Format

Send to

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

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

Author information

1
Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, 149 East 13th Street, Charlestown, MA 02129, USA; RASA Center in Tomsk, Tomsk Polytechnic University, Tomsk 634050, Russia. Electronic address: atochin@cvrc.mgh.harvard.edu.
2
RASA Center in Tomsk, Tomsk Polytechnic University, Tomsk 634050, Russia; Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59715, USA.
3
Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia; Department of Chemistry, Altai State Technical University, Barnaul 656038, Russia.
4
Immanuel Kant Baltic Federal University, Kaliningrad 236041, Russia.
5
Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, 149 East 13th Street, Charlestown, MA 02129, USA.
6
Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59715, USA.

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

PMID:
26923672
PMCID:
PMC5491393
DOI:
10.1016/j.neulet.2016.02.033
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center