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Combined tetrahydroberberine and protopanaxadiol synergistically improves sleep in PCPA-induced insomnia in rats via microbiota-gut-brain axis and PI3K/AKT/AGE-RAGE pathways.

In a rat model of PCPA-induced insomnia, the combination of tetrahydroberberine (THB) and protopanaxadiol (PPD) showed synergistic effects, shortening sleep latency by 56.2% and prolonging sleep duration by 112.8% compared to the model group. The combination outperformed monotherapies and restored gut microbiota balance, neurotransmitter levels, and blood-brain barrier integrity.

Last updated: Jul 7, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score26/100
Human RCT☆☆☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism☆☆☆☆☆
Safety☆☆☆☆☆
Confidencelow

Study Evidence

Study 1. Synergistic Therapeutic Effects of Tetrahydroberberine Combined with Protopanaxadiol on PCPA-Induced Insomnia in Rats: Involvement of the Microbiota-Gut-Brain Axis and Regulation of PI3K/AKT/AGE-RAGE Pathways.

observational

Li M, Wang Y, Liang Z, Li H, Zhao Y, Kong L, Guo N, Dai G, Zhang G, Lu X, Yao J · Pharmaceuticals (Basel, Switzerland) (2026)

Participants: N/A
Duration: Not specified in abstract
Intervention: Combined oral administration of tetrahydroberberine (THB) and protopanaxadiol (PPD)
Outcome: Sleep latency, sleep duration, body weight gain, hippocampal neuronal damage, neurotransmitter levels (serotonin, dopamine, glutamate), HPA axis markers (CRH, corticosterone), inflammatory cytokines, gut microbiota composition, and PI3K/AKT/AGE-RAGE pathway protein expression
Effect Size: Sleep latency reduced by 56.2% (combination) vs 44.2% (THB alone) and 20.7% (PPD alone); sleep duration increased by 112.8% (combination) vs 70.2% (THB) and 59.6% (PPD); p-PI3K increased 1.9-fold, p-AKT increased 2.5-fold; RAGE decreased 31.8%
Population: PCPA-induced insomnia rat model (Sprague-Dawley rats)

Result:

PubMed: 41901236DOI: 10.3390/ph19030390

Mechanism Graph

Combined THB+PPD activates PI3K/AKT neurotrophic pathway (upregulates p-PI3K and p-AKT).
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Combined THB+PPD inhibits AGE/RAGE pro-inflammatory axis (downregulates RAGE).
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Combined THB+PPD restores gut microbial homeostasis (increases beneficial bacteria like Lactobacillus) and modulates glycine-serine-threonine metabolism.
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Result: Reduced sleep latency, prolonged sleep duration, restored neurotransmitter balance, suppressed HPA axis overactivation, decreased inflammation, and improved blood-brain barrier integrity.

Limitations

  • ⚠Animal model (rats) may not directly translate to human insomnia.
  • ⚠Exact doses and treatment duration for THB and PPD are not reported in the abstract, limiting replicability.

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References

  1. 1.Li M, Wang Y, Liang Z, Li H, Zhao Y, Kong L, Guo N, Dai G, Zhang G, Lu X, Yao J. "Synergistic Therapeutic Effects of Tetrahydroberberine Combined with Protopanaxadiol on PCPA-Induced Insomnia in Rats: Involvement of the Microbiota-Gut-Brain Axis and Regulation of PI3K/AKT/AGE-RAGE Pathways.." Pharmaceuticals (Basel, Switzerland), 2026. PMID: 41901236 DOI: 10.3390/ph19030390
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.