Banxia Shumi Decoction Improves Sleep and Neural Function in Insomnia Male Rats via BDNF/TrkB/CREB-Dependent Melatonin Signaling Activation

Insomnia seriously affects people’s quality of life and health. Currently available insomnia medications demonstrate notable side effect profiles and lack well-established evidence regarding their sustained efficacy. The aim of this study was to investigate the efficacy of Banxia Shumi decoction (BXSMD) in insomnia and the molecular mechanism involved. The effect of BDNF/TrkB/CREB pathway on BSXMD treatment of insomnia was investigated by using p-chlorophenylalanine (PCPA) induced insomnia male rat model. The results of open field test, Morris water maze and hypnosis experiments implied that circadian dysrhythmia, increased open-field activity, decreased sleep quality and learning and memory impairments were observed in insomnia male rat. Besides, the levels of BDNF/TrkB/CREB pathway, 5-HT, MT, MT1 and MT2 were reduced, accompanied with neural tissue damage in insomnia male rats by ELISA, qRT-PCR, WB, immunohistochemistry and HE staining. BXSMD alleviated neural tissue damage and improved sleep quality along with cognitive functions (learning and memory) in insomnia male rats. Moreover, BXSMD caused activation of BDNF/TrkB/CREB pathway and upregulation of 5-HT, MT, MT1 and MT2 levels in insomnia male rats. BDNF overexpression-mediated activation of BDNF/TrkB/CREB pathway enhanced the pharmacological effects of BXSMD described above. Notably, MT1/MT2 antagonist attenuated the therapeutic effects of BXSMD on sleep disturbances and neural tissue damage in insomnia male rats, while BDNF knockdown in the hippocampus suppressed BXSMD-mediated activation of MT signaling, sleep enhancement, and neuroprotection. In summary, this study elucidated that BXSMD enhanced MT signaling by activating BDNF/TrkB/CREB pathway in the hippocampus, thereby ameliorating sleep disorders and neural damage in insomnia male rats.