Modified Xiaoyaosan (MXYS) Exerts Anti-depressive Effects by Rectifying the Brain Blood Oxygen Level-Dependent fMRI Signals and Improving Hippocampal Neurogenesis in Mice

Abstract

As the traditional Chinese herbal formula, Xiaoyaosan and its modified formula have been described in many previous studies with definite anti-depressive effects, but its underlying mechanism remains mystery. Previous work in our lab has demonstrated that depression induced by chronic stress could generate brain blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals disorder, accompanied by the impairment of hippocampal neuronal plasticity, decrease of brain-derived neurotrophic factor, and reduction of the number and complexity of adult neurons in the dentate gyrus. We hypothesized that herbal formula based on Xiaoyaosan could exert anti-depressive effects through restoring these neurobiological dysfunctions and rectifying BOLD-fMRI signals. To test this hypothesis, we examined the effect of modified Xiaoyaosan (MXYS) on depressive-like behaviors, as well as hippocampal neurogenesis and BOLD signals in a mice model of chronic unpredictable mild stress (CUMS)-induced depression. MXYS exerted anti-depressant effects on CUMS-induced depression that were similar to the effects of classical antidepressants drug (fluoxetine hydrochloride), with a significant alleviation of depressive-like behaviors, an improvement of hippocampal neurogenesis, and a reversal of activation of BOLD in the limbic system, particularly in the hippocampus. These results suggested that MXYS attenuated CUMS-induced depressive behaviors by rectifying the BOLD signals in the mice hippocampus. These novel results demonstrated that MXYS had anti-depressive effects accompanied by improving BOLD signals and hippocampal neurogenesis, which suggested that BOLD-fMRI signals in brain regions could be a key component for the evaluation of novel antidepressant drugs.

Modified Xiaoyaosan reverses aberrant brain regional homogeneity to exert antidepressive effects in mice

“…In accordance with the Regulation on Processing of Traditional Chinese Medical Herbal Pieces, all raw herbs were purchased from Nanfang Hospital and processed into a no‐decocted extract by EFONG Pharmaceutical Company (Guangdong, China). The putative major ingredients, targets of 10 herbs in MXYS, and the production procedure of no‐decocted MXYS have been described in our previous studies . The quality of MXYS was controlled by regular items regarding granules under the 2010 edition of the Pharmacopeia .…”

“…The drug was packaged into a medicinal composite film, in line with the pharmaceutical packaging specifications. In order to confirm the quality control, critical compounds from MXYS samples were previously identified by employing an high‐performance liquid chromatography LTQ‐Orbitrap mass spectrometry eluted system …”

“…As previously described, all drug doses were converted according to the human and animal equivalent dose formulas. All drugs were administered by gavage once a day for 6 weeks.…”

“…Accumulated evidence has shown that Xiaoyaosan, a traditional Chinese herbal formula, exerts antidepressant effects via improving the core symptoms of behavioral despair and anhedonia . Xiaoyaosan has been prescribed to treat mental disorders for thousands of years in China and was originally recorded in Taiping Huimin Heji Jufang , the first official compilation of materia medica around the world during the Song Dynasty in China (960–1127 AD).…”

“…Using functional magnetic resonance imaging (fMRI), we previously demonstrated using amplitude of low‐frequency fluctuations (ALFFs) analysis that blood oxygen level‐dependent (BOLD) signals were significantly upregulated, primarily in the limbic system, in the chronic unpredictable mild stress (CUMS) mouse model of depression. Intriguingly, we further uncovered that modified Xiaoyaosan (MXYS) normalized BOLD signals to exert antidepressant effects in CUMS mice . However, BOLD analysis involves technical challenges because the hemodynamic response may vary among regions and even among trials .…”