Kamikihito (KKT) is a Kampo medicine that is prescribed in Japan for the treatment of anemia, insomnia and mental anxiety in Japan. However, its precise mechanism of action remains unclear. This study aimed to evaluate the possible antistress effect of KKT in rats with acute stress and the contribution of oxytocin to the process. Acute immobilization stress (AIS; for 90 min) was used to assess the effect of KKT on acute stress. Male Wistar rats were orally treated with KKT. Parameters of stress were evaluated, and concentrations of oxytocin in plasma and cerebrospinal fluid (CSF) were measured. AIS-induced defecation and fecal weight were significantly decreased because of treatment with KKT. The plasma levels of stress-related hormones following AIS were investigated. The pre-administration of KKT significantly increased adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels following AIS. Conversely, there was no significant change in the plasma oxytocin level. Microdialysis and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were used to monitor the oxytocin secretion in CSF. Oxytocin level increased during AIS following the treatment of KKT. At 30 min after AIS, the level remained higher than before AIS. Furthermore, using an open field test, the locomotion (exploratory behavior) immediately after AIS was examined. The total traveled distance decreased after AIS; however, the decrease was significantly inhibited by the treatment of KKT. However, the effect of KKT was obstructed by the pre-administration of the oxytocin receptor antagonist. These results suggest that KKT has antistress activity and increased oxytocin secretion may be a mechanism underlying this phenomenon.

Stomatitis is occasionally multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem. Effective treatments have not been established and the treatment of numerous cases remains a challenge for physicians. Traditional Japanese herbal medicines termed Kampo formulae (i.e., Hangeshashinto, Orengedokuto, Inchinkoto, Orento, Byakkokaninjinto, Juzentaihoto, Hochuekkito, and Shosaikoto) are used for treating various types of stomatitis and mucositis. Its use has been based on the Kampo medical theories—empirical rules established over thousands of years. However, recently, clinical and basic research studies investigating these formulae have been conducted to obtain scientific evidence. Clinical studies investigating efficacies of Shosaikoto and Orento for the treatment of cryptogenic stomatitis and acute aphthous stomatitis and those investigating the effects of Hangeshashinto, Orengedokuto, and Juzentaihoto on chemotherapy- or radiotherapy-induced mucositis have been conducted. The Kampo formulae comprise several crude drugs, whose mechanisms of action are gradually being clarified. Most of these drugs that are used for the treatment of stomatitis possess anti-inflammatory, analgesic, and antioxidative properties. In this review, we introduce the clinical applications and summarize the available evidence on the Kampo formulae for the treatment of stomatitis and oral mucositis.

Background: Considering the anti-inflammatory properties of the Japanese traditional Kampo medicine Boiogito (BO), we aimed to investigate the therapeutic effect of BO to prevent the development of knee osteoarthritis (KOA) in rats with surgically induced KOA. Methods: Destabilization of the medial meniscus (DMM) was performed to induce osteoarthritis in the right knees of 12-week-old Wistar rats under general anesthesia. The rats were orally administered 3% BO in standard powder chow for 4 weeks after surgery (controls: n = 6; sham group: n = 6; DMM group: n = 5; DMM + BO group: n = 5). During this period, the rotarod test was performed to monitor locomotive function. After 4 weeks, histological assessment was performed on the right knee. Results: Oral administration of BO improved locomotive function in the rotarod test. Walking time on postoperative days 1, 14, or later was significantly longer in the DMM + BO group than in the DMM group. Histologically, the DMM group showed significant progression of KOA, which, in the DMM + BO group, was strongly suppressed, as assessed by the Osteoarthritis Research Society International score. Conclusions: Our results showed that oral administration of BO had a clinically preventive effect on early stage posttraumatic KOA.

Boiogito (BO), a Japanese traditional herbal medicine, has been proven to be clinically effective against knee osteoarthritis (KOA)-associated pain. However, the therapeutic mechanism of BO remains unclear. Thus, we investigated the analgesic mechanism of BO using a rat KOA model. KOA was induced by destabilization of the medial meniscus (DMM). Rats were allocated into the following four groups: control, sham, DMM, and DMM + BO groups. Rotarod test was performed to evaluate the pain-related locomotive dysfunction. Expression of phosphorylated extracellular signal-regulated kinase1/2 (pERK1/2) in the spinal dorsal horn was examined using immunofluorescence staining and Western blotting on days 1 and 28 after DMM surgery. A mitogen-activated protein kinase inhibitor, U0126, was intrathecally injected and rotarod test and Western blotting were performed. The rotarod test revealed hampered locomotive function in the DMM group, which was significantly improved upon BO administration. The number of pERK1/2-positive cells was increased in the DMM group, whereas it was significantly decreased in the DMM + BO group. U0126 significantly inhibited ERK1/2 phosphorylation and increased walking time in the rotarod test, suggesting that the DMM-related pain was associated with ERK1/2 phosphorylation in the spinal dorsal horn. In conclusion, BO administration improved the pain-related locomotive dysfunction by suppressing ERK1/2 phosphorylation.

Boiogito (BO), a Japanese traditional herbal medicine, has been reported to prevent knee osteoarthritis (KOA) development in in vivo studies. In the early stage of KOA, osteoclasts proliferate in the subchondral bone. This study aimed to investigate the preventive effect of BO on osteoclast proliferation, which remains unclear, in a KOA-induced rat model. KOA was induced in 12-week-old male Wistar rats using surgical destabilization of the medial meniscus (DMM). BO was mixed with powdered chow, applying 1%, 3%, and 5% of the total feed, and administered to KOA-induced rats. The rats were divided into 6 groups: control, sham, DMM, DMM + BO 1%, DMM + BO 3%, and DMM + BO 5%. Rotarod tests were performed each week to assess the locomotor function, and the right knees were harvested 28 days after surgery for histological analysis. Oral administration of BO significantly inhibited the decrease in the latency to fall off in the rotarod test, which was aggravated in the DMM group. Furthermore, KOA development was significantly prevented in the BO-administrated groups as assessed by the Osteoarthritis Research Society International score. The number of multinucleated activated osteoclasts in the subchondral bone was decreased in the BO-treated groups, which was increased in the DMM group. Therefore, oral administration of BO may reduce articular cartilage degeneration, osteoclast differentiation and proliferation in the KOA patients.