PET<\/jats:styled-content> results in rats suggest penetration into the central nervous system. <jats:italic>Ex vivo<\/jats:italic> data in perfused animals suggest that trapping of [<jats:sup>11<\/jats:sup>C]sildenafil within the cerebral vascular endothelium limits accumulation in the central nervous system parenchyma. Peroral sildenafil administration to <jats:italic>Macaca fascicularis<\/jats:italic> and subsequent chemical analysis of plasma and cerebrospinal fluid (<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content>) using liquid chromatography coupled with tandem mass spectrometry showed that drug content in the <jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content> was high enough to achieve <jats:styled-content style=\"fixed-case\">PDE<\/jats:styled-content>5 inhibition, which was also demonstrated by the significant increases in <jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content> cyclic guanosine monophosphate levels. Central actions of sildenafil include both relaxation of the cerebral vasculature and inhibition of <jats:styled-content style=\"fixed-case\">PDE<\/jats:styled-content>5 in neurons and glia. This central action of sildenafil may underlie its efficacy in neuroprotection models, and may justify the continued search for a <jats:styled-content style=\"fixed-case\">PDE<\/jats:styled-content>5 ligand suitable for <jats:styled-content style=\"fixed-case\">PET<\/jats:styled-content> imaging.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13454-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\nSildenafil interacts with phosphodiesterase type 5 (<jats:styled-content style=\"fixed-case\">PDE<\/jats:styled-content>5) expressed in the endothelium and\/or smooth muscle cells of brain vessels and also crosses the blood\u2013brain barrier to interact with <jats:styled-content style=\"fixed-case\">PDE<\/jats:styled-content>5 expressed in brain cells. At therapeutic doses, the concentration of sildenafil in the cerebrospinal fluid (<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content>) is high enough to inhibit <jats:styled-content style=\"fixed-case\">PDE<\/jats:styled-content>5 in the neural cells (neurons and glia). In turn, the concentration of <jats:styled-content style=\"fixed-case\">cGMP<\/jats:styled-content> likely increases in parenchymal cells and, as shown in this report, in the <jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content>.<\/jats:p><jats:p>Read the <jats:bold>Editorial Highlight<\/jats:bold> for this article on page <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/dx.doi.org\/10.1111\/jnc.13453\">220<\/jats:ext-link>.<\/jats:p><jats:p><jats:bold>Cover Image<\/jats:bold> for this issue: doi: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1111\/jnc.13302\">10.1111\/jnc.13302<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13454","type":"journal-article","created":{"date-parts":[[2015,12,8]],"date-time":"2015-12-08T18:30:41Z","timestamp":1449599441000},"page":"403-415","source":"Crossref","is-referenced-by-count":50,"title":["Pharmacokinetic investigation of sildenafil using positron emission tomography and determination of its effect on cerebrospinal fluid <scp>cGMP<\/scp> levels"],"prefix":"10.1111","volume":"136","author":[{"given":"Vanessa","family":"G\u00f3mez\u2010Vallejo","sequence":"first","affiliation":[{"name":"Radiochemistry Platform CIC biomaGUNE San Sebastian Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ugarte","sequence":"additional","affiliation":[{"name":"Small Molecule Discovery Platform Molecular Therapeutics Program Centre for Applied Medical Research (CIMA) University of Navarra Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Garc\u00eda\u2010Barroso","sequence":"additional","affiliation":[{"name":"Neurobiology of Alzheimer's disease Neurosciences Division Centre for Applied Medical Research (CIMA) University of Navarra Pamplona 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