The novel ROCK2 selective inhibitor NRL-1049 preserves the blood-brain barrier after acute injury

• Published in: Journal of cerebral blood flow and metabolism 2024-11, Vol.44 (11), p.1238-1252
• Main Authors: Mulder, Inge A, Abbinanti, Matt, Woller, Sarah A, Ruschel, Joerg, Coutinho, Jonathan M, de Vries, Helga E, van Bavel, Ed, Rosen, Kenneth, McKerracher, Lisa, Ayata, Cenk
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain Injuries - drug therapy; Brain Injuries - metabolism; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Original; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Rats; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism
• ISSN: 0271-678X; 1559-7016; 1559-7016
• DOI: 10.1177/0271678X241238845

Endothelial blood-brain barrier (BBB) dysfunction is critical in the pathophysiology of brain injury. Rho-associated protein kinase (ROCK) activation disrupts BBB integrity in the injured brain. We aimed to test the efficacy of a novel ROCK2 inhibitor in preserving the BBB after acute brain injury. We characterized the molecular structure and pharmacodynamic and pharmacokinetic properties of a novel selective ROCK2 inhibitor, NRL-1049, and its first metabolite, 1-hydroxy-NRL-1049 (referred to as NRL-2017 hereon) and tested the efficacy of NRL-1049 on the BBB integrity in rodent models of acute brain injury. Our data show that NRL-1049 and NRL-2017 both inhibit ROCK activity and are 44-fold and 17-fold more selective towards ROCK2 than ROCK1, respectively. When tested in a mouse model of cortical cryoinjury, NRL-1049 significantly attenuated the increase in water content. Interestingly, 60% of the mice in the vehicle arm developed seizures within 2 hours after cryoinjury versus none in the NRL-1049 arm. In spontaneously hypertensive rats, NRL-1049 attenuated the dramatic surge in Evans Blue extravasation compared with the vehicle arm after transient middle cerebral artery occlusion. Hemorrhagic transformation was also reduced. We show that NRL-1049, a selective ROCK2 inhibitor, is a promising drug candidate to preserve the BBB after brain injury.