A Novel Anti-Inflammatory Small Molecule MW189 Reduces Microglial Activation and Improves Functional Outcomes in a Murine Model of Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease with significant neurological morbidity. In current practice, there are limited pharmacological interventions to reduce the neurologic and functional deficits after SAH. The current study tests a novel therapy designed to reduce neuroinflammatory responses and improve functional outcomes in a clinically relevant murine model of SAH. METHODS: The effect of MW189, an anti-inflammatory small molecule investigational drug, was tested in a murine model of SAH induced by endovascular filament perforation. Male C57BL/6 J mice (10-12 weeks old) were treated with MW189 at a dose of 5 mg/kg in 100 µl 0.9% NaCl or vehicle delivered by intraperitoneal injection at 30 min post-SAH and every 12 h (q12h) for 7 days. Functional outcomes, including Rotarod latency, neuroseverity score, and gait performance were assessed, as well as the effect of treatment on histological evidence of microgliosis, using unbiased stereological measurements with TMEM119 immunohistochemistry. To assess sex effects, functional outcomes were determined in a separate cohort of female mice using the same SAH induction/treatment paradigm. RESULTS: In male mice, treatment with MW189 was associated with durable functional improvements during the 35-day testing period, including improvements in Rotarod latency, neuroseverity score, CatWalk gait speed, and shortened run duration. MW189 treatment reduced microglial activation as assessed by TMEM119 staining. In female animals, there was overall increased mortality following SAH induction, but MW189 treatment was associated with increased survival compared with vehicle treatment, significant improvements in Rotarod latency and CatWalk run duration, and trends toward improvement in CatWalk speed and neuroseverity score. CONCLUSIONS: Treatment with MW189 was associated with durable functional improvement in a murine model of SAH. MW189-treated mice also showed a reduction in microgliosis and several proinflammatory proteins consistent with an anti-inflammatory mechanism of action.

Duke Scholars

Author Daniel Todd Laskowitz Neurology, Neurocritical Care

Author Haichen Wang Neurology, Neurocritical Care