{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:57:50Z","timestamp":1791320270888,"version":"4.3.1"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001734","name":"Copenhagen University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001734","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Headache Pain"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Phosphodiesterase 3 (PDE-3) inhibition have been implicated in the neurobiologic underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to ascertain whether PDE-3 inhibition can elicit migraine-like headache in persons with PPTH.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We tested cilostazol, which inhibits PDE-3, in a randomized, double-blind, placebo-controlled, two-way crossover study involving persons with PPTH attributed to mild traumatic brain injury. The randomized participants were allocated to receive oral administration of either 200-mg cilostazol or placebo (calcium tablet) on two separate experiment days. The primary end point was the incidence of migraine-like headache during a 12-hour observation window post-ingestion. The secondary endpoint was the area under the curve (AUC) for reported headache intensity scores during the same observation window.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Twenty-one persons underwent randomization and completed both experiment days. The mean participants\u2019 age was 41.4 years, and most (<jats:italic>n<\/jats:italic>\u2009=\u200917) were females. During the 12-hour observation window, 14 (67%) of 21 participants developed migraine-like headache post-cilostazol, in contrast to three (14%) participants after placebo (<jats:italic>P<\/jats:italic>\u2009=.003). The headache intensity scores were higher post-cilostazol than after placebo (<jats:italic>P<\/jats:italic>\u2009&lt;.001).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our results provide novel evidence showing that PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. Given that PDE-3 inhibition increases intracellular cAMP levels, our findings allude to the potential therapeutic value of targeting cAMP-dependent signaling pathways in the management of PPTH. Further investigations are imperative to substantiate these insights and delineate the importance of cAMP-dependent signaling pathways in the neurobiologic mechanisms underlying PPTH.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>ClinicalTrials.gov Identifier<\/jats:title>\n                <jats:p>NCT05595993.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s10194-024-01762-x","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T23:02:11Z","timestamp":1713308531000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Effects of PDE-3 inhibition in persistent post-traumatic headache: evidence of cAMP-dependent signaling"],"prefix":"10.1186","volume":"25","author":[{"given":"Haidar M.","family":"Al-Khazali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rune H.","family":"Christensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basit Ali","family":"Chaudhry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna G.","family":"Melchior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Messoud","family":"Ashina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Burstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kan","family":"Ashina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"1762_CR1","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/s41582-019-0243-8","volume":"15","author":"H Ashina","year":"2019","unstructured":"Ashina H, Porreca F, Anderson T et al (2019) Post-traumatic headache: epidemiology and pathophysiological insights. 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R.B. reports research support received from Allergan, Dr. Reddy\u2019s Laboratories, Eli Lilly, and Teva, outside of the submitted work. In addition, R.B. has received honoraria, acted as a consultant or advisory board member for Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Biohaven, CGRP Diagnostics, Dr. Reddy\u2019s Laboratories, ElectroCore, Eli Lilly, GlaxoSmithKline, Merck, Pernix, Teva, and Trigemina. R.B. also reports receiving CME fees from Healthlogix, Medlogix, and WebMD\/Medscape, and holds patents for several products, including (9061025, 11732265.1, 10806890, US2021-0015908, WO21007165, US2021-0128724, WO21005497). M.A. reports receiving personal fees from AbbVie, Amgen, Astra Zeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals, outside of the submitted work. M.A. also serves as an Associate editor of Brain and The Journal of Headache and Pain. R.B. is a reviewer for the National Institute of Neurological Disorders and Stroke (NINDS) and holds stock options in Allay Lamp and Percept, outside of the submitted work. H.A. reports personal fees from Lundbeck and Teva, outside of the submitted work. The remaining authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"56"}}