Dynamics of changes in markers of apoptosis, circadian rhythms and antioxidant processes in the model of temporal lobe epilepsy in rats

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Temporal lobe epilepsy is a common neurological disorder that in many cases is accompanied by drug resistance. The current approach to the treatment of patients with drug resistance includes surgical intervention, which does not guarantee full recovery. At present, new antiepileptic drugs that affect signaling cascades inherent in epileptogenesis are being developed. The development of such drugs requires knowledge of the basic mechanisms of epilepsy pathogenesis. The aim of the work was to investigate the dynamics of expression of proteins involved in the regulation of apoptosis, circadian rhythms and antioxidant response in the temporal cortex of the brain during prolonged kindling in the Krushinsky-Molodkina (KM) rat model with hereditary audiogenic epilepsy. The dynamics of expression of studied proteins – p53, CLOCK, Nrf2, p105 - was investigated in the temporal cortex (immunohistochemistry, Western blotting). It was found that p53 level was lower in KM control rats than in Wistar rats. In KM rats subjected to 21 days kindling, p53 content is increased compared to KM control. CLOCK level was downregulated in the KM control group compared to the negative control and elevated in the KM group after kindling 21 days relative to the KM group after 7 days kindling. No changes in Nrf2 and p105 production were detected. The data obtained suggest that the changes in the levels of the studied proteins in control KM rats compared to Wistar rats are genetically determined. Induced epileptogenesis (kindling) for 21 days leads to activation of p53-dependent apoptosis pathway and, possibly, to desynchronosis - change of circadian rhythms. The findings contribute to the study of temporal lobe epilepsy mechanisms and require further studies related to mitochondrial apoptosis and sleep-wake cycle shift in the pathogenesis of temporal lobe epilepsy.

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作者简介

A. Nuzhnova

Peter the Great Saint Petersburg Polytechnic University

Email: bazhanovae@mail.ru
俄罗斯联邦, Saint Petersburg

D. Lisenkova

Peter the Great Saint Petersburg Polytechnic University

Email: bazhanovae@mail.ru
俄罗斯联邦, Saint Petersburg

A. Bidzhiev

Pasteur Research Institute of Epidemiology and Microbiology

Email: bazhanovae@mail.ru
俄罗斯联邦, Saint Petersburg

A. Ivlev

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: bazhanovae@mail.ru
俄罗斯联邦, Saint Petersburg

E. Chernigovskaya

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: bazhanovae@mail.ru
俄罗斯联邦, Saint Petersburg

E. Bazhanova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences; Golikov Research Center of Toxicology

编辑信件的主要联系方式.
Email: bazhanovae@mail.ru
俄罗斯联邦, Saint Petersburg; Saint Petersburg

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2. Fig. 1. Experimental plan.

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3. Fig. 2. (a) – Comparison of the p53 level in the temporal lobe cortex of the brain in experimental animals (IHC); (b) – Temporal cortex of the rat from the WC group. IHC with antibodies to p53, x200; (c) – Temporal cortex of the rat from the KMC group. IHC with antibodies to p53, x200. WC – control group of Wistar rats, KMC – control group of KM rats, KM7+7 – experimental group of rats, which were kindled for 7 days + 7 days of rest, KM21+7 – experimental group of rats, which were kindled for 21 days + 7 days of rest.

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4. Fig. 3. (a) – Comparison of CLOCK level in the temporal lobe cortex of the brain in experimental animals (IHC); (b) – Temporal cortex of rats from the KMC group. IHC with antibodies to CLOCK, x200; (c) – Temporal cortex of rats from the KM7+7 group. IHC with antibodies to CLOCK, x200. WC – control group of Wistar rats, KMC – control group of KM rats, KM7+7 – experimental group of rats kindled for 7 days + 7 days of rest, KM21+7 – experimental group of rats kindled for 21 days + 7 days of rest.

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5. Fig. 4. (a), (b) – Comparison of the CLOCK level in the temporal lobe cortex of the brain in experimental animals (WB); WC – control group of Wistar rats, KMC – control group of KM rats, KM7+7 – experimental group of rats that were kindled for 7 days + 7 days of rest, KM21+7 – experimental group of rats that were kindled for 21 days + 7 days of rest.

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6. Fig. 5. (a) – Comparison of Nrf2 levels in the temporal lobe cortex of the brain in experimental animals (IHC); (b) – Temporal cortex of rats from the WC group. IHC with antibodies to Nrf2, x200; (c) – Temporal cortex of rats from the KMC group. IHC with antibodies to Nrf2, x200. WC – control group of Wistar rats, KMC – control group of KM rats, KM7+7 – experimental group of rats kindled for 7 days + 7 days of rest, KM21+7 – experimental group of rats kindled for 21 days + 7 days of rest.

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7. Fig. 6. (a), (b) – Comparison of the NRF2 level in the temporal lobe cortex of the brain in experimental animals (WB); WC – control group of Wistar rats, KMC – control group of KM rats, KM7+7 – experimental group of rats that were kindled for 7 days + 7 days of rest, KM21+7 – experimental group of rats that were kindled for 21 days + 7 days of rest.

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8. Fig. 7. (a) – Comparison of the p105 level in the temporal lobe cortex of the brain in experimental animals (IHC); (b) – Cortex of the temporal region of the rat from the WC group. IHC with antibodies to p105, x200; (c) – Cortex of the region of the rat from the KM7+7 group. IHC with antibodies to p105, x200. WC – control group of Wistar rats, KMC – control group of KM rats, KM7+7 – experimental group of rats, which were kindled for 7 days + 7 days of rest, KM21+7 – experimental group of rats, which were kindled for 21 days + 7 days of rest.

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