Hangekobokuto, a traditional Japanese herbal medicine, ameliorates postoperative ileus through its anti-inflammatory action.

BACKGROUND/AIMS: Gastroprokinetic agents are used for patients with postoperative ileus (POI), and the Japanese traditional herbal medicine daikenchuto (DKT) is one such agent used in the clinical setting. POI is caused by inflammation. DKT and rikkunshito have anti-inflammatory abilities in addition to their gastroprokinetic effects. The efficacy of Kampo formulations, including hangekobokuto (HKT), in patients with POI has been reported recently. Several authors have described the efficacy of honokiol, the primary component of Magnoliae Cortex, in HKT in mouse models of POI. We therefore analyzed the effect of HKT on POI model mice to determine the similarities in the mechanism of action between HKT and DKT. METHODS: HKT was administered orally to each mouse before and after intestinal manipulation was performed on the distal ileum. The gastrointestinal transit in vivo, leukocyte infiltration, and levels of inflammatory mediators, such as cytokines and chemokines, were analyzed. RESULTS: HKT significantly inhibited the infiltration of neutrophils and macrophages and led to the recovery of delayed intestinal transit. In addition, it significantly decreased inducible nitric oxide synthase (iNOS) as well as honokiol levels, suggesting anti-inflammatory activity. However, it did not inhibit the increase in levels of interleukin (IL)-1beta and IL-6, which are related to iNOS induction. In contrast, HKT increased levels of nerve growth factor (NGF) and suppressed those of nuclear factor-κB (NFκB), which are related to iNOS induction, suggesting the possibility of a neuronal anti-inflammatory mechanism. CONCLUSIONS: HKT exerted a POI-relieving effect similar to DKT in a murine POI model, and findings suggest that it may exert its anti-inflammatory activity through NGF.

Metabolic fingerprinting for discrimination of DNA-authenticated Atractylodes plants using 1H NMR spectroscopy.

Identifying different species of the genus Atractylodes which are commonly used in Chinese and Japanese traditional medicine, using chromatographic approaches can be difficult. 1H NMR metabolic profiling of DNA-authenticated, archived rhizomes of the genus Atractylodes was performed for genetic and chemical evaluation. The ITS region of the nuclear rDNA was sequenced for five species, A. japonica, A. macrocephala, A. lancea, A. chinensis, and A. koreana. Our samples had nucleotide sequences as previously reported, except that part of the A. lancea cultivated in Japan had a type 5, hybrid DNA sequence. Principal component analysis (PCA) using 1H NMR spectra of extracts with two solvent systems (CD3OD, CDCl3) was performed. When CDCl3 extracts were utilized, the chemometric analysis enabled the identification and classification of Atractylodes species according to their composition of major sesquiterpene compounds. The 1H NMR spectra using CD3OD contained confounding sugar peaks. PCA removal of these peaks gave the same result as that obtained using CDCl3 and allowed species distinction. Such chemometric methods with multivariate analysis of NMR spectra will be useful for the discrimination of plant species, without specifying the index components and quantitative analysis on multi-components.

Possible anti-inflammatory role of Zingiberis processum rhizoma, one component of the Kampo formula daikenchuto, against neutrophil infiltration through muscarinic acetylcholine receptor activation.

Zingiberis processum rhizoma (ZPR) is a major active component of daikenchuto (DKT), which induces anti-inflammatory action by inhibiting macrophage infiltration. However, it is unclear whether ZPR is related to DKT-induced anti-inflammatory action via a reduction of neutrophil infiltration against postoperative ileus (POI). In this study, we orally administered individual herbal components of DKT to mice four times before and after intestinal manipulation (IM). The anti-inflammatory action of each crude drug was evaluated by histochemical analysis of relevant molecules. The results showed that treatment with all herbal components of DKT significantly inhibits neutrophil infiltration. This inhibition of neutrophil infiltration by ZPR was significantly reduced in 5-hydroxytryptamine receptor 4 (5-HT4R) knockout (KO) mice but not in alpha-7 nicotinic acetylcholine receptor (α7nAChR) KO mice. Also, transient receptor potential ankyrin 1 (TRPA1) and muscarinic acetylcholine receptor (mAChR) antagonists partly and significantly inhibited the amelioration of neutrophil infiltration by ZPR. Therefore, DKT-induced anti-inflammatory action, mediated by inhibition of neutrophil infiltration in POI, depends, in part, on the effects of ZPR. ZPR activates TRPA1 channels, possibly in enterochromaffin (EC) cells, to release 5-HT. This 5-HT stimulates 5-HT4R in the myenteric plexus neurons to release acetylcholine, which, in turn, activates mAChR to inhibit inflammation in POI.

Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice.

BACKGROUND: Kososan, 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. METHODS: In 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. RESULTS: Oral 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. CONCLUSIONS: Our 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.

Rikkunshito, a Kampo medicine, ameliorates post-operative ileus by anti-inflammatory action.

Rikkunshito (RKT), a Kampo (Japanese herbal) medicine, is used as a prokinetic for patients with various diseases including functional dyspepsia. RKT promotes delayed gastric emptying via 5-HT3 receptor blockade. Otherwise, RKT increases ghrelin release via 5-HT2B and 5-HT2C receptor activation. Recent studies revealed that ghrelin and 5-HT3 receptor antagonists have an anti-inflammatory effect. So we hypothesize that RKT may have an anti-inflammatory action in the post-operative ileus. Intestinal manipulation (IM) was applied to the distal ileum of mice. RKT was administered orally 4 times before and after IM. Gastrointestinal transit in vivo, leukocyte infiltration, and gastric emptying were analyzed. We also investigated the effects of the 5-HT3 receptor agonist m-chlorophenylbiguamide (mCPBG) and ghrelin-receptor antagonist [D-Lys3]-GHRP-6 on the ameliorative action of RKT. RKT treatment led to recovery of the delayed intestinal transit and gastric emptying rate induced by IM. RKT significantly inhibited the infiltration of neutrophils and macrophages. [D-Lys3]-GHRP-6 reduced and mCPBG partially reduced the RKT-mediated anti-inflammatory activity, as monitored by infiltrating macrophages and neutrophils. RKT serves as a novel therapeutic agent for POI characterized by its anti-inflammatory potency, in addition to prokinetic action. The RKT-induced anti-inflammatory activity may be partly mediated by inhibition of the 5-HT3 receptor and ghrelin release.

Daikenchuto, a traditional Japanese herbal medicine, ameliorates postoperative ileus by anti-inflammatory action through nicotinic acetylcholine receptors.

BACKGROUND: Daikenchuto (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. METHOD: Intestinal 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. RESULTS: DKT 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. CONCLUSIONS: In 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.

The (13)C-butyrate breath test: a new non-invasive method for assessing colitis in a murine model.

The conventional method for the real-time assessment of murine colitis requires a large number of animals. The (13)C-butyrate breath test could be useful for evaluating disease activity and the amelioration of human ulcerative colitis non-invasively. The purpose of this study was to investigate whether this test can be used to assess the phase of inflammation in murine colitis. We investigated the excretion of (13)CO2 measured by the (13)C-butyrate breath test after rectal instillation of butyrate in the DSS colitis model. The colon length, MPO activity, and histological damage were analyzed as parameters. The efficacy of salicylazosulfa-pyridine (SASP) on (13)CO2 excretion was also studied. The (13)CO2 excretion curves in the 0.5% DSS- and 0.75% DSS-treated groups were significantly lower than those in the normal group (P < 0.01, P < 0.01). Good correlation between the results of the breath test and the inflammation parameters was observed. The (13)CO2 excretion curve in DSS murine colitis after the administration of SASP was significantly higher than in the normal group (P < 0.01). The (13)C-butyrate breath test can be used to evaluate the inflammatory phase of DSS murine colitis, and it may be a new non-invasive method for assessing murine colitis.

Go-rei-San, a Kampo medicine, reduces postoperative nausea and vomiting: a prospective, single-blind, randomized trial.

OBJECTIVE: The objective of this study was to determine the efficacy of Go-rei-San (GRS), a Kampo medicine, in the treatment of postoperative nausea, vomiting, or both nausea and vomiting (PONV). DESIGN: The study was a randomized, controlled, single-blind study of two groups of adult female patients who were scheduled to undergo benign gynecological laparoscopic surgery under general anesthesia. Patients in each group possessed an American Society of Anesthesiologists physical status of 1 (normal, healthy patient) to 2 (patient with a mild systemic disease). Patients were randomly assigned to the GRS group or the no-intervention group. INTERVENTION: Patients in the GRS group were given 7.5 g of GRS orally the day before surgery. OUTCOME MEASURES: The primary outcome measure was the severity of nausea at 0-3 h and 0-24 h after tracheal extubation. The secondary outcome measures were the incidence of vomiting at 0-3 h and 0-24 h and the frequency of vomiting at 0-24 h. The severity of nausea was measured by the patient, who used an 11-point verbal scale to indicate her strongest nausea. RESULTS: Of the 100 female patients selected for the study, 99 completed the trial, and no adverse events occurred. The severity of nausea, frequency of vomiting, and incidence of vomiting were significantly lower in the GRS group than in the no-intervention group. CONCLUSIONS: This study suggests that GRS may be effective for the reduction of PONV.

Involvement of neuropeptide Y signaling in the antidepressant-like effect and hippocampal cell proliferation induced by kososan, a Kampo medicine, in the stress-induced depression-like model mice.

Neuropeptide Y (NPY) and Orexin-A (OX-A), well-known neuropeptides associated with feeding and arousal, show antidepressant-like properties via hippocampal cell proliferation. Previous studies have revealed that kososan, a Kampo (Japanese herbal) medicine, has an antidepressant-like effect in behavioral animal models of depression; the mechanisms underlying this effect may involve the orexinergic system and subsequent upregulation of hippocampal cell proliferation. However, the roles of NPY in kososan's antidepressant-like effect remain unclear. Here we investigated whether the regulation of the NPY system could play crucial roles in this effect in the stress-induced depression-like model mice. The antidepressant-like effect of kososan administered orally (1.0 g/kg) for 28 d was abolished by a continuous intracerebroventricular injection of BIBO3304, a neuropeptide Y1 receptor antagonist, for 7 d. Likewise, BIBO3304 injection blocked the kososan-induced increases in hippocampal cell proliferation and cluster formation of neural progenitor cells. On the other hand, BIBO3304 injection did not affect kososan-induced increases in hypothalamic OX-A-producing cells or in serum OX-A levels. These results suggest that the control of the NPY system in the brain plays an essential role in kososan's antidepressant-like effect and facilitates hippocampal cell proliferation, both of which could be attributed, at least in part, to the control of the NPY system subsequent to the control of the OX-A system.

Discrepancy between clinical course and drug-induced lymphocyte stimulation tests in a case of saireito-induced liver injury accompanied by Sjögren syndrome.

BACKGROUND: Saireito consists of components of shosaikoto and goreisan. There are several reports of liver injury caused by shosaikoto and saireito, whereas cases caused by goreisan are rarely seen. PATIENT: A 70-year-old woman suffered from sicca of the eyes and oral cavity that arose in 2003. In June 2004, we diagnosed her as having Sjögren syndrome on the basis of Schirmer's test, salivary scintigraphy, presence of anti-SS-A/Ro antibody, and subjective symptoms. Although a muscarinic agonist was commenced, her sicca symptoms did not improve. INTERVENTIONS: In February 2008, 7.5 g/day of shosaikoto extract granules (for ethical use, Tsumura & Co., Tokyo, Japan) was introduced. Her symptoms and laboratory data did not change. The next month, the treatment was replaced by 9.0 g/day of saireito extract granules (for ethical use, Tsumura & Co., Tokyo, Japan). RESULTS: After 10 weeks, elevation of liver enzymes was observed. On suspicion of drug-induced liver injury (DILI), saireito was withdrawn, and the patient's liver enzymes returned to normal the next month. Drug-induced lymphocyte stimulation tests (DLSTs) for saireito, shosaikoto, and goreisan were all positive. CONCLUSIONS: The clinical course suggested allergy to the goreisan component of saireito. It is important to be aware of the limitation of DLST as a diagnostic tool for DILI, especially for herbal medicines.

A possible mechanism underlying an antidepressive-like effect of Kososan, a Kampo medicine, via the hypothalamic orexinergic system in the stress-induced depression-like model mice.

Kososan, a Kampo (Japanese herbal) medicine, has an antidepressive-like effect in behavioral animal models of depression and has been used clinically for the improvement of depressive mood. However, mechanism(s) underlying the antidepressive-like effect of kososan remain unknown. Previous studies showed that orexin-A (OX-A), a neuropeptide that is involved in feeding and arousal, exhibits an antidepressive-like property via hippocampal cell proliferation. Here, we used immunohistochemical analysis with bromodeoxyuridine (BrdU), a marker of proliferating cells, to investigate the effect of long-term treatment with kososan on the orexinergic system and on hippocampal cell proliferation. Oral administration of kososan (1.0 g/kg) or milnacipran (60 mg/kg), a serotonin and noradrenaline reuptake inhibitor, for 28 d led to an antidepressive-like effect in the stress-induced depression-like model mice and reversed the stress-induced decrease in the number of OX-A-positive cells in the lateral hypothalamic area. In addition, both kososan and milnacipran alleviated the stress-induced decrease in the number of BrdU-positive cells in the hippocampal dentate gyrus. Moreover, the antidepressive-like effect and the increase in cell proliferation and in the number of neuropeptide Y (NPY, which is closely associated with orexinergic system)-positive cells in the dentate gyrus induced by kososan were blocked by treatment with SB-334867, an orexin receptor 1 antagonist. These results suggest that kososan exerts an antidepressive-like effect via the improvement of the stress-induced decrease in hippocampal cell proliferation and that the mechanism underlying the antidepressive-like effect of kososan, but not of milnacipran, may be associated with the regulation of orexinergic and/or NPYergic transmission.

Hangekobokuto (Banxia-houpo-tang), a Kampo Medicine that Treats Functional Dyspepsia.

Although abdominal bloating is one of the most bothersome symptoms experienced by patients with functional dyspepsia (FD), therapeutic drugs to relieve abdominal bloating have not been established. We investigated the Kampo (Chinese herbal) medicine, Hangekobokuto (Banxia-houpo-tang, HKT) for patients with FD from the standpoint of bowel gas retention. The bowel gas volume calculated from a plain abdominal radiogram (gas volume score, GVS) in FD patients was significantly higher than that in healthy subjects. Two week administration of HKT in the FD patients showed a significant decrease of GVS. Furthermore, gastrointestinal symptoms, especially symptoms of abdominal pain, indigestion and constipation, all of which are closely related to abdominal bloating, improved significantly in FD patients after the administration of HKT. These results suggest that HKT improves abdominal bloating accompanied by the reduction of bowel gas in FD patients.

Clinical efficacy of Kampo medicine (Japanese traditional herbal medicine) in the treatment of primary dysmenorrhea.

OBJECTIVE: We intended to evaluate the clinical efficacy of Kampo medicine, a Japanese traditional herbal medicine, for primary dysmenorrhea which was prescribed according to the Kampo diagnosis, with classification of its severity. METHOD: A retrospective evaluation of Kampo treatment in 176 subjects with dysmenorrhea during the previous 12 years was performed. In order to minimize the subjective discretion of the severity of symptoms, classification of the severity level of abdominal pain during menstruation was applied by considering the requirement for non-steroidal anti-inflammatory drugs (NSAIDs) and disturbance of daily activities. The following severity levels were used: no abdominal pain (level 0), abdominal pain with no requirement of NSAIDs (level 1), abdominal pain with no daily activity disturbances with use of NSAIDs (level 2), and painful menstruation which required absenteeism even with use of NSAIDs (level 3). RESULTS: Severity levels before and after Kampo treatment were defined in 108 subjects. Distribution of the severity levels in 108 subjects was significantly changed by Kampo treatment; the numbers of cases in levels 0, 1, 2, and 3 changed from 0 (0%), 0 (0%), 47 (43.5%), and 61 (56.5%) to 5 (4.6%), 42 (38.9%), 51 (47.2%), and 10 (9.3%), respectively. (P<0.0001) There were 25 kinds of Kampo formulae prescribed in effective cases. CONCLUSION: Kampo medicine prescribed according to Kampo diagnosis reduced the severity of primary dysmenorrhea and is therefore suggested to be beneficial in improving quality of life.

Effects of goshuyuto on lateralization of pupillary dynamics in headache.

Autonomic nervous imbalance is implicated in chronic headache. We investigated the effects of goshuyuto-a representative Kampo medicine for headache-on the lateralization of the pupillary autonomic nervous system by using binocular infrared video pupillography. Patients with chronic headache were administered goshuyuto extract for 1 month (1st stage). Goshuyuto was discontinued for 1 month, following which the patients were randomly divided into 2 groups: placebo and goshuyuto. In the 2nd stage, the respective groups were administered placebo or goshuyuto for 3 months. The average laterality of the pupillary dynamics decreased significantly in the goshuyuto group. These results suggest that the reduction of the difference in pupillary autonomic balance between the left and right eyes might be one of the action mechanisms of goshuyuto to relieve chronic headache.