English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

Objective  Rho‐associated kinase ( ROCK ) is a key regulator of numerous processes in multiple cell types relevant in stroke pathophysiology.  ROCK  inhibitors have improved outcome in experimental models of acute ischemic or hemorrhagic stroke. However, the relevant  ROCK  isoform ( ROCK 1 or  ROCK 2) in acute stroke is not known.    Methods  We characterized the pharmacodynamic and pharmacokinetic profile, and tested the efficacy and safety of a novel selective  ROCK 2 inhibitor  KD 025 (formerly  SL x‐2119) in focal cerebral ischemia models in mice.    Results   KD 025 dose‐dependently reduced infarct volume after transient middle cerebral artery occlusion. The therapeutic window was at least 3 h from stroke onset, and the efficacy was sustained for at least 4 weeks.  KD 025 was at least as efficacious in aged, diabetic or female mice, as in normal adult males. Concurrent treatment with atorvastatin was safe, but not additive or synergistic.  KD 025 was also safe in a permanent ischemia model, albeit with diminished efficacy. As one mechanism of protection,  KD 025 improved cortical perfusion in a distal middle cerebral artery occlusion model, implicating enhanced collateral flow. Unlike isoform‐nonselective  ROCK  inhibitors,  KD 025 did not cause significant hypotension, a dose‐limiting side effect in acute ischemic stroke.    Interpretation  Altogether, these data show that  KD 025 is efficacious and safe in acute focal cerebral ischemia in mice, implicating  ROCK 2 as the relevant isoform in acute ischemic stroke. Data suggest that selective  ROCK 2 inhibition has a favorable safety profile to facilitate clinical translation.

Selective ROCK 2 inhibition in focal cerebral ischemia