A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia-reperfusion injury in mice

Neurosci Lett. 2016 Apr 8;618:45-49. doi: 10.1016/j.neulet.2016.02.033. Epub 2016 Feb 26.

Abstract

The c-Jun N-terminal kinase (JNK) has been shown to be an important regulator of neuronal cell death. Previously, we synthesized the sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one (IQ-1S) and demonstrated that it was a high-affinity inhibitor of the JNK family. In the present work, we found that IQ-1S could release nitric oxide (NO) during its enzymatic metabolism by liver microsomes. Moreover, serum nitrite/nitrate concentration in mice increased after intraperitoneal injection of IQ-1S. Because of these dual actions as JNK inhibitor and NO-donor, the therapeutic potential of IQ-1S was evaluated in an animal stroke model. We subjected wild-type C57BL6 mice to focal ischemia (30min) with subsequent reperfusion (48h). Mice were treated with IQ-1S (25mg/kg) suspended in 10% solutol or with vehicle alone 30min before and 24h after middle cerebral artery (MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30min of MCAO provoked by a filament and during the first 30min of subsequent reperfusion. In mice treated with IQ-1S, ischemic and reperfusion values of CBF were not different from vehicle-treated mice. However, IQ-1S treated mice demonstrated markedly reduced neurological deficit and infarct volumes as compared with vehicle-treated mice after 48h of reperfusion. Our results indicate that the novel JNK inhibitor releases NO during its oxidoreductive bioconversion and improves stroke outcome in a mouse model of cerebral reperfusion. We conclude that IQ-1S is a promising dual functional agent for the treatment of cerebral ischemia and reperfusion injury.

Keywords: Cerebral reperfusion; Nitric oxide; c-Jun N-terminal kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / chemistry
  • Brain Infarction / pathology
  • Brain Infarction / prevention & control
  • Brain Ischemia / metabolism
  • Brain Ischemia / physiopathology
  • Brain Ischemia / prevention & control*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Motor Skills / drug effects
  • Nitric Oxide / metabolism
  • Nitric Oxide Donors / chemistry
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Donors / therapeutic use*
  • Oximes / chemistry
  • Oximes / pharmacology
  • Oximes / therapeutic use*
  • Permeability
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology
  • Quinoxalines / therapeutic use*
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / prevention & control*

Substances

  • 11H-indeno(1,2-b)quinoxalin-11-one oxime
  • Nitric Oxide Donors
  • Oximes
  • Quinoxalines
  • Nitric Oxide
  • JNK Mitogen-Activated Protein Kinases