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Identification of Kinome Representatives with Neuroprotective Activity

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Abstract—Regulation of adaptive mechanisms in the central nervous system in cerebrovascular disorders and during the development of pathological processes is an urgent problems in neurobiology and medicine. Kinases, enzymes that perform a wide range of functions in the central nervous system, are of great interest as molecular targets and possible therapeutic agents in various neurodegenerative processes and impaired energy metabolism in the nervous tissue. The vast majority of intracellular reactions that lead to activation of neuroprotective mechanisms or, conversely, cell death reactions are associated with kinase activity. Nevertheless, the functioning of kinases in pathological processes in the central nervous system is poorly understood. Here, we identified components of the neuronal kinome with previously undescribed neuroprotective properties. We evaluated cell viability and characterized the morphology of primary brain cell cultures after treatment with 34 kinase inhibitors under conditions of modeled stress (glucose deprivation). We identified several groups of neuronal kinome with different actions and characterized the most physiologically relevant kinases. It was shown that blockage of eEF2K, SRC, and IKKb (IKK2) kinases, and the structurally close associated group of kinases JAK2, CDK2/CyclinA, CDK2/CyclinE, and FLT3 maintain cell viability in primary neuronal cultures during glucose deprivation in vitro. For the several most functionally important kinases, we estimated their influence on functional calcium activity of primary neuronal cultures. The data revealed that blockage of IKKb and eEF2K kinases effectively preserves the viability of neuronal cells under glucose deprivation but does not maintain the functional calcium activity of neuron-glial networks.

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ACKNOWLEDGMENTS

This study was performed in the Center for Common Use of Research Equipment for Molecular Biological Studies of Nizhny Novgorod State University.

Funding

The study was supported by the Russian Science Foundation, project no. 18-75-10071.

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Authors and Affiliations

  1. Nizhny Novgorod State University, pr. Gagarina 25, korp. 1, 603950, Nizhny Novgorod, Russia

    E. V. Mitroshina, T. A. Mishchenko, M. M. Loginova, V. S. Tarabykin & M. V. Vedunova

  2. Privolzhskiy Medical Research University, Nizhny Novgorod, Russia

    M. M. Loginova

  3. Institute of Cell Biology and Neurobiology, Charité—Universitätsmediz in Berlin, Berlin, Germany

    V. S. Tarabykin

Authors
  1. E. V. Mitroshina
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  2. T. A. Mishchenko
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  3. M. M. Loginova
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  4. V. S. Tarabykin
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  5. M. V. Vedunova
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Correspondence to E. V. Mitroshina.

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Conflict of interest. The authors declare no conflicts of interest.

Ethical approval. The study was performed in accordance with the requirements of Order No. 267 of The Ministry of Health of the Russian Federation from June 19, 2003, as well as in accordance with the international rules “Guide for the Care and Use of Laboratory Animals,” the requirements of the European Convention on the protection of vertebrates used for experimental and other scientific purposes (Strasbourg, 2006), and was approved by the bioethics committee of Lobachevsky University.

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Mitroshina, E.V., Mishchenko, T.A., Loginova, M.M. et al. Identification of Kinome Representatives with Neuroprotective Activity. Neurochem. J. 14, 394–407 (2020). https://doi.org/10.1134/S1819712420040133

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  • DOI: https://doi.org/10.1134/S1819712420040133

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