Elsevier

Journal of Ethnopharmacology

Volume 209, 14 September 2017, Pages 219-229
Journal of Ethnopharmacology

Banxia-houpu decoction restores glucose intolerance in CUMS rats through improvement of insulin signaling and suppression of NLRP3 inflammasome activation in liver and brain

https://doi.org/10.1016/j.jep.2017.08.004Get rights and content

Abstract

Ethnopharmacological relevance

Banxia-houpu decoction is a famous formula in traditional Chinese medicine (TCM) with the powerful anti-depressant activity.

Aim of the study

This study aimed to investigate the effect of Banxia-houpu decoction on glucose intolerance associated with anhedonia in chronic unpredictable mild stress (CUMS) rats, then to explore its underlying pharmacological mechanisms.

Materials and methods

After 6-week CUMS procedure, male Wistar rats were given Banxia-houpu decoction (3.29 and 6.58 g/kg, intragastrically) for 6 weeks. Sucrose solution consumption test was employed to evaluate the anhedonia behavior. Oral glucose tolerance test (OGTT) was used to determine glucose tolerance. Serum levels of corticosterone, corticotropin-releasing factor (CRF), insulin and interleukin-1 beta (IL-1β) were measured by commercial enzyme-linked immunosorbent assay kits, respectively. Furthermore, the key proteins for insulin signaling, as well as nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, were analyzed by Western blot in periphery liver and brain regions hypothalamus, hippocampus and prefrontal cortex, respectively.

Results

Banxia-houpu decoction significantly increased sucrose solution consumption and decreased serum corticosterone and CRF levels in CUMS rats, further demonstrating its antidepressant activity. More importantly, Banxia-houpu decoction improved glucose tolerance in OGTT in this animal model. Furthermore, it protected against CUMS-induced insulin signaling impairment in the liver, as well as hypothalamus and prefrontal cortex in rats. Although without significant effect on serum IL-1β levels, Banxia-houpu decoction inhibited NLRP3 inflammasome activation in the liver, hypothalamus, hippocampus and prefrontal cortex of CUMS rats, respectively.

Conclusions

The present study demonstrates that Banxia-houpu decoction suppresses NLRP3 inflammasome activation and improves insulin signaling impairment in both periphery liver and brain regions in CUMS rats, possibly contributing to its anti-depressive effect with glucose tolerance improvement. These results may provide the evidence that Banxia-houpu decoction is a potential antidepressant with the advantage to reduce the risk of comorbid depression with type 2 diabetes mellitus.

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].

References (78)

  • J.M. Li et al.

    Behavioral and biochemical studies on chronic mild stress models in rats treated with a Chinese traditional prescription Banxia-houpu decoction

    Life Sci.

    (2003)
  • Y.H. Lin et al.

    Effect of chronic unpredictable mild stress on brain-pancreas relative protein in rat brain and pancreas

    Behav. Brain Res.

    (2005)
  • D.L. Musselman et al.

    Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment

    Biol. Psychiatry

    (2003)
  • Y. Pan et al.

    Icariin attenuates chronic mild stress-induced dysregulation of the LHPA stress circuit in rats

    Psychoneuroendocrinology

    (2010)
  • Y. Pan et al.

    Impaired hypothalamic insulin signaling in CUMS rats: restored by icariin and fluoxetine through inhibiting CRF system

    Psychoneuroendocrinology

    (2013)
  • Y. Pan et al.

    Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats

    Brain Behav. Immun.

    (2014)
  • C.M. Pariante et al.

    The HPA axis in major depression: classical theories and new developments

    Trends Neurosci.

    (2008)
  • M. Park et al.

    Depression and risk of mortality in individuals with diabetes: a meta-analysis and systematic review

    Gen. Hosp. Psychiatry

    (2013)
  • S.S. Patel et al.

    Depression mediates impaired glucose tolerance and cognitive dysfunction: a neuromodulatory role of rosiglitazone

    Horm. Behav.

    (2016)
  • Y. Sugimoto et al.

    The tricyclic antidepressant clomipramine increases plasma glucose levels of mice

    J. Pharmacol. Sci.

    (2003)
  • K. Sulakhiya et al.

    Beneficial effect of honokiol on lipopolysaccharide induced anxiety-like behavior and liver damage in mice

    Pharmacol. Biochem. Behav.

    (2015)
  • J.F. Tanti et al.

    Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation

    Curr. Opin. Pharmacol.

    (2009)
  • Q. Xu et al.

    Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2008)
  • W.F. Yeung et al.

    A systematic review on the efficacy, safety and types of Chinese herbal medicine for depression

    J. Psychiatr. Res.

    (2014)
  • K. Yokoyama et al.

    Relationship between hypothalamic-pituitary-adrenal axis dysregulation and insulin resistance in elderly patients with depression

    Psychiatry Res.

    (2015)
  • P. Zhang et al.

    Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-kappaB activation and cytokine production of glial cells

    Neurosci. Lett.

    (2013)
  • Y. Zhang et al.

    NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation

    Int. J. Neuropsychopharmacol.

    (2015)
  • B. Bellaver et al.

    Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway

    Purinergic Signal.

    (2015)
  • E. Blazquez et al.

    Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease

    Front. Endocrinol. (Lausanne)

    (2014)
  • S.S. Choi et al.

    Honokiol and magnolol stimulate glucose uptake by activating PI3K-dependent Akt in L6 myotubes

    Biofactors

    (2012)
  • A.C. d'Audiffret et al.

    Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease?

    J. Appl. Physiol.

    (2010)
  • M. Deuschle et al.

    Depression and diabetes mellitus type 2

    Nervenarzt

    (2012)
  • C. D'Mello et al.

    Liver-brain inflammation axis

    Am. J. Physiol. Gastrointest. Liver Physiol.

    (2011)
  • R.H. Du et al.

    Fluoxetine inhibits NLRP3 inflammasome activation: implication in depression

    Int. J. Neuropsychopharmacol.

    (2016)
  • R. Ghasemi et al.

    Insulin in the brain: sources, localization and functions

    Mol. Neurobiol.

    (2013)
  • P.W. Gold et al.

    Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-gamma systems

    Mol. Psychiatry

    (2013)
  • P.J. Goodnick et al.

    Treatment of depression in patients with diabetes mellitus

    J. Clin. Psychiatry

    (1995)
  • C. Gragnoli

    Depression and type 2 diabetes: cortisol pathway implication and investigational needs

    J. Cell. Physiol.

    (2012)
  • C. Gragnoli

    Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome

    Appl. Clin. Genet.

    (2014)
  • Cited by (45)

    View all citing articles on Scopus
    View full text