Isoform-selective and non-selective rho-kinase inhibitors do not affect collagenase-induced intracerebral hemorrhage outcomes in mice: Influence of sex and circadian cycle.

Abstract

Rho-associated protein kinase (ROCK) inhibitors are therapeutic candidates in ischemic stroke and subarachnoid hemorrhage. However, their efficacy in intracerebral hemorrhage (ICH) is unknown. Here, we tested the efficacy of fasudil (10 mg/kg), an isoform-nonselective ROCK inhibitor, and NRL-1049 (10 mg/kg), a novel inhibitor with 43-fold higher selectivity for ROCK2 isoform compared with ROCK1, in a collagenase-induced ICH model in mice. Both short (1-3 days) and prolonged (14 days) therapeutic paradigms were tested using robust sample sizes in both males and females and in active and inactive circadian stages. Outcome readouts included weight loss, mortality, hematoma volume, hemispheric swelling, brain water content, BBB permeability to large molecules, and sensorimotor and cognitive function. We found the treatments safe but not efficacious in improving the hematoma volume, BBB disruption, or neurological deficits in this collagenase-induced ICH model. Intriguingly, however, induction of ICH during the active circadian stage was associated with worse tissue and behavioral outcomes compared with the inactive stage.