{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:53:08Z","timestamp":1791355988087,"version":"4.3.1"},"reference-count":88,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Multiple sclerosis (MS) is a demyelinating disorder characterized by oligodendrocyte apoptosis, microglial activation at demyelination sites, with ROS production. These pathological processes are closely associated with phosphodiesterase\u20104 (PDE\u20104) activity. Roflumilast (ROFL), a selective PDE\u20104 inhibitor, has demonstrated neuroprotective effects in various central nervous system disorders. However, its specific role in MS pathogenesis remains to be fully elucidated. This study aims to investigate the effects of ROFL on oligodendrocyte maturation, microglial polarization and the impact on protein kinase A\/cAMP\u2010response element binding protein pathway. An MS model was induced in mice via dietary administration of cuprizone (CPZ) for 7 days, starting with 0.7% (w\/w), followed by 0.2% for 5 weeks. Beginning in week 5, mice received ROFL (5\u2009mg\/kg\/day, p.o) for 2 weeks. ROFL improved the motor abnormalities in the rotarod and open field tests. Together, ROFL downregulated the PDE4\/cAMP\u2010dependent pathway, exerting anti\u2010inflammatory effects by suppressing NF\u2010\u03baB and TNF\u2010\u03b1. Additionally, microglial polarization shifted toward the anti\u2010inflammatory M2 phenotype, with CD163 increment, in contrast to the pro\u2010inflammatory M1 marker CD83. Furthermore, ROFL's antioxidant capacity was evidenced by reduced malondialdehyde levels, replenishment of glutathione levels, and reduced phosphorylation of ERK1\/2. Oligodendrocyte differentiation and maturation were enhanced, as indicated by elevated levels of proteolipid protein, myelin\u2010associated glycoprotein, CNPase, and myelin basic protein. Remyelination was confirmed through Luxol fast blue staining, accompanied by reduced apoptotic marker, caspase\u20103, in oligodendrocytes. Collectively, these findings suggest that ROFL exerts neuroprotective effects and highlight the therapeutic potential of PDE\u20104 inhibition as a strategy for MS treatment.<\/jats:p>","DOI":"10.1002\/ddr.70329","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T18:35:20Z","timestamp":1779993320000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unveiling Remyelinating Properties of Roflumilast in CPZ\u2010Induced Neuronal Demyelination in Mice"],"prefix":"10.1002","volume":"87","author":[{"given":"Ahmed S.","family":"Kamel","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Giza Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy and Drug Technology Egyptian Chinese University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israa","family":"Sameh","sequence":"additional","affiliation":[{"name":"Postgraduate program in Pharmacology and Toxicology department, Faculty of Pharmacy Cairo University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Khattab","sequence":"additional","affiliation":[{"name":"Department of Cytology and Histology, Faculty of Veterinary Medicine Cairo University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-2352","authenticated-orcid":false,"given":"Ayman E.","family":"El\u2010Sahar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala F.","family":"Zaki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama A.","family":"Badary","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmacy Ain Shams University Cairo Egypt"},{"name":"Clinical Pharmacy Department, College of Pharmaceutical Sciences and Drug Manufacturing Misr University for Science and Technology (MUST) 6th of October City Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sama M.","family":"Farrag","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences and Drug Manufacturing Misr University for Science and Technology  Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2009.03188.x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.29228\/jrp.320"},{"key":"e_1_2_11_4_1","first-page":"882","article-title":"Improved Method for the Determination of Blood Glutathione","volume":"61","author":"Beutler E.","year":"1963","journal-title":"Journal of Laboratory and Clinical Medicine"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.0C00636"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2018.03.020"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2017.05.045"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph5050514"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.2815"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.05.013"},{"key":"e_1_2_11_11_1","volume-title":"Handbook of Histopathological and Histochemical Techniques: Including Museum Techniques","author":"Culling C. 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