Journal article
Fingolimod as a Potential Cerebroprotectant Results From the Stroke Preclinical Assessment Network
Stroke (1970), Vol.56(11), pp.3280-3293
11/2025
DOI: 10.1161/STROKEAHA.125.050903
PMID: 40899256
Abstract
Fingolimod is an immunomodulatory drug that has shown promising effects in stroke treatment, including improvements in neurofunctional recovery and a reduction in infarct size. Fingolimod modulates the sphingosine-1-phosphate receptors, which leads to the internalization of sphingosine-1-phosphate receptors on T and B lymphocytes, thereby preventing their egress from secondary lymphoid organs. Here, we report a secondary analysis from the Stroke Preclinical Assessment Network trial. We assessed the effects of fingolimod versus vehicle on stroke outcomes to better evaluate its therapeutic potential.
The animal population (n=409) comprised male and female animals treated with fingolimod or vehicle. We used 4 clinically relevant models: young healthy mice (10-12 weeks-old), aging mice (16±1 month-old), obesity induced-hyperglycemic mice fed with a high-fat diet for 12 weeks (16 weeks-old), and spontaneously hypertensive rats (16±1 weeks-old). Stroke was induced by the middle cerebral artery occlusion for 1 hour, followed by reperfusion. Animals received a total of 6 intraperitoneal injections of 0.5 mg/kg twice daily of fingolimod or vehicle. Functional outcomes in the corner test and foot-faults test were measured at days 7 and 28. Lesion size and brain morphometry were evaluated at days 2 and 30 by magnetic resonance imaging.
Overall, fingolimod did not improve morphological and functional outcomes. However, fingolimod effects varied depending on sex or the comorbidity model. Fingolimod promoted a better outcome in the corner test in aging females. In contrast, it favored a worse outcome in obesity-induced hyperglycemic mice at day 7. Despite having no effect on survival rates or lesion size, fingolimod attenuated the midline retraction at day 30 in aging males, consistent with less atrophy.
Although fingolimod did not significantly benefit the overall primary functional outcome, its effects varied with sex and comorbidity models, underscoring how the therapeutic potential of a particular drug can differ in a heterogeneous population.
Details
- Title: Subtitle
- Fingolimod as a Potential Cerebroprotectant Results From the Stroke Preclinical Assessment Network
- Creators
- Ligia S B Boisserand - Yale UniversityAlison L Herman - Yale UniversityBasavaraju G Sanganahalli - Yale UniversityJelena Mihailovic - Yale UniversityHannah E Beatty - Yale UniversityConor W Johnson - Yale UniversitySebastian Diaz - Yale School of MedicineJonathan H DeLong - Yale UniversitySofia Velazquez - Yale UniversityJaime Grutzendler - Yale UniversityCharles Dela Cruz - University of PittsburghJiangbing Zhou - Yale UniversityKevin N Sheth - Yale UniversityCharles Matouk - Yale UniversityShenqi Zhan - University of New HavenAndreia Morais - Massachusetts General HospitalTakahiko Imai - Massachusetts General HospitalAnjali Chauhan - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (A.C., L.D.M.C., J.A.)Rakesh B Patel - University of Iowa, Internal MedicineMariia Kumskova - University of IowaYanrong Shi - Johns Hopkins UniversityBrooklyn D Avery - Johns Hopkins UniversityJessica Lamb - Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (J.L., K.A.N., P.L.)Karisma A Nagarkatti - Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (J.L., K.A.N., P.L.)Mohammad B Khan - Augusta UniversityPradip K Kamat - Augusta UniversityKrishnan M Dhandapani - Augusta UniversityLouise D McCullough - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (A.C., L.D.M.C., J.A.)Jaroslaw Aronowski - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (A.C., L.D.M.C., J.A.)David Hess - Augusta UniversityRaymond C Koehler - Johns Hopkins UniversityPatrick Lyden - Keck Hospital of USCEnrique C Leira - University of IowaAnil K Chauhan - University of IowaCenk Ayata - Massachusetts General HospitalMu-Hsun Chen - Icahn School of Medicine at Mount SinaiMarcio A Diniz - Icahn School of Medicine at Mount SinaiFahmeed Hyder - Yale UniversityLauren H Sansing - Yale UniversitySPAN investigators
- Resource Type
- Journal article
- Publication Details
- Stroke (1970), Vol.56(11), pp.3280-3293
- DOI
- 10.1161/STROKEAHA.125.050903
- PMID
- 40899256
- NLM abbreviation
- Stroke
- ISSN
- 1524-4628
- eISSN
- 1524-4628
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- Grant note
- National Institutes of Health: U01NS113388, R35 HL139926 University of Southern California: U24NS113452 Yale University School of Medicine: U01NS113445 Johns Hopkins University: U01NS113444, R01NS102583, R01NS105894 Augusta University: R01 NS099455, 1UO1NS113356, R01NS112511 Massachusetts General Hospital: U01 NS113443 University of Texas: U01NS113451 National Institutes of HealthUniversity of Southern CaliforniaUniversity School of MedicineJohns Hopkins UniversityAugusta UniversityMassachusetts General HospitalUniversity of Texas
This study was funded by National Institutes of Health funding to the University of Iowa (U01NS113388, R35 HL139926, Dr Chauhan and U01NS113388, Dr Leira), the University of Southern California (U24NS113452, Dr Lyden), the Yale University School of Medicine (U01NS113445, Dr Sansing), the Johns Hopkins University (U01NS113444, R01NS102583, and R01NS105894, Dr Koehler), the Augusta University(R01 NS099455, 1UO1NS113356, and R01NS112511, Dr Hess), the Massachusetts General Hospital (U01 NS113443, Dr Ayata), the University of Texas (U01NS113451, Dr McCullough and Dr Aronowski).
- Language
- English
- Electronic publication date
- 09/03/2025
- Date published
- 11/2025
- Academic Unit
- Neurology; Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
- Record Identifier
- 9984958607102771
Metrics
9 Record Views