Open AccessSelective ROCK 2 inhibition in focal cerebral ischemia
Author(s) -
Hyun Lee Jeong,
Zheng Yi,
Bornstadt Daniel,
Wei Ying,
Balcioglu Aygul,
Daneshmand Ali,
Yalcin Nilufer,
Yu Esther,
Herisson Fanny,
Atalay Yahya B.,
Kim Maya H.,
Ahn YongJoo,
Balkaya Mustafa,
Sweetnam Paul,
Schueller Olivier,
Poyurovsky Masha V.,
Kim HyungHwan,
Lo Eng H.,
Furie Karen L.,
Ayata Cenk
Publication year - 2014
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.19
Subject(s) - medicine , rock2 , stroke (engine) , ischemia , pharmacology , rock1 , brain ischemia , anesthesia , cerebral blood flow , rho associated protein kinase , kinase , protein kinase a , mechanical engineering , engineering , biology , microbiology and biotechnology
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.