Abstract WP163: Therapeutic Efficacy and Safety Evaluation of Cilostazol for Intracerebral Hemorrhage Through Enhancing Meningeal Lymphatic Function: A Preclinical Study

Background: Intracerebral hemorrhage (ICH) is the deadliest form of stroke with no effective treatment to date. Toxic byproducts from hematoma-lysis affected ICH-induced brain injury and long-term behavioral impairment. Enhancing hematoma clearance has shown therapeutic potential in reducing brain damage and neurologic deficits. Our previous work shows that cilostazol (CSZ) promotes meningeal lymphangiogenesis and drainage, aiding hematoma resolution and brain recovery after ICH. Here we explore the optimal dosage, therapeutic window, and potential adverse effects of CSZ treatment in preclinical ICH.

Methods: A dose of 200 mg/day CSZ is used in clinics which translates to around 40 mg/kg in mice. CSZ (10, 20, and 40 mg/kg) or vehicle was given after ICH induction and was continued for various durations. Pretreatment of CSZ before ICH induction was used to assess its antiplatelet property on intra-parenchymal bleeding. Meningeal lymphatic vessel (mLV) complexity and coverage rate were measured. Lymphatic drainage was evaluated by fluorescent microbead accumulation in the mLV and deep cervical lymph nodes. Neurobehaviors were tested by corner turn test, whisker-evoked tactile responses, hindlimb abduction test, and neurologic deficit scoring. Iron deposition, hematoma, and neuron loss were assessed by immunohistochemistry.

Results: ICH mice treated with CSZ showed enhanced mLV complexity and proliferation at the transverse, superior sagittal, and confluence of sinuses in the meninges. In parallel, histological, and behavioral outcomes also improved. Pretreatment with CSZ for 3 days before ICH induction did not increase hematoma volume, suggesting minimal to no adverse anticoagulant effect of CSZ in this setting.

Conclusion: In all, our results unfold the effects of CSZ on mLV function regarding ICH. These findings may be applied as outcome parameters and provide a roadmap for sample size estimation in future clinical trials using CSZ as ICH treatment.