BackgroundDaikenchuto (DKT), a gastrointestinal prokinetic Japanese herbal medicine, is prescribed for patients with postoperative ileus (POI) and adhesive bowel obstruction following abdominal surgery. Several mechanisms for the amelioration of POI by DKT have been suggested; however, it has remained unclear whether DKT shows anti-inflammatory effects in POI. In the present study, we investigated the effects of DKT in a mouse POI model and attempted to clarify the detailed mechanisms of action.MethodIntestinal manipulation (IM) was applied to the distal ileum of mice. DKT was administered orally to the animals 4 times before and after IM. Gastrointestinal transit in vivo, leukocyte infiltration, cytokine mRNA expression and gastrointestinal motility were analyzed. We also investigated the effects of the α7nAChR antagonist methyllycaconitine citrate (MLA) on the DKT-mediated ameliorative action against POI, and we studied the effects of DKT on inflammatory activity in α7nAChR knockout mice.ResultsDKT treatment led to recovery of the delayed intestinal transit induced by IM. DKT significantly inhibited the infiltration of neutrophils and CD68-positive macrophages, and inhibited mRNA expressions of TNF-α and MCP-1. MLA significantly reduced the anti-inflammatory action of DKT, and the amelioration of macrophage infiltration by DKT was partially suppressed in α7nAChR knockout mice.ConclusionsIn conclusion, in addition to the gastrointestinal prokinetic action, DKT serves as a novel therapeutic agent for POI characterized by its anti-inflammatory potency. The DKT-induced anti-inflammatory activity may be partly mediated by activation of α7nAChR.
BackgroundKososan, a Kampo (traditional Japanese herbal) medicine, has been used for the therapy of depressive mood in humans. However, evidence for the antidepressant efficacy of kososan and potential mechanisms are lacking. Recently, it has been recognized that stress triggers neuroinflammation and suppresses adult neurogenesis, leading to depression and anxiety. Here, we examined whether kososan extract affected social behavior in mice exposed to chronic social defeat stress (CSDS), an animal model of prolonged psychosocial stress, and neuroinflammation induced by CSDS.MethodsIn the CSDS paradigm, C57BL/6J mice were exposed to 10 min of social defeat stress from an aggressive CD-1 mouse for 10 consecutive days (days 1–10). Kososan extract (1.0 g/kg) was administered orally once daily for 12 days (days 1–12). On day 11, the social avoidance test was performed to examine depressive- and anxious-like behaviors. To characterize the impacts of kososan on neuroinflammation and adult neurogenesis, immunochemical analyses and ex vivo microglial stimulation assay with lipopolysaccharide (LPS) were performed on days 13–15.ResultsOral administration of kososan extract alleviated social avoidance, depression- and anxiety-like behaviors, caused by CSDS exposure. CSDS exposure resulted in neuroinflammation, as indicated by the increased accumulation of microglia, the resident immune cells of the brain, and their activation in the hippocampus, which was reversed to normal levels by treatment with kososan extract. Additionally, in ex vivo studies, CSDS exposure potentiated the microglial pro-inflammatory response to a subsequent LPS challenge, an effect that was also blunted by kososan extract treatment. Indeed, the modulatory effect of kososan extract on neuroinflammation appears to be due to a hippocampal increase in an anti-inflammatory phenotype of microglia while sparing an increased pro-inflammatory phenotype of microglia caused by CSDS. Moreover, reduced adult hippocampal neurogenesis in defeated mice was recovered by kososan extract treatment.ConclusionsOur findings suggest that kososan extract prevents a social avoidant behavior in socially defeated mice that is partially mediated by the downregulation of hippocampal neuroinflammation, presumably by the relative increased anti-inflammatory microglia and regulation of adult hippocampal neurogenesis. Our present study also provides novel evidence for the beneficial effects of kososan on depression/anxiety and the possible underlying mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0876-8) contains supplementary material, which is available to authorized users.
Perillae Herba (a leaf of Perilla frutescens) has been prescribed as one of the component herbs in certain Kampo (Japanese herbal) medicines that are used clinically for the improvement of depressive mood. l-Perillaldehyde (PAH) is a major component in the essential oil containing in Perillae Herba, but its antidepressant-like effect has not been reported. To clarify the antidepressant-like effect of PAH, the inhaled effect of PAH on stress-induced depression-like model mice prepared by subjection to a combination of forced swimming and chronic mild stresses was investigated. The degree of the depression-like state was measured by the animal's duration of immobility using a forced swimming test. Inhalation of PAH (0.0965 and 0.965 mg/mouse/day, 9 days) significantly shortened the duration of immobility of the depression-like model mice and did not affect locomotor activity. However, another odor substance, cinnamaldehyde containing in Cinnamomi Cortex, exhibited no reduction in the immobility. The reduction in the immobility induced by the inhalation of PAH was prevented on anosmia-induced mice prepared by intranasal irrigation with zinc sulfate. These results suggest that the inhalation of PAH shows antidepressant-like activity through the olfactory nervous function.
Kososan, a Kampo (Japanese herbal) medicine (Xiang-SuSan in Chinese), is composed of five herbs (Cyperi Rhizoma, Perillae Herba, Aurantii Nobilis Pericarpium, Glycyrrhizae Radix, and Zingiberis Rhizoma) and is clinically used to treat the depression-like symptoms associated with the initial stage of the common cold, anorexia, food-related allergic urticaria, irritable bowel syndrome, chronic fatigue syndrome, insomnia, and autonomic imbalance. It has been also clinically suggested that kososan can alleviate the depression induced by interferon (IFN)-a therapy for hepatitis C. 1) Our previous studies using two animal models of depression, stress-and IFN-a-induced depression-like model mice, demonstrated that oral administration of kososan leads to an antidepressive-like effect via the normalization of the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, which is strongly associated with the pathogenesis of depression.2,3) These findings provide supporting evidence that kososan may be beneficial in the treatment of depression.Depressive disorder is thought to reflect maladaptive changes in stress-responsive systems.4) Numerous studies have reported that excessive exposure to stressful life events induces the onset of depression, which is accompanied by a decrease in neurogenesis in the dentate gyrus of the hippocampus. [5][6][7][8] Therefore, disruption of neurogenesis plays a crucial role in the mechanism by which stress facilitates depression.9,10) Furthermore, chronic treatment with antidepressants increases neurogenesis in the rat hippocampus 11) and adult hippocampal neurogenesis is required for the behavioral recovery effects of antidepressants.12) Thus, neurogenesis-inducing compounds may directly and/or indirectly produce antidepressive-like effects.Recent studies have reported that orexin-A (OX-A), which is a neuropeptide produced especially in the lateral hypothalamic area (LHA) and in the posterior hypothalamus, 13,14) is involved in the pathology of depression. A decrease in the number and size of OX-A-producing neurons in the LHA was observed in male Wistar-Kyoto rats, which exhibit a hyper-responsiveness of the HPA axis, a characteristic of depression. 15) Suicidal patients with major depression exhibit significantly lower OX-A levels in the cerebrospinal fluid when compared with patients who suffer from adjustment disorder and dysthymia.16) In addition, our previous study demonstrated that intracerebroventricular administration of OX-A induces an antidepressive-like effect via hippocampal cell proliferation in mice.17) The orexin receptor 1 (OXR1), which is a subtype of the orexin receptor, is expressed in the granule cell layer, hilus, and CA1-3 regions of the hippocampus.18) In addition, orexin-producing neurons also project to the hippocampus, in which neurogenesis occurs. Therefore, hippocampal neurogenesis may, at least in part, be regulated by a change in OX-A expression in the LHA. The neuropeptide Y (NPY) is implicated in the stimulation of feeding behavior 19) and its effect ...
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