Fingolimod as a Neuroprotective Agent in Ischemic Stroke: A Review of Preclinical and Clinical Evidence.

Ischemic stroke remains a leading cause of mortality and disability worldwide, with current therapies such as intravenous thrombolysis and mechanical thrombectomy benefiting only a limited proportion of patients. Neuroinflammation is a key contributor to secondary brain injury, creating a strong rationale for adjunctive therapies targeting immune modulation. Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator originally approved for multiple sclerosis, has shown promising effects in both preclinical and early clinical studies of acute ischemic stroke. METHODS: We conducted a structured narrative review of preclinical and clinical studies published between 2015 and 2024, using PubMed, Scopus, and Web of Science databases. Inclusion criteria were original studies evaluating fingolimod in ischemic stroke models or human patients, either as monotherapy or in combination with reperfusion therapies. Exclusion criteria included conference abstracts without peer review, studies lacking mechanistic insight, and non-English publications. RESULTS: Preclinical evidence demonstrates that fingolimod reduces infarct size, preserves blood-brain barrier integrity, and modulates neuroinflammation through multiple mechanisms, including T cell sequestration, microglial polarization, and mitochondrial protection. Clinical trials, though limited in size, suggest improved short- and long-term outcomes when fingolimod is used in combination with intravenous thrombolysis or endovascular therapy, with a manageable safety profile. Novel nanotechnology-based delivery systems further enhance central nervous system (CNS) targeting and reduce systemic side effects. CONCLUSIONS: Fingolimod represents a promising multi-targeted adjunctive strategy for ischemic stroke, acting at the intersection of immune modulation, vascular protection, and neuroprotection. While current findings are encouraging, larger randomized controlled trials and biomarker-driven patient selection are needed to validate its clinical utility. This review highlights the translational potential of fingolimod and outlines key directions for future research.