{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:40:12Z","timestamp":1760031612681,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["25460910","16K09255","19K07873"],"award-info":[{"award-number":["25460910","16K09255","19K07873"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dysphagia is a serious complication of stroke, yet effective pharmacological treatments remain limited. This study investigated the effects of FAD012 (3,5-dimethyl-4-hydroxy cinnamic acid), a synthetic derivative of ferulic acid (FA), on cerebral damage and swallowing dysfunction in a rat model of bilateral common carotid artery occlusion (2VO). Sprague\u2013Dawley rats were orally administered FAD012 (3 or 10 mg\/kg), FA (10 mg\/kg), or 0.5% carboxymethyl cellulose (CMC, suspension vehicle) starting one week before 2VO. Two weeks after 2VO surgery, which was performed under isoflurane anesthesia, reflex swallowing was assessed by electromyographic recordings of the mylohyoid muscle under urethane anesthesia. Two weeks after 2VO, cerebral blood flow (CBF) declined to approximately 40% of baseline, and the number of reflex swallowing responses was significantly reduced in the CMC group. Additionally, 2VO induced O2\u2212 production, apoptotic cell death in the striatum, and a reduction in tyrosine hydroxylase expression. Substance P (SP) levels in the laryngopharyngeal mucosa, positively regulated by dopaminergic signaling in the basal ganglia, also decreased. FAD012 (10 mg\/kg) effectively prevented the 2VO-induced reduction in CBF, enhanced the reflex swallowing, and preserved the dopamine-SP system. Notably, FAD012 exerted significantly stronger effects than FA at the same dose. These findings suggest that FAD012 maintains CBF under cerebral hypoperfusion and enhances the swallowing reflex by maintaining neuronal function in the striatal and laryngopharyngeal regions of 2VO rats.<\/jats:p>","DOI":"10.3390\/ijms26073277","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T04:06:05Z","timestamp":1743566765000},"page":"3277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Chronic Administration with FAD012 (3,5-Dimethyl-4-hydroxycinnamic Acid) Maintains Cerebral Blood Flow and Ameliorates Swallowing Dysfunction After Chronic Cerebral Hypoperfusion in Rats"],"prefix":"10.3390","volume":"26","author":[{"given":"Takashi","family":"Asano","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0592-5160","authenticated-orcid":false,"given":"Hirokazu","family":"Matsuzaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiyan","family":"Xuan","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3406-258X","authenticated-orcid":false,"given":"Bo","family":"Yuan","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Takayama","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S1474-4422(19)30034-1","article-title":"Global, regional, and national burden of stroke, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Johnson","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e347","DOI":"10.1161\/CIR.0000000000001209","article-title":"2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association","volume":"149","author":"Martin","year":"2024","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1159\/000069936","article-title":"Long-term outcome after ischaemic stroke\/transient ischaemic attack","volume":"16","author":"Hankey","year":"2003","journal-title":"Cerebrovasc. 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