379 Matrix Metalloproteinase-9: A Key Contributor to Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

INTRODUCTION Delayed cerebral ischemia (DCI) is an independent risk factor for poor outcome after subarachnoid hemorrhage (SAH) and is multi-factorial in etiology. A few prior studies have suggested a key role for matrix metalloproteinase-9 (MMP-9) in the pathogenesis of early brain injury (EBI) after SAH. In contrast, the role of MMP-9 in DCI is poorly understood. In this study, we examined the contribution of MMP-9 to DCI after SAH. METHODS Wild type (WT) and MMP-9-/− mice were subjected to sham or endovascular perforation SAH surgery. Daily neurobehavioral assessments were performed, and vasospasm was assessed on post-SAH Day 3. MMP-9 expression and activity were also assessed. In separate experiments, WT mice or MMP-9-/− were administrated vehicle or Minocycline and subjected to vasospasm, neurobehavioral, and microthrombi assessments. In another experiment, male New Zealand White rabbits were subjected to sham surgery or cisterna magna injection SAH, and administered vehicle or Minocycline, followed by vasospasm assessment on post-SAH day 3. RESULTS >SAH resulted in a significant increase in MMP-9 expression and activity. Genetic inhibition of MMP-9 (MMP-9-/− mice) and pharmacological inhibition of MMP-9 (pre-SAH Minocycline administration) resulted in significantly decreased vasospasm and neurobehavioral deficits after SAH. Post-SAH administration of Minocycline resulted in significant attenuation of multiple components of DCI including vasospasm, microthrombosis and neurobehavioral deficits. Consistent with experiments in mice both pre- and post-SAH administration of Minocycline attenuated vasospasm in rabbits. CONCLUSION Our study provides definitive mechanistic evidence that MMP-9 is a key player in the pathogenesis of DCI after SAH. We observed consistent attenuation of SAH-induced neurovascular deficits with both pre- and post-SAH administration of minocycline across different species and experimental models of SAH, and against multiple components of DCI. The excellent safety profile of minocycline in humans and promising results in experimental SAH studies suggest that a clinical trial in SAH patients is warranted.