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Pifithrin-α Inhibits Neural Differentiation of Newborn Cells in the Subgranular Zone of the Dentate Gyrus at Initial Stages of Audiogenic Kindling in Krushinsky–Molodkina Rat Strain

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Abstract

One of the main challenges of modern neurobiology is finding approaches to prevent structural abnormalities in the brain, specifically, in the hippocampus affected by epileptic activity. It is well known that epilepsy leads to an increase in proliferation in the hippocampal neurogenic niche, the subgranular layer of the dentate gyrus. In the recent years, there is a prevalent idea that newborn neural cells contribute to epileptogenesis to a larger extent than prevent neurodegenerative disorders associated with increased cell death. We hypothesized that a proapoptotic protein p53 can be one of the possible therapeutic targets in treating epilepsy and its neurodegenerative consequences. In the present work, we used the Krushinsky–Molodkina (KM) inbred rats, which are genetically prone to audiogenic seizures (AGS). Audiogenic kindling, a commonly accepted model of epileptogenesis, induces epileptiform activity in the limbic system and cerebral cortex. In KM rats, it has been shown that 4 AGS lead to an increase in proliferation, aberrant migration of newborn cells to the hilus, and accelerated neural differentiation of these cells. We revealed abnormalities neither in apoptosis nor in autophagy levels at the initial stages of temporal lobe (limbic) epilepsy. Treatment with pifithrin-α, a chemical p53 inhibitor, did not change apoptosis and autophagy levels but caused an increase in proliferation and migration of newborn cells to the granule cell layer of the dentate gyrus and to the hilus. However, a week after the last seizure, p53 inactivation entailed a decrease in the number of differentiating cells, as compared to the vehicle control group, despite a significant increase in the number of newborn cells. These data indicate a decrease in the neural differentiation rate of newborn cells, thus allowing pifitrin-α to be considered as a potential therapeutic agent to alleviate neurodegenerative disorders in epilepsy.

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Funding

This study was supported by the Russian Foundation for Basic Research, grant no. 19-015-00070.

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A.A. Kulikov: experiment design, Western blot analysis, TUNEL staining, discussion of the results. E.V. Nasluzova: immunohistochemical staining. N.A. Dorofeeva: animal handling, sample preparation. M.V. Glazova: data interpretation. E.A. Lavrova: statistical data processing. E.V. Chernigovskaya: task setting, experiment planning, manuscript writing.

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Correspondence to A. A. Kulikov.

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All procedures met the ethical principles formulated in the European Convention on protection of vertebrate animals used for experimental and other scientific purposes (no. 123 01/01/1991) and approved by the Ethics Committee at Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences.

This study did not involve human subjects as research objects.

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Russian Text © The Author(s), 2021, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2021, Vol. 107, No. 3, pp. 332–351https://doi.org/10.31857/S0869813921030079.

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Kulikov, A.A., Nasluzova, E.V., Dorofeeva, N.A. et al. Pifithrin-α Inhibits Neural Differentiation of Newborn Cells in the Subgranular Zone of the Dentate Gyrus at Initial Stages of Audiogenic Kindling in Krushinsky–Molodkina Rat Strain. J Evol Biochem Phys 57, 304–318 (2021). https://doi.org/10.1134/S0022093021020125

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