Open Access

Molecules, volume 24, issue 9, pages 1722

Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats

Plotnikov Mark B. ^{1, 2}

Chernysheva Galina A. ¹

Aliev Oleg I. ¹

Smoliakova Vera I ¹

Fomina Tatiana I ³

Osipenko Anton N ⁴

Rydchenko Victoria S ⁵

Anfinogenova Y. J. ^{6, 7}

Khlebnikov Andrei I. ^{7, 8}

Schepetkin Igor A. ^{7, 9}

Atochin Dmitriy N ^{7, 10}

Hide authors affiliations Show authors affiliations: 10 affiliations

Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, Tomsk 634028, Russia |

National Research Tomsk State University, Tomsk 634050, Russia |

Department of Medicine Toxicology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, Tomsk 634028, Russia |

⁴

Department of Pharmacology, Siberian State Medical University, Tomsk 634050, Russia |

⁵

Department of Biophysics, Siberian State Medical University, Tomsk 634050, Russia |

⁶

Cardiology Research Institute, Tomsk NRMC, Tomsk 634012, Russia |

⁷

Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia |

⁸

Research Institute of Biological Medicine, Altai State University, Barnaul 656049, Russia |

⁹

Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA |

¹⁰

Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA |

Publication type: Journal Article

Publication date: 2019-05-03

Multidisciplinary Digital Publishing Institute (MDPI)

Journal: Molecules

Quartile SCImago

Quartile WOS

Impact factor: 4.6

ISSN: 14203049

DOI: 10.3390/molecules24091722

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PubMed ID: 31058815

Organic Chemistry

Drug Discovery

Physical and Theoretical Chemistry

Pharmaceutical Science

Molecular Medicine

Analytical Chemistry

Chemistry (miscellaneous)

Abstract

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5′-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 μM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.

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Plotnikov M. B. et al. Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats // Molecules. 2019. Vol. 24. No. 9. p. 1722.

GOST all authors (up to 50) Copy

Plotnikov M. B., Chernysheva G. A., Aliev O. I., Smoliakova V. I., Fomina T. I., Osipenko A. N., Rydchenko V. S., Anfinogenova Y. J., Khlebnikov A. I., Schepetkin I. A., Atochin D. N. Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats // Molecules. 2019. Vol. 24. No. 9. p. 1722.

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TY - JOUR

DO - 10.3390/molecules24091722

UR - https://doi.org/10.3390%2Fmolecules24091722

TI - Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats

T2 - Molecules

AU - Plotnikov, Mark B.

AU - Chernysheva, Galina A.

AU - Aliev, Oleg I.

AU - Smoliakova, Vera I

AU - Fomina, Tatiana I

AU - Osipenko, Anton N

AU - Schepetkin, Igor A.

AU - Atochin, Dmitriy N

AU - Rydchenko, Victoria S

AU - Anfinogenova, Y. J.

AU - Khlebnikov, Andrei I.

PY - 2019

DA - 2019/05/03 00:00:00

PB - Multidisciplinary Digital Publishing Institute (MDPI)

SP - 1722

IS - 9

VL - 24

PMID - 31058815

SN - 1420-3049

ER -

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@article{2019_Plotnikov,

author = {Mark B. Plotnikov and Galina A. Chernysheva and Oleg I. Aliev and Vera I Smoliakova and Tatiana I Fomina and Anton N Osipenko and Igor A. Schepetkin and Dmitriy N Atochin and Victoria S Rydchenko and Y. J. Anfinogenova and Andrei I. Khlebnikov},

title = {Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats},

journal = {Molecules},

year = {2019},

volume = {24},

publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},

month = {may},

url = {https://doi.org/10.3390%2Fmolecules24091722},

number = {9},

pages = {1722},

doi = {10.3390/molecules24091722}

}

MLA

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MLA Copy

Plotnikov, Mark B., et al. “Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats.” Molecules, vol. 24, no. 9, May. 2019, p. 1722. https://doi.org/10.3390%2Fmolecules24091722.

Found error?

Publisher

Multidisciplinary Digital Publishing Institute (MDPI)

Journal

Molecules

Quartile SCImago

Quartile WOS

Impact factor

4.6

ISSN

14203049 (Print)

Labs

Research Institute of Biological Medicine