Identification of Kinome Representatives with Neuroprotective Activity

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.