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PPARβ/δ Agonist GW0742 Modulates Microglial and Astroglial Gene Expression in a Rat Model of Temporal Lobe Epilepsy
Olga E Zubareva1, Adeliya R Kharisova1, Anna I Roginskaya1
1Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 194223 Saint Petersburg, Russia.
Abstract:
The role of astroglial and microglial cells in the pathogenesis of epilepsy is currently under active investigation. It has been proposed that the activity of these cells may be regulated by the agonists of peroxisome proliferator-activated nuclear receptors (PPARs). This study investigated the effects of a seven-day treatment with the PPAR β/δ agonist GW0742 (Fitorine, 5 mg/kg/day) on the behavior and gene expression of the astroglial and microglial proteins involved in the regulation of epileptogenesis in the rat brain within a lithium-pilocarpine model of temporal lobe epilepsy (TLE). TLE resulted in decreased social and increased locomotor activity in the rats, increased expression of astro- and microglial activation marker genes (Gfap, Aif1), pro- and anti-inflammatory cytokine genes (Tnfa, Il1b, Il1rn), and altered expression of other microglial (Nlrp3, Arg1) and astroglial (Lcn2, S100a10) genes in the dorsal hippocampus and cerebral cortex. GW0742 attenuated, but did not completely block, some of these impairments. Specifically, the treatment affected Gfap gene expression in the dorsal hippocampus and Aif1 gene expression in the cortex. The GW0742 injections attenuated the TLE-specific enhancement of Nlrp3 and Il1rn gene expression in the cortex. These results suggest that GW0742 may affect the expression of some genes involved in the regulation of epileptogenesis.
Insights
Peroxisome proliferator-activated nuclear receptor (PPAR) agonists, like GW0742, may influence brain cell activity in temporal lobe epilepsy (TLE). This study shows GW0742 partially improved TLE-related behavioral and gene expression changes in rats.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Astroglial and microglial cells are implicated in epilepsy pathogenesis.
- Peroxisome proliferator-activated nuclear receptors (PPARs) may regulate glial cell activity.
- Temporal lobe epilepsy (TLE) involves complex molecular and behavioral changes.
Purpose of the Study:
- To investigate the effects of the PPAR β/δ agonist GW0742 on TLE in a rat model.
- To assess GW0742's impact on behavior and gene expression of glial markers and inflammatory mediators.
Main Methods:
- A lithium-pilocarpine-induced TLE rat model was used.
- Rats received a seven-day treatment with GW0742 (5 mg/kg/day).
- Behavioral tests (social interaction, locomotor activity) and gene expression analysis (hippocampus, cortex) were performed.
Main Results:
- TLE induced social deficits, increased locomotor activity, and altered expression of glial activation and inflammatory genes.
- GW0742 treatment partially attenuated some behavioral impairments and modulated specific gene expressions (e.g., Gfap, Aif1, Nlrp3, Il1rn).
- The PPAR agonist affected glial gene expression in the hippocampus and cortex, but did not fully reverse TLE-induced changes.
Conclusions:
- GW0742 demonstrates a modulatory effect on glial cell-related gene expression in the context of TLE.
- PPARs represent a potential therapeutic target for managing epileptogenesis.
- Further research is needed to fully elucidate GW0742's role and efficacy in epilepsy.
