Banxia-houpu decoction restores glucose intolerance in CUMS rats through improvement of insulin signaling and suppression of NLRP3 inflammasome activation in liver and brain
Graphical abstract
Introduction
Depression is a common illness with the leading cause of disability worldwide. Seriously, depression increases the risk of insulin resistance and developing type 2 diabetes mellitus (T2DM) (Vancampfort et al., 2016, Vancampfort et al., 2015, Winokur et al., 1988), and mortality among diabetic individuals (Park et al., 2013). It has been hypothesized that some physiopathological changes, such as the activation of hypothalamic-pituitary-adrenocortical (HPA) axis with signaling pathway of glucocorticoids (cortisol or corticosterone) and corticotropin-releasing factor (CRF), induce comorbidity of depression and T2DM (Gragnoli, 2012, Gragnoli, 2014, Pan et al., 2013). However, the mechanisms underlying are still unclear and warrant further investigation.
Chronic unpredictable mild stress (CUMS) model is a commonly recognized and widely used model to mimic clinical depression, showing the depressive-like behavior (anhedonia) in animals (Pan et al., 2014, Willner, 1997). Our previous study observed that CUMS procedure induced glucose intolerance in rats, supporting an increased risk of comorbid T2DM in depressed animals (Pan et al., 2013). Similar results in chronic unpredictable stress rats and mice are also reported by others (d'Audiffret et al., 2010, Patel et al., 2016). Thus, this animal model of depression is suitable to investigate the effect of drugs on depression comorbid T2DM.
Perturbation in insulin signaling pathway, as impaired signaling cascade of phosphorylation of insulin receptor (IR), insulin receptor substrate 1 (IRS1) and downstream serine/threonine kinase (Akt), promotes insulin resistance in periphery as well as in brain (Ramnanan et al., 2011, Saltiel and Kahn, 2001, Tanti and Jager, 2009). Inflammation induced by pro-inflammatory cytokine interleukin-1 beta (IL-1β), is a most common cause for insulin signaling impairment (Tack et al., 2012, Wen et al., 2011). Actually, inflammation or pro-inflammatory cytokine hypothesis is prevalent in depression, supported by previous studies in CUMS animals (Kubera et al., 2011, Pan et al., 2014). Recently, Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, modulating IL-1β maturation and secretion, is observed in periphery and brain of CUMS animals, possibly being critical in pathophysiology of depression and pharmacology of antidepressants (Alcocer-Gomez et al., 2014, Du et al., 2016, Iwata et al., 2013, Pan et al., 2014, Zhang et al., 2015). Of note, some antidepressants produce the mixed or even negative effects on glycemic control (Goodnick et al., 1995, van Reedt Dortland et al., 2010). For example, tricyclic antidepressant may lead to hyperglycemia or metabolic syndrome (Sugimoto et al., 2003). These observations strongly argue for the importance to find new effective drugs for comorbid depression with T2DM.
Traditional Chinese medicine (TCM) and the active ingredients are therapeutically beneficial in chronic diseases including depression and T2DM (Yeung et al., 2014, Zhang and Jiang, 2012). Banxia-houpu decoction is a TCM formula consisted of Pinellia tuber, Magnolia cortex, Poria, Perilla leaf and Ginger rhizome. Banxia-houpu decoction is firstly recorded in TCM book, “Jin Gui Yao Lue” written by Zhong-Jing Zhang in the early 3rd century, and then has been applied with good efficiency in depressed patients (Naito et al., 2003). Our previous studies demonstrated the antidepressant-like activity of water- and ethanol-extracts and polysaccharides from Banxia-houpu decoction, with the regulatory effects on multiple biochemical systems related to neurotransmitters, the HPA axis and immune-inflammation (Guo et al., 2004, Li et al., 2003, Wang et al., 2005, Yi et al., 2009). However, there is little report of Banxia-houpu decoction on comorbid depression with metabolic diseases.
In the present study, the effect of Banxia-houpu decoction against glucose intolerance was investigated in depressed CUMS rats. Insulin signaling controls glucose homeostasis not only in periphery but also in brain (Ghasemi et al., 2013). Therefore, to explore the possible mechanisms underlying the impairment of glucose tolerance, IR/IRS1/Akt insulin signaling and the activation of NLRP3 inflammasome were detected in peripheral liver tissue, as well as in brain regions hypothalamus, hippocampus and prefrontal cortex in CUMS rats, respectively. More importantly, the ability of Banxia-houpu decoction to attenuate insulin signaling impairment and NLRP3 inflammasome activation was evaluated in depressed animals. These results may provide experimental evidence to strengthen our understanding about the pharmacological mechanisms by which Banxia-houpu decoction reduces the risk of comorbid depression with T2DM.
Section snippets
Preparation of Banxia-houpu decoction
Banxia-houpu decoction was consisted of five herbs, Pinellia tuber, Magnolia cortex, Poria, Perilla leaf and Ginger rhizome (Table 1), and prepared according to our previous study (Li et al., 2003). All of these herbs were purchased from Medicinal Materials Company of Jiangsu Province (P.R. China). These herbs were immersed in 10 times volume of water for 0.5 h; then decocted at boiling temperature for 1 h and get the filtrate. The residues were added with 8 times volume of water and decocted for
Qualitative and quantitative analysis of components in water extract of Banxia-houpu decoction
Qualitative analysis of components in water extract of Banxia-houpu decoction was performed by a LC-MS/MS method. Chromatograms of total ion in ESI negative and positive-ion mode for Banxia-houpu decoction water extract were shown in Fig. 2. We preliminarily identified 23 compounds in this extract. They were citric acid, succinic acid, 3,4-Dihydroxybenzoic acid, caffeic acid, acteoside, apigenin7-glucuronosyl-(1->2)-glucuronide, luteolin 7-O-β-glucuronide, sinapaldehyde, apigenin
Discussion
Banxia-houpu decoction is an efficacious and well-tolerated antidepressant prescription in TCM clinic. We have reported that Banxia-houpu decoction exhibited the antidepressant-like activity in animal models of depression (Guo et al., 2004, Li et al., 2003, Wang et al., 2005). In our continuing investigation of Banxia-houpu decoction, we demonstrated its improvement of glucose tolerance in CUMS rats with anhedonia and the HPA axis hyperactivity. Furthermore, Banxia-houpu decoction was found to
Conclusions
In the present study, Banxia-houpu decoction, a classic TCM formula, was found to improve glucose tolerance with anti-depressive effect in CUMS rats. Its underlying pharmacological mechanisms may be involved the inhibition of NLRP3 inflammasome activation and consequent IL-1β maturation, and improvement of insulin signaling in periphery (liver) and brain regions (hypothalamus, hippocampus and prefrontal cortex) in CUMS rats. Therefore, these findings provide the experimental evidence that
Authors' contributions
Ling-Dong Kong designed the experiments. Ke-Ke Jia, Yan-Jing Zheng, Yan-Xiu Zhang, Jia-Hui Liu, Rui-Qing Jiao performed the experiments. Ke-Ke Jia performed the qualitative and quantitative analysis of components in Banxia-houpu decoction water extract. Ke-Ke Jia, Ying Pan and Ling-Dong Kong analyzed the data. Ke-Ke Jia, Ying Pan and Ling-Dong Kong wrote the manuscript. Ling-Dong Kong and Ying Pan critically revised the manuscript.
Acknowledgments
This project was supported by the National Natural Science Foundation of China (No. 81373788) and the Program for Changjiang Scholars and Innovative Research Team in University [IRT_14R27].
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