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E4BP4-Driven Circadian SLC6A1 Expression Governs Tiagabine Chronoefficacy in Temporal Lobe Epilepsy

Yu Yang1, Xingchang Li1, Shuxian Gong1

  • 1Institute of Molecular Rhythm and Metabolism, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.

Molecular Neurobiology
|December 3, 2025
PubMed

Insights

Optimizing tiagabine dosing time enhances its anticonvulsant effect in temporal lobe epilepsy (TLE). This chronotherapy aligns drug efficacy with circadian rhythms in GABAergic neurotransmission, improving TLE management.

Area of Science:

  • Neuroscience
  • Chronobiology
  • Pharmacology

Background:

  • Temporal lobe epilepsy (TLE) is a common focal epilepsy with intractable cases.
  • Understanding factors influencing drug efficacy is crucial for TLE management.

Purpose of the Study:

  • To investigate the impact of dosing time on tiagabine's anticonvulsant effects in TLE.
  • To elucidate the circadian mechanisms underlying tiagabine's efficacy variations.

Main Methods:

  • Utilized pilocarpine-induced acute and chronic TLE models.
  • Assessed tiagabine efficacy across different dosing times (light vs. dark phase).
  • Investigated the role of circadian transcription factor E4bp4 and SLC6A1 expression.

Main Results:

  • Tiagabine significantly reduced seizure severity and progression in TLE models.
  • Tiagabine demonstrated greater efficacy when administered during the light phase.
  • E4bp4 ablation disrupted SLC6A1 rhythms and abolished tiagabine's chronoefficacy.
  • Circadian oscillations in SLC6A1 expression mediated tiagabine's time-dependent efficacy.

Conclusions:

  • Dosing time significantly impacts tiagabine's efficacy in TLE.
  • Chronotherapeutic optimization of tiagabine, aligned with SLC6A1 rhythms, is a promising precision medicine approach for TLE.
  • Circadian regulation of GABAergic neurotransmission is key to understanding tiagabine's effectiveness.
Keywords:
ChronoefficacyCircadian ClockSLC6A1Temporal lobe epilepsyTiagabine

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