Serum neurofilament light chain predicts stroke outcome and is a potential marker for treatment effects of neural stem cell-derived extracellular vesicles in a rat stroke model

Abstract

Acute ischemic stroke (AIS) remains a leading cause of disability worldwide, and effective treatments are urgently needed beyond reperfusion therapy. Translating preclinical success to clinical impact has been hindered by variability in animal models and the lack of translational biomarkers that predict outcomes across species. To overcome these barriers, we developed a robust rat AIS model optimized for consistency and severity, enabling rigorous therapeutic testing. Additionally, we tested a panel of common clinical serum biomarkers to improve translation from rodents to humans. We demonstrated that serum neurofilament light chain (NfL) -a biomarker widely used in clinical stroke studies-strongly correlated with functional outcomes, establishing a translational link that has not been previously reported in rats. Notably, NfLs predictive capabilities outperformed infarct volume, a key prognostic factor in moderate and severe strokes, as well as traditional serum biomarkers intercellular adhesion molecule-1 (ICAM-1) and S100 calcium binding protein (S100B). Using this platform, we evaluated the therapeutic impact of neural stem cell-derived extracellular vesicles (NSC EVs), a novel biologic therapy poised for clinical trials, on stroke outcome in our rat AIS model. A three-dose regimen of NSC EV over 48 hours produced the best outcomes in stroked animals evidenced by smaller infarct volume, improved neurologic score, and reduced serum NfL, although single-dose and two-dose regimens were both effective at some endpoints. These findings not only validate NfL as a cross-species biomarker but also provide critical dosing insights for NSC EV therapy, accelerating the path from bench to bedside for AIS treatment.