A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia–reperfusion injury in mice / D. N. Atochin, I. A. Schepetkin (Shchepyotkin), A. I. Khlebnikov [et al.]

Уровень набора: Neuroscience Letters = 1975-Альтернативный автор-лицо: Atochin, D. N., neuroscientist, The Head of the Laboratory of Tomsk Polytechnic University, 1960-, Dmitry Nikolaevich;Schepetkin (Shchepyotkin), I. A., doctor-biophysicist, leading researcher of Tomsk Polytechnic University, candidate of medical science, 1962-, Igor Aleksandrovich;Khlebnikov, A. I., Chemist, Professor of Tomsk Polytechnic University, 1963-, Andrey Ivanovich;Seledtsov, V. I., Victor I.;Swanson, H., Helen;Quinn, M. T., Mark T.;Huang, P. L., Paul L.Коллективный автор (вторичный): Национальный исследовательский Томский политехнический университет (ТПУ), Управление проректора по научной работе и инновациям (НРиИ), Лаборатория изучения механизмов нейропротекции;Национальный исследовательский Томский политехнический университет (ТПУ), Институт физики высоких технологий (ИФВТ), Кафедра биотехнологии и органической химии (БИОХ)Язык: английский.Страна: .Резюме или реферат: 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 (30 min) with subsequent reperfusion (48 h). Mice were treated with IQ-1S (25 mg/kg) suspended in 10% solutol or with vehicle alone 30 min before and 24 h after middle cerebral artery (MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30 min of MCAO provoked by a filament and during the first 30 min 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 48 h 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..Примечания о наличии в документе библиографии/указателя: [References.: p. 49 (45 tit.)].Аудитория: .Тематика: электронный ресурс | труды учёных ТПУ Ресурсы он-лайн:Щелкните здесь для доступа в онлайн
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[References.: p. 49 (45 tit.)]

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 (30 min) with subsequent reperfusion (48 h). Mice were treated with IQ-1S (25 mg/kg) suspended in 10% solutol or with vehicle alone 30 min before and 24 h after middle cerebral artery (MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30 min of MCAO provoked by a filament and during the first 30 min 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 48 h 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.

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