Cilostazol Treatment for Intracerebral Hemorrhage: Targeting Dural Lymphatics.

Abstract

The meningeal lymphatic system contributes to hematoma resolution and neurological recovery after intracerebral hemorrhage (ICH). We previously demonstrated that intraperitoneal cilostazol administration promotes dural lymphatic growth and enhances clearance of intracerebrally injected red blood cells; however, the antiplatelet effects of cilostazol raise safety concerns in ICH, potentially limiting clinical translation. Here, we evaluated whether oral cilostazol at clinical-equivalent doses in mice enhances dural lymphatic function and improves outcomes after ICH. ICH was induced by collagenase injection to model microvascular rupture. Cilostazol was orally administered to ICH mice at clinically equivalent doses, given at different time points and for varying durations. Prolymphangiogenic effects of cilostazol were examined in healthy in vivo and ex vivo meninges. Flow cytometry and immunofluorescence were performed to assess lymphatic endothelial cell proliferation and dural lymphatic remodeling. Lymphatic function was evaluated by in vivo live imaging and histological analysis of fluorescent tracer drainage. Short- and long-term histopathologic and behavioral outcomes were also evaluated. Oral cilostazol treatment initiated either 3 hours or 3 days after ICH enhanced dural lymphatic coverage and function, accompanied by reduced hematoma volume, neuronal injury, synapse loss, and long-term neurological deficits. Cilostazol increased CD31⁺PDPN⁺ lymphatic endothelial cells in ex vivo meninges, induced dural lymphatic hyperplasia, and enhanced lymphatic drainage in healthy mice. Both pretreatment and delayed treatment of cilostazol did not increase hematoma volume but rather improved ICH outcomes. By promoting dural lymphatic remodeling and drainage, cilostazol facilitates hematoma resolution and neurological recovery after ICH. Cilostazol treatment does not exacerbate initial bleeding or provoke hematoma expansion in the experimental ICH. These findings support clinical translation and provide mechanistic and dosing rationale for an ongoing phase II randomized trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT06504576).