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Fenofibrate as a PPARα Agonist Modulates Neuroinflammation and Glutamate Receptors in a Rat Model of Temporal Lobe Epilepsy: Region-Specific Effects and Behavioral Outcomes

  • 0Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint Petersburg, Russia.
International Journal of Molecular Sciences +

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September 27, 2025

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September 27, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Fenofibrate, a PPARα agonist, reduced anxiety and improved behavior in a rat epilepsy model. However, it showed region-specific effects on neuroinflammation and synaptic plasticity, with potential hippocampal drawbacks.

Area Of Science

  • Neuroscience
  • Pharmacology
  • Epilepsy Research

Background

  • Temporal lobe epilepsy (TLE) is often pharmacoresistant.
  • The region-specific effects of PPARα agonists, like fenofibrate, during epileptogenesis are largely unknown.
  • Understanding these effects is crucial for developing new TLE treatments.

Purpose Of The Study

  • To investigate the region-specific effects of fenofibrate on neuroinflammation, synaptic plasticity, and behavior during the latent phase of epileptogenesis in a rat model.
  • To assess fenofibrate's impact on glutamate receptor expression, inflammatory markers, and astrocyte/microglial markers.
  • To evaluate behavioral changes, including anxiety and exploratory deficits.

Main Methods

  • Utilized the lithium-pilocarpine rat model of TLE during the latent phase.
  • Administered fenofibrate (100 mg/kg) for 7 days.
  • Assessed behavioral changes, plasma short-chain fatty acids, gene expression of glutamate receptors (NMDAR, AMPAR), neuroinflammation markers (Nlrp3, Il1rn), astrocyte marker (Ptx3), and microglial markers (Arg1, Gfap, Aif1).

Main Results

  • Fenofibrate reduced anxiety-like behaviors and exploratory deficits.
  • It decreased plasma short-chain fatty acids.
  • Fenofibrate modulated glutamate receptor expression differently across brain regions, restoring cortical NMDAR/AMPAR expression but exacerbating hippocampal AMPAR downregulation.
  • It prevented cortical neuroinflammation and modulated hippocampal and cortical astrocyte/microglial markers.
  • No significant effects were observed on astrogliosis, microgliosis, or trophic factors.

Conclusions

  • Fenofibrate demonstrates region-specific modulation of neuroinflammation and synaptic plasticity during epileptogenesis.
  • While offering behavioral benefits, fenofibrate presents potential drawbacks in the hippocampus.
  • Further research is needed to optimize fenofibrate's dosing and timing for TLE treatment to mitigate regional disparities.

Keywords:

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