Administration of chinpi, a component of the herbal medicine ninjin-youei-to, reverses age-induced demyelination.

The disruption of myelin causes severe neurological diseases. An understanding of the mechanism of myelination and remyelination is essential for the development of therapeutic strategies for demyelination diseases. Our previous findings indicated that the FcRγ/Fyn cascade is a potential therapeutic target for remyelination caused by the Chinese/Japanese traditional herbal (Kampo) medicine ninjin'youeito (Ninjin-youei-to, NYT), which is a hot-water extract made from 12 medicinal herbs. To identify which constituents of NYT are involved in the reversal of demyelination and to examine the potential therapeutic effect, we tested several of the chemical constituents of NYT. Here, we report that Chinpi, a constituent of NYT, upregulates the FcRγ/Fyn signaling cascade resulting in a potentially therapeutic effect against age-induced demyelination. In addition, we observed that phosphorylated (activated) FcRγ/Fyn upregulated the expression of the 21.5 kDa isoform of myelin basic protein, inducing rapid morphological differentiation, when oligodendrocyte precursor cells (OPCs) were cultured in the presence of hesperidin and/or narirutin (the major active constituents of Chinpi). These results suggest that hesperidin and narirutin participate in the FcRγ/Fyn signaling pathway in OPCs causing these cells to differentiate into myelinating oligodendrocytes.

Suppressive effect of a traditional Japanese medicine, Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan), on the hyperresponsiveness to IL-18 in autoimmune MRL/MPJ-lpr/lpr mice.

Oral administration of Hachimi-jio-gan (HMG, Ba-Wei-Di-Huang-Wan), a traditional Japanese herbal medicine, for several weeks, ameliorates some autoimmune symptoms of MRL/lpr mice. In the short time treatment for 9 days, hyperresponsiveness of mesenteric lymph node (MLN) cells to interleukin (IL)-18 manifested by the proliferation or the production of interferon (IFN)-gamma was significantly suppressed. Additionally, the treatment with HMG suppressed the expressions of IL-18Ralpha and IL-18Rbeta mRNA in CD45R(-) T cells, and also the expression of IL-18Ralpha mRNA in unpurified whole cells. Although the short treatment with HMG had no effect on the mRNA expressions of IL-10, IL-12 and IL-18, or the phosphorelated signal transducer and activator transcription (STAT)4 protein level in CD45R(-) MLN cells, the IL-4 mRNA expression or the phosphorelated STAT6 protein level were up-regulated by HMG, and the IL-4 mRNA up-regulation was clearer in whole cells than CD45R(-) cells. Furthermore, the treatment with HMG promoted the mRNA expression of invariant Valpha14 TCR that is uniquely expressed on NKT cells. Valpha14 NKT cells can produce large amount of IL-4 and play a crucial role in controlling the development of MRL/lpr mouse autoimmune disease. Therefore, these results suggested that HMG reduced the hyperresponsiveness of MRL/lpr mouse MLN cells to IL-18 through the reduction of IL-18Rs caused by Valpha14 NKT cell-produced IL-4, and consequently HMG suppressed the development of MRL/lpr autoimmune diseases.

Effects of Sairei-to on the pharmacokinetics of nifedipine in rats.

Sairei-to is a traditional herbal medicine used to complement, and as an alternative to, Western drugs. The aim of this study was to evaluate the pharmacokinetic interactions between Sairei-to and nifedipine (NFP), a substrate for CYP3A, in rats. NFP-oxidizing activity and the pharmacokinetics of NFP were examined after a single or 1-week of administration of Sairei-to (EK-114). NFP-oxidizing activity was enhanced transiently around 24 h after a single administration of EK-114 (1400 mg/kg). In vivo, the first-pass metabolism of NFP increased in the small intestine at 24 h after the administration of EK-114, and this effect disappeared at 72 h. Co-administration of EK-114 tended to inhibit the metabolism of NFP. On the other hand, when EK-114 was given at a high dose (1400 mg/kg) for 1 week, the oxidation of NFP in the small intestine was inhibited, and Cmax and AUC after the oral administration of NFP increased. In addition, a clinical dose of EK-114 (140 mg/kg) did not alter the pharmacokinetics of NFP, regardless of the administration schedule. EK-114 was suggested to affect the metabolism of NFP. However, the CYP3A-mediated pharmacokinetic interaction on the concomitant use of EK-114 may not be clinically significant.

Effects of Hochu-ekki-to and Ninjin-youei-to, traditional Japanese medicines, on porcine serum-induced liver fibrosis in rats.

In this study, we estimated the effects of traditional Japanese medicines on liver fibrosis in Wistar rats injected with porcine serum twice a week for 8 weeks. The rats were orally administered Hochu-ekki-to, Ninjin-youei-to (100 and 300 mg/kg/day) or Sho-saiko-to (300 mg/kg/day) 5 days per week. Serum and liver samples were obtained 2 days after the last porcine serum injection. Hochu-ekki-to and Ninjin-youei-to showed significant suppressive effects on the increase in hepatic hydroxyproline, namely total collagen. Further, Ninjin-youei-to significantly suppressed the increases of type IV collagen localized in the basement membrane and prolyl 4-hydroxylase, a collagen synthesis enzyme, in serum or liver. Hochu-ekki-to showed a similar trend. Although Sho-saiko-to did not significantly suppress the increase in hepatic hydroxyproline, it intensely suppressed serum type IV collagen. Further, Hochu-ekki-to, Ninjin-youei-to, and Sho-saiko-to inhibited the production of fibrogenic cytokines, namely TGF-beta1 and IL-13, in the serum and liver. Additionally, we showed that IL-13 levels were positively correlated with hydroxyproline contents in the liver. These results suggest that Ninjin-youei-to as well as Hochu-ekki-to suppress porcine serum-induced liver fibrosis more effectively than Sho-saiko-to. The effects of these three medicines probably depend on the inhibition of fibrogenic cytokine production, resulting in the suppression of collagen synthesis and deposition in the liver, though different mechanisms underlie their anti-fibrogenic effects.

Participation of contrasting changes in IL-10 and IL-12 production in the reduction of Th1-predominance by Hachimi-jio-gan in autoimmune MRL/MP-lpr/lpr mice.

Hachimi-jio-gan (Chinese name: Ba-Wei-Di-Huang-Wan, HMG), a traditional Japanese herbal medicine, has been used for disorders accompanying aging. Our previous studies suggested that HMG ameliorated Thl-predominant autoimmune diseases in MRL/lpr mice through inhibition of IL-12 production. In the present study, the oral administration of HMG down-regulated phosphorylated STAT4 and up-regulated phosphorylated STAT6 in CD4 T cells. In the T cells, IL-12Rbeta1 and IL-12Rbeta2 mRNA expression levels were suppressed. In antigen-presenting cells (CD45R- MHC class II+ cells) which control Th1 and Th2 immune responses, the total cell number and the percentage of cells expressing co-stimulatory molecules decreased in the HMG-treated group. In addition, the levels of IL-12 and 18 mRNA expression increased and conversely, IL-10 mRNA expression decreased. Further, the production of IL-10 was up-regulated and that of IL-12 was down-regulated by HMG in the presence of anti-CD40 antibody. These results suggest that the opposite effects on IL-10 production and, IL-12 or IL-18 production in antigen-presenting cells of oral administration of HMG are due a decline in IL-12R expression, and consequently, amelioration of MRL/lpr autoimmune diseases occurs through the suppression of Th1 predominance via STAT4/STAT6 signaling.