Effect of Cardarin on Gene Expression of Proteins Involved in Epileptogenesis in Rat Hippocampus in the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

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Abstract

In recent years, the role of astro- and microglial cells and associated neuroinflammation in the pathogenesis of epilepsy has been extensively discussed. These cells can be in different functional states, the extreme A1 and M1 phenotypes producing predominantly pro-inflammatory (promoting epileptogenesis) proteins, and the A2 and M2 phenotypes producing anti-inflammatory (preventing epileptogenesis) proteins. It has been suggested that the use of drugs that can stimulate polarisation from M1 and A1 to M2 and A2 phenotypes may be a successful strategy for the treatment of epilepsy. Such drugs include agonists of peroxisome proliferator-activated receptor nuclear receptors (PPARs). The aim of this study was to investigate changes in the expression of micro- and astroglial proteins involved in the regulation of epileptogenesis in the dorsal hippocampus of rats in the lithium-pilocarpine model of temporal lobe epilepsy (TLE) and to investigate the effect of the PPAR agonist beta/delta cardarine on these processes. Cardarin was administered at the initial stages of epileptogenesis (within 7 days after induction of the TLE model), and two months later (chronic phase of the model) we analysed the expression of genes of interest in the dorsal hippocampus by real-time RT-PCR. The performed study revealed changes in gene expression of astro- and microglial proteins during epileptogenesis, mainly associated with the enhancement of neuroinflammatory processes and weakening of neuroprotective properties of these cells. In TLE rats the expression of genes of markers of astro- (Gfap) and microglia activation (Aif1), pro- (Il1b, Nlrp3) and anti-inflammatory (Il1rn) proteins, markers of the A1 phenotype of astrocytes (Lcn2, Gbp2) and growth factors (Bdnf, Fgf2) was increased. Gene expression of the protective M2 phenotype Arg1 gene was decreased in TLE rats. The most striking effect of cardarine administration was manifested in the enhanced expression of the marker A2 gene of the S100a10 astrocyte phenotype.

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About the authors

A. R. Kharisova

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

Email: ZubarevaOE@mail.ru
Russian Federation, St. Petersburg

A. I. Roginskaya

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

Email: ZubarevaOE@mail.ru
Russian Federation, St. Petersburg

O. E. Zubareva

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

Author for correspondence.
Email: ZubarevaOE@mail.ru
Russian Federation, St. Petersburg

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2. Fig. 1. The scheme of the experiment. Cntr+Veh – control group without administration of cardarin; TLE+Veh – experimental group without administration of cardarin; Cntr+GW – control group with administration of cardarin; TLE+GW – experimental group with administration of cardarin. A diagram of the allocation of the dorsal hippocampus is presented on a brain slice.

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3. Fig. 2. Relative expression of genes for the activation marker of astrocytes Gfap (a) and microglial cells Aif1 (b) in the dorsal hippocampus of experimental and control rats; * p < 0.05, two-factor ANOVA (model x treatment) with a posteriori multiple comparison test of Sidak or a nonparametric analogue of the ANOVA Kruskal–Wallis test with a posteriori multiple comparison test Danna.

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4. 3. Relative expression of genes of proinflammatory proteins Il1b (a), Nlrp3 (b), Tnfa (d) and anti-inflammatory cytokine Il1rn (c) in the dorsal hippocampus of experimental and control rats; * p < 0.05, ** p < 0.01, two-factor ANOVA (model x treatment) with a posteriori test of multiple Sidak comparisons or a nonparametric analogue of the Kruskal–Wallis ANOVA test with the posteriori Dunn multiple comparison test.

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5. Fig. 4. Relative expression of marker genes of the proinflammatory A1 phenotype (a, b) and neuroprotective A2 phenotype (c, d) of astroglia in the dorsal hippocampus of experimental and control rats; * p < 0.05, ** p < 0.01, two-factor ANOVA (model x treatment) with a posteriori multiple comparison test of Sidak.

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6. Fig. 5. Relative expression of genes for markers of proinflammatory M1 (a) and anti-inflammatory M2 (b) phenotypes of microglia, as well as their ratio (c) in the dorsal hippocampus of experimental and control rats. * p < 0.05 in a two-factor ANOVA (x treatment model) with a posteriori multiple comparison test of Sidak.

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7. Fig. 6. Relative expression of the genes of the neurotrophic factors Bdnf (a), Gdnf (b) and Fgf2 (c) in the dorsal hippocampus of rats; * p < 0.05; two-factor ANOVA (model x treatment) with a posteriori multiple comparison test of Sidak.

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8. Fig. 7. Relative expression of the PPARs genes: Ppara (a), Ppard (b), Pparg (c) in the dorsal hippocampus of rats; two-factor ANOVA (model x treatment).

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