title: A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia-reperfusion injury in mice.
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.
authors.affiliation: 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.
authors.forename: Dmitriy N
authors.initials: DN
authors.lastname: Atochin
authors.affiliation: RASA Center in Tomsk, Tomsk Polytechnic University, Tomsk 634050, Russia; Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59715, USA.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.affiliation: Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia; Department of Chemistry, Altai State Technical University, Barnaul 656038, Russia.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Khlebnikov
authors.affiliation: Immanuel Kant Baltic Federal University, Kaliningrad 236041, Russia.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Seledtsov
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, 149 East 13th Street, Charlestown, MA 02129, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Swanson
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59715, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, 149 East 13th Street, Charlestown, MA 02129, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000737:chemistry; D020520:Brain Infarction / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009048:Motor Skills / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010539:Permeability; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: C000599103:11H-indeno(1,2-b)quinoxalin-11-one oxime; D020030:Nitric Oxide Donors; D010091:Oximes; D011810:Quinoxalines; D009569:Nitric Oxide; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cerebral reperfusion; Nitric oxide; c-Jun N-terminal kinase