Ferulic acid methylester improves the comorbidity of insomnia and anxiety in a rat model of PCPA-induced sleep disorder by activating DRN 5-HT neurons

  • Neurosci Lett. 2025 Jul 13:859-861:138276. doi: 10.1016/j.neulet.2025.138276.
Quntao Li  1 ,  Jingwen Zhai  1 ,  Tongyu Du  2 ,  Junjie He  1 ,  Jingbin Zhang  1 ,  Yuhe Tian  3 ,  Ketao Ma  4 ,  Junqiang Si  4 ,  Jiangwen Yin  5 ,  Yan Li  6
Affiliations
  • 1. Department of Anesthesiology, The First Affiliated Hospital of Shihezi University, Shihezi 832003, China; National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases(Co-construction), The First Affiliated Hospital of Shihezi University, Shihezi 832003, China.
  • 2. Department of Anesthesiology, The First Affiliated Hospital of Shihezi University, Shihezi 832003, China.
  • 3. Department of Physiology, Shihezi University School of Medicine, Shihezi 832003, China.
  • 4. Department of Physiology, Shihezi University School of Medicine, Shihezi 832003, China; Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China.
  • 5. Department of Anesthesiology, The First Affiliated Hospital of Shihezi University, Shihezi 832003, China; National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases(Co-construction), The First Affiliated Hospital of Shihezi University, Shihezi 832003, China. Electronic address: [email protected].
  • 6. Department of Anesthesiology, The First Affiliated Hospital of Shihezi University, Shihezi 832003, China; National Health Commission(NHC) Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases(Co-construction), The First Affiliated Hospital of Shihezi University, Shihezi 832003, China. Electronic address: [email protected].
PMID: 40441597 DOI: 10.1016/j.neulet.2025.138276
Abstract

Objective: Previous studies have indicated that ferulic acid possesses sedative and hypnotic functions. As a derivative of ferulic acid, ferulic acid methylester (FAM) exhibits stronger activity and lower toxicity than ferulic acid. This study is intended to establish a rat model of insomnia induced by PCPA, with the aim of exploring the improvement effect of FAM on the comorbidity of anxiety and insomnia in PCPA-induced insomnia model rats and its underlying mechanisms.

Methods: Insomnia models were established by intraperitoneal injection of 400 mg/kg p-chlorophenylalanine (PCPA) in SD rats. FAM was administered at three doses: 10, 20, and 40 mg/kg. Anxiety levels were assessed using the elevated plus maze and open field tests. Sleep status was evaluated through 24-hour in vivo EEG monitoring. Immunofluorescence staining was used to observe changes in DRN 5-HT neuron activity. Chemogenetic techniques were employed to inhibit DRN 5-HT neurons to elucidate the underlying mechanism.

Results: Behavioral tests revealed that FAM at 20 mg/kg significantly reduced anxiety levels (P < 0.001) and increased total sleep time (P < 0.001). EEG recordings showed improved sleep structure, with increased NREM and REM sleep times. Immunofluorescence staining indicated increased activity of DRN 5-HT neurons following FAM treatment. Chemogenetic inhibition of DRN 5-HT neurons reversed the beneficial effects of FAM on anxiety and sleep, thereby confirming the involvement of these neurons in the mechanism of action of FAM.

Conclusions: Ferulic acid methylester improves comorbidity of anxiety and insomnia in PCPA-induced insomnia model rats by activating DRN 5-HT neurons.

Keywords
5-hydroxytryptamine neurons; Anxiety; Dorsal raphe nucleus; Ferulic acid methylester; Insomnia.
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