An Integrated Liver, Hippocampus and Serum Metabolomics Based on UPLC-Q-TOF-MS Revealed the Therapeutical Mechanism of Ziziphi Spinosae Semen in P-chlorophenylalanine-induced Insomnia Rats

Ziziphi Spinosae Semen (ZSS), a well-known herbal medicine for treating insomnia, is popular in not only China but also in Europe, India and Iran. However, its underlying mechanisms remain unclear. In this work, taking the targeted organs of insomnia, the liver and hippocampus, as the objects, a combination metabolomics based on ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was established to illustrate the abnormality of metabolic characteristics of the liver, hippocampus and serum of p-chlorophenylalanine (PCPA)-induced insomnia rats and to demonstrate the mechanism of ZSS in treating insomnia. The results showed that ZSS could restore the brain cell morphology, decrease the degree of hepatocyte necrosis and regulate the disturbance of neurotransmitters and hormones in insomnia rats. In terms of metabolomics, a total of 33 liver metabolites, 25 hippocampal metabolites and 18 serum metabolites were finally selected as the potential biomarkers and an important pathway of phenylalanine, tyrosine and tryptophan biosynthesis was common in three tissues in PCPA rats. Meanwhile, ZSS significantly reversed the levels of 23 liver metabolites, 15 hippocampal metabolites and 5 serum metabolites. The present study demonstrates the actions of ZSS in treating insomnia by enhancing both cerebral and hepatic functions.