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

  • J Cereb Blood Flow Metab. 2024 Jun 4:271678X241238845. doi: 10.1177/0271678X241238845.
Inge A Mulder  1  2  3  4 ,  Matt Abbinanti  5 ,  Sarah A Woller  5 ,  Joerg Ruschel  5 ,  Jonathan M Coutinho  4  6 ,  Helga E de Vries  4  7 ,  Ed van Bavel  2  3  4 ,  Kenneth Rosen  5 ,  Lisa McKerracher  5  8 ,  Cenk Ayata  1  9
Affiliations
  • 1. Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 2. Department of Biomedical Engineering and Physics, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands.
  • 3. Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, the Netherlands.
  • 4. Amsterdam Neurosciences, Neurovascular Disorders, Amsterdam, the Netherlands.
  • 5. BioAxone BioSciences Inc, Boston, MA, USA.
  • 6. Department of Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands.
  • 7. Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit, Amsterdam, the Netherlands.
  • 8. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
  • 9. Stroke Service, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
PMID: 38833563 DOI: 10.1177/0271678X241238845
Abstract

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.

Keywords
ROCK; Rho-associated kinase; acute brain injury; blood-brain barrier; ischemic stroke.
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