{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T05:50:52Z","timestamp":1767765052433,"version":"3.48.0"},"reference-count":136,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T00:00:00Z","timestamp":1767398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000156","name":"Fonds de Recherche du Qu\u00e9bec - Sant\u00e9","doi-asserted-by":"publisher","award":["21667"],"award-info":[{"award-number":["21667"]}],"id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s Disease (HD) is characterized by prominent degeneration of the principal neurons of the striatum and by progressive motor and cognitive deterioration. Striatal neurons degenerate in HD due to multiple cell-autonomous and non-autonomous factors. Impaired neurotrophin signaling by brain-derived neurotrophic factor (BDNF) and its cognate receptor Tropomyosin receptor kinase B (TrkB) is an important mechanism underlying neuronal loss in HD. Fingolimod, a clinically approved oral drug for Multiple Sclerosis, was originally developed based on its anti-inflammatory properties. Recent work suggests that fingolimod can also promote BDNF expression and enhance neurotrophic support in the brain. We hypothesized that fingolimod treatment initiated during the presymptomatic phase would increase striatal BDNF levels and protect against motor dysfunction in HD. In wild-type mice, fingolimod treatment increases striatal BDNF levels and enhances BDNF-TrkB signaling. However, chronic fingolimod therapy (0.1 mg\/kg, i.p., twice per week, over 7 weeks) initiated at age 4 weeks in the R6\/2 mouse model of HD failed to improve behavioral locomotor deficits and exacerbated limb clasping. Furthermore, fingolimod treatment in these presymptomatic R6\/2 mice acutely decreased BDNF-TrkB signaling in the striatum in a dose-dependent manner. In contrast, acute administration of fingolimod in symptomatic 7-week-old R6\/2 mice increased striatal BDNF-TrkB signaling in a dose-dependent manner, consistent with previous work suggesting that chronic fingolimod can improve motor behavior when given during the symptomatic phase. Thus, the effects of fingolimod striatal BDNF-TrkB signaling and motor behavior in HD are complex and vary with disease stage. Addressing this variability is critical for the design of neuroprotective drug trials in HD, including those utilizing sphingosine-1-phosphate receptor (S1P) modulators.<\/jats:p>","DOI":"10.3390\/ijms27010494","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T12:38:56Z","timestamp":1767616736000},"page":"494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fingolimod Effects on Motor Function and BDNF-TrkB Signaling in a Huntington\u2019s Mouse Model Are Disease-Stage-Dependent"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5378-6671","authenticated-orcid":false,"given":"Khanh Q.","family":"Nguyen","sequence":"first","affiliation":[{"name":"Cone Laboratory, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir V.","family":"Rymar","sequence":"additional","affiliation":[{"name":"Cone Laboratory, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abbas F.","family":"Sadikot","sequence":"additional","affiliation":[{"name":"Cone Laboratory, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/0166-2236(89)90074-X","article-title":"The functional anatomy of basal ganglia disorders","volume":"12","author":"Albin","year":"1989","journal-title":"Trends Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0165-0173(94)00007-C","article-title":"Functional anatomy of the basal ganglia. 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