Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase-9 inhibition

Abstract

Objective: Delayed cerebral ischemia (DCI) is an independent risk factor for poor outcome after aneurysmal subarachnoid hemorrhage (SAH) and is multifactorial in etiology. While prior studies have suggested a role for matrix metalloproteinase-9 (MMP-9) in early brain injury after SAH, its contribution to the pathophysiology of DCI is unclear. Methods: In the first experiment, wild-type (WT) and MMP-9−/− mice were subjected to sham or endovascular perforation SAH surgery. In separate experiments, WT and MMP-9−/−mice were administered vehicle or minocycline either pre- or post-SAH. All mice underwent assessment of multiple components of DCI including vasospasm, neurobehavioral function, and microvessel thrombosis. In another experiment, rabbits were subjected to sham or cisterna magna injection SAH surgery, and administered vehicle or minocycline followed by vasospasm assessment. Results: MMP-9 expression and activity was increased after SAH. Genetic (MMP-9−/− mice) and pharmacological (pre-SAH minocycline administration) inhibition of MMP-9 resulted in decreased vasospasm and neurobehavioral deficits. A therapeutically feasible strategy of post-SAH administration of minocycline resulted in attenuation of multiple components of DCI. Minocycline administration to MMP-9−/− mice did not yield additional protection. Consistent with experiments in mice, both pre- and post-SAH administration of minocycline attenuated SAH-induced vasospasm in rabbits. Interpretation: MMP-9 is a key player in the pathogenesis of DCI. The consistent attenuation of multiple components of DCI with both pre- and post-SAH administration of minocycline across different species and experimental models of SAH, combined with the excellent safety profile of minocycline in humans suggest that a clinical trial in SAH patients is warranted.