Sini-Suanzaoren decoction regulates mitochondrial biogenesis mediated by MT-SIRT1 in the treatment of insomnia rats

BACKGROUND Insomnia is closely associated with anxiety and depression, with its pathogenesis involving biological, psychological, and social factors. Sini powder and Suanzaoren decoction are clinically effective traditional Chinese medicine formulas for insomnia, demonstrating promising bioactivity. However, the capability of the active components of Sini-Suanzaoren decoction (SNSZRD) to cross the blood-brain barrier (BBB) and their precise molecular mechanisms, particularly concerning the MT-SIRT1 pathway and mitochondrial function, remain largely unexplored. AIM To elucidate the bioactive components of SNSZRD that are capable of BBB penetration and investigate the therapeutic mechanism of SNSZRD against insomnia. METHODS The chemical components of SNSZRD were analyzed through liquid chromatography-mass spectrometry (LC-MS). Male Sprague-Dawley rats were intraperitoneally injected with DL-4-chlorophenylalanine (PCPA) to establish an insomnia model. Rats were divided into control, model, eszopiclone (positive control), and SNSZRD low-/medium-/high-dose groups. Molecular docking predicted BBB-penetrating components and their binding affinity for SIRT1. Key pathways were analyzed through open-field tests, elevated plus-maze tests, pentobarbital-induced sleep experiments, Haematoxylin and eosin staining, Nissl staining, ELISA, Western blot analysis, quantitative real-time PCR, and immunohistochemistry. RESULTS LC-MS identified 1574 compounds in SNSZRD, of which eight prototype components (e.g. , pachymic acid and senkyunolide G) could cross the BBB. Molecular docking revealed that these components formed stable hydrogen bonds with the SIRT1 protein. SNSZRD treatment significantly ameliorated PCPA-induced anxiety-like behaviors and sleep latency/sleep duration, as well as reduced neuronal degeneration and Nissl body loss in the hypothalamus of treated rats. Additionally, SNSZRD elevated serum melatonin and hypothalamus ATP levels and upregulated the mRNA and protein expression levels of arylalkylamine N-acetyltransferase, SIRT1, PPARγ coactivator-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A in the MT-SIRT1-mitochondrial biogenesis pathway. CONCLUSION SNSZRD might exert its therapeutic effects on insomnia by modulating MT-SIRT1 axis-regulated mitochondrial biogenesis in rats and might serve as an effective therapeutic agent for insomnia.