Neuroprotective properties of the C-Jun N-terminal kinase (JNK) inhibitor in hypoxic hypoxia

The aim of the study was to reveal the influence of the JNK inhibitor on the induction of disturbances in the psychoneurological status of experimental animals in the modeling of posthypoxic encephalopathy and to reveal the mechanisms of its action related to the functioning of the neural stem cells of the brain.
Materials and methods. The experiments were performed on 64 male outbred mice. Posthypoxic encephalopathy was modeled in non-native mice with hypoxia of the hermetic volume. The JNK inhibitor was administered to mice subcutaneously at a dose of 15 mg/kg once before hypoxic exposure. We studied the neuropsychiatric status, the content of neuronal stem cells in the subventricular zone of the brain of experimental animals, and the direct effect of the JNK inhibitor on intact neural stem cells in vitro.
Results. The expressed cerebroprotective action of the pharmacological agent was revealed, which consisted of normalizing the indices of orientation and exploratory behavior and conditioned activity in experimental animals. These effects developed against a background of a significant increase in the content of neural stem cells in the subventricular zone of the brain. In the experiments in vitro, a direct stimulating effect of the JNK inhibitor on neural stem cells was found.
Conclusions. The obtained results showed a neuroprotective action of the JNK inhibitor. At the same time, the prevention and compensation of the development of disturbances in the activity of the central nervous system is based on the preservation of the ability of the nerve tissue to repair andassociated with the functioning of resident neural stem cells.

1. Dygai A.M., Zyuz’kov G.N., Zhdanov V.V., Udut E.V., Khrichkova T.Y., Miroshnichenko L.A., Simanina E.V., Stavrova L.A. Methodological recommendations for studying the specific activity of agents for regenerative medicine; edited by A.N. Mironova. M.: Grif i K Publ., 2013: 776–787 (in Russ.).

2. Voronina T.A., Seredenin S.B. Nootropic and neuroprotective agents. Experimental and Сlinical Рharmacology. 2007; 70 (4): 44–58 (in Russ.).

3. Gol’dberg E.D., Dygai A.M., Zyuz’kov G.N. Hypoxia and the blood system. Tomsk: Publishing house of Tomsk State University, 2006: 142 (in Russ.).

4. Faden A.I., Wu J.F., Stoica B.A., Loane D.J. Progressive inflammation-mediated neuro-degeneration after traumatic brain or spinal cord injury. British Journal of Pharmacology. 2016; 173: 681–691. DOI: 10.1111/bph.13179.

5. Binan L., Ajji A., De Crescenzo G., Jolicoeur M. Approaches for neural tissue re-generation. Stem Cell Reviews and Reports. 2014; 10 (1): 44–59. DOI: 10.1007/s12015-013-9474-z.

6. Yuan T.F., Gu S., Shan C., Marchado S., Arias-Carriуn O. Oxidative Stress and Adult Neurogenesis. Stem Cell Reviews and Reports. 2015; 11 (5): 706–709. DOI: 10.1007/s12015-015-9603-y.

7. Zjuz’kov G.N., Zhdanov V.V., Danilec M.G., Miroshnichenko L.A., Udut E.V., Dygaj A.M. Patent 2599289 RU, Agents that stimulate the regeneration of tissues. № 2013156908; Stated 14.09.2016; Published 10.10.2016. Bulletin № 28 (in Russ.).

8. Zyuz’kov G.N., Udut E.V., Miroshnichenko L.A., Polyakova T.Y., Simanina E.V., Stavrova L.A., Chaikovskii A.V., Agafonov V.I., Borodulina E.V., Timofeev M.S., Zyuz’kova Y.N., Danilets M.G., Zhdanov V.V., Udut V.V. Particular role of JAK/STAT3 signaling in functional control of mesenchymal progenitor cells. Bulletin of Experimental Biology and Medicine. 2018; 164 (3): 316–319. DOI: 10.1007/s10517-018-3980-6.

9. Luk’janova L.D., Kirova Ju.I., Sukojan G.V. [New on the signal mechanisms of adaptation to hypoxia and their role in systemic regulation. Pathogenesis. 2011; 9 (3): 4–14 (in Russ.)].

10. Zyuz’kov G.N., Suslov N.I., Povet’eva T.N., Nesterova Y.V., Afanas’eva O.G., Udut E.V., Miroshnichenko L.A., Simanina E.V., Polyakova T.Y., Stavrova L.A., Chaikovskii A.V., Kul’pin P.V., Udut V.V., Dygai A.M., Zhdanov V.V. Psychopharmacological effects of JNK inhibitor in posthypoxic encephalopathy and mechanisms of their development. Bulletin of Experimental Biology and Medicine. 2017; 163 (1): 18–21. DOI: 10.1007/s10517-017-3727-9.

11. Curzon P., Zhang M., Radek R.J., Fox G.B. The behavioral assessment of sensorimotor processes in the mouse: acoustic startle, sensory gating, locomotor activity, rotarod, and beam walking / in «Methods of behavior analysis in neuroscience». Second Edition, ed. J.J. Buccafusco. Boca Raton–London–New York: Taylor & Francis Group, LLC, 2009: 145–178. PMID: 21204341.

12. Guo W., Patzlaff N.E., Jobe E.M., Zhao X. Isolation of multipotent neural stem or progenitor cells from both the dentate gyrus and subventricular zone of a single adult mouse. Nature Protocols. 2012; 7 (11): 2005–2012. DOI: 10.1038/nprot.2012.123.

13. Zhou L., Yang Z., Lu X., Li X., An X., Chai J., Yang Q., Yan S., Li Y. JNK inhibitor alleviates apoptosis of fetal neural stem cells induced by emulsified isoflurane. Oncotarget. 2017; 8 (55): 94009–94019. DOI: 10.18632/oncotarget.21505.

14. Kucinski I., Dinan M., Kolahgar G., Piddini E. Chronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status. Nat. Commun. 2017; 8 (1):136. DOI: 10.1038/s41467-017-00145-y.

15. Bergantiсos C., Corominas M., Serras F. Cell death-induced regeneration in wing imaginal discs requires JNK signaling. Development. 2010; 137 (7): 1169–1179. DOI: 10.1242/dev.045559.