Goshajinkigan Research Articles

Goshajinkigan, a Traditional Japanese Medicine, Prevents Oxaliplatin-Induced Acute Peripheral Neuropathy by Suppressing Functional Alteration of TRP Channels in Rat

The acute peripheral neuropathy induced by oxaliplatin treatment occurs very frequently and is aggravated by exposure to cold. Goshajinkigan (GJG), a traditional Japanese (kampo) medicine, was recently shown to be effective against oxaliplatin-induced acute neuropathy. However, because the effects of GJG and its mechanism in relation to those of its ingredients and its mechanism are not well understood, we examined the effects of GJG on acute neuropathy. Further, we investigated whether GJG affects the functions and gene expressions of transient receptor potential (TRP) channels using a rat model of oxaliplatin-induced neuropathy. Administration of oxaliplatin increased withdrawal responses from cold stimulation, and GJG or calcium gluconate/magnesium sulfate significantly inhibited the oxaliplatin-induced cold hypersensitivity. Application of menthol, a TRPA1/TRPM8 agonist, or allyl isothiocyanate (AITC), a selective TRPA1 agonist, to the hind paw of oxaliplatin-treated rats enhanced the nocifensive behaviors evoked by each agonist, whereas oxaliplatin had no significant effect on nocifensive behaviors evoked by capsaicin, a TRPV1 agonist. GJG treatment reduced menthol- or AITC-evoked withdrawal responses potentiated by oxaliplatin. Furthermore, GJG suppressed the increase of TRPA1 and TRPM8 mRNA expression induced by oxaliplatin in dorsal root ganglia. These findings suggest that GJG prevented oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels, especially TRPA1 and TRPM8.

Gosha-jinki-gan reduced oxaliplatin-induced hypersensitivity to cold sensation and its effect would be related to suppression of the expression of TRPM8 and TRPA1 in rats

Peripheral neuropathy is a common side effect of the chemotherapeutic agent oxaliplatin (Oxp), and is associated with hypersensitivity to cold sensation in the acute stage. Recently, gosha-jinki-gan (GJG), a Japanese herbal medicine, was reported to improve Oxp-induced cold hypersensitivity. However, the mechanism for this effect was not elucidated. We hypothesized that the effect of GJG on Oxp-induced cold hypersensitivity may be associated with the expression of the transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) channels, which are cold-gated ion channels. To assess this hypothesis, we examined alteration of the withdrawal response to cold stimulation following coadministration of GJG and Oxp in rats, and the relationship between this altered withdrawal response and the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG). Assessment of cold hypersensitivity was performed at 4 and 10°C using a cold plate. Compared with Oxp administration alone, coadministration of GJG (oral dose: 1 g/kg/day for 12 days) and Oxp (intraperitoneal dose: 4 mg/kg twice a week) significantly reduced the withdrawal response to cold stimulation. On the 12th day of drug administration, the L4-L6 DRG were removed and the expression of TRPM8 and TRPA1 mRNA was determined using RT-PCR. The expression of TRPM8 and TRPA1 in the DRG of rats that were coadministered GJG and Oxp decreased significantly compared with that in the rats administered Oxp alone. These results suggest that coadministration of GJG may improve Oxp-induced cold hypersensitivity by suppressing the overexpression of TRPM8 and TRPA1 mRNA.

The prophylactic effects of a traditional Japanese medicine, goshajinkigan, on paclitaxel-induced peripheral neuropathy and its mechanism of action.

BackgroundThis study aimed to evaluate the prophylactic effect of goshajinkigan (GJG) on paclitaxel (PTX)-induced neuropathy and to elucidate the mechanism of action.ResultsThere was a time-dependent irreversible decrease in pain threshold in PTX group. In PTX/GJG group, pain threshold showed changes in the same level as control. Electron microscope showed that although the ganglion cells of control and PTX/GJG groups were normal, degeneration of the nucleus and swelling of the mitochondria were observed in PTX group. Expression of transient receptor potential vanilloid 4 (TRPV4) gene in PTX group significantly increased compared with that in control and PTX/GJG groups. In TRPV4 knock-out mice, no PTX-induced hyperalgesia was observed, and there was no significant difference in pain threshold between the 3 groups.ConclusionsThese results showed that PTX induced hyperalgesia by enhancing TRPV4 expression, and suggested that GJG might alleviate hyperalgesia by preventing degeneration of the ganglion cells and suppressing TRPV4 expression.

The Kampo Medicine Goshajinkigan Prevents Neuropathy in Breast Cancer Patients Treated with Docetaxel

Goshajinkigan (GJG) is used for the treatment of several neurological symptoms. We investigated the efficacy of GJG and mecobalamin (B12) against neurotoxicity associated with docetaxel (DOC) in breast cancer patients. Sixty breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG and 27 patients (B12 group) received oral administration of 1500 μg/day B12. Neuropathy was evaluated according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (NCI-CTC) ver. 3.0, and a visual analogue scale (VAS). This study employed a randomized open design. The incidence of neuropathy was 39.3% in the GJG group, and 88.9% in the B12 group (p<0.01). In the GJG group, grade 1 DEB-NTC was observed in 2 cases, grade 2 in 5 cases and grade 3 in 5 cases. Grade 1 NCI-CTC was observed in 7 cases, grade 2 in 6 cases, and VAS was 2.7 ± 2.2. In the B12 group, grades 1, 2 and 3 DEB-NTC were observed in one case, 12 cases and 12 cases, respectively; and grades 1, 2 and 3 NCI-CTC were observed in 11 cases, 12 cases and one case, and VAS was 4.9 ± 2.4. Concomitant administration of GJG is useful in preventing neuropathy in breast cancer patients treated with a DOC regimen.

Effects of Gosha-jinki-gan (Chinese herbal medicine: Niu-Che-Sen-Qi-Wan) on hyperinsulinemia and hypertriglyceridemia in prediabetic Zucker fatty rats

The Chinese herbal medicine, Goshajinki-gan (GJ) (Niu-Che-Sen-Qi-Wan), has been widely used for treating patients with melalgia, lower back pain, numbness, and diabetic neuropathy. We investigated the effects of GJ on the regulation of serum insulin and triglyceride levels in obese Zucker fatty rats (fa/fa; ZFR). We administrated GJ to 6-week-old ZFR and non-obese lean rats (LR) for 12 weeks. Body weight and serum glucose, insulin, total cholesterol, and triglyceride levels were significantly increased at 18 weeks in ZFR as compared to the LR. GJ treatment in ZFR significantly suppressed elevation in serum glucose, insulin, and triglyceride levels, but no significant differences were observed in body weight and serum cholesterol levels in the ZFR group with GJ treatment compared to the ZFR group without GJ treatment. These results suggest that GJ may improve hyperinsulinemia and hypertriglyceridemia in ZFR and that GJ may be useful for preventing or delaying the onset of diabetes mellitus in a pre-diabetic state.

Beneficial Effects of Gosha-jinki-gan and Green Tea Extract in Rats With Chemical Cystitis

The aim of this study was to characterize pharmacological effects of gosha-jinki-gan (GJG) and green tea extract (GTE), on urodynamic parameters, bladder receptors, and urinary cytokines in rats with cyclophosphamide (CYP)-induced cystitis. Urodynamic parameters in CYP-treated rats were measured using the cystometric method. Muscarinic and purinergic receptors in rat tissues were measured by radioreceptor assays. Urinary cytokine levels were measured with ELISA kits. GJG and GTE were orally administered to rats once a day for 7 days. The GJG treatment significantly ameliorated changes in urodynamic parameters in CYP-treated rats. Similar treatment with GTE slightly attenuated changes in urodynamic parameters. The maximal number of binding sites for [3H]NMS and [3H]αβ-MeATP in the bladder was significantly lower in CYP-treated rats than in sham rats. Such a reduction in receptor density was significantly attenuated by the GJG treatment. GTE treatment also significantly attenuated the down-regulation of muscarinic receptors, but not P2X receptors in bladders of rats with CYP-induced cystitis. The elevation in urinary cytokine levels in CYP-treated rats was effectively attenuated by GJG treatment. The elevation in cytokine levels in CYP-treated rats was alleviated by GTE treatment. In conclusion, GJG may be a pharmacologically useful plant extract for cystitis.

Abstract P1-15-11: The Kampo medicine Goshajinkigan prevents docetaxel-related peripheral neuropathy in breast cancer patients

Abstract Background: Although taxanes have become a key chemotherapeutic drug in breast cancer treatment. Taxanes inhibit the growth of cancer cells by disrupting the functioning of their microtubules; however, the microtubules of nerve cells are also affected by this process, which can cause neurological disorders. The Kampo medicine Goshajinkigan (GJG) is a traditional Japanese medicine that is used for the treatment of several neurological symptoms including pain and numbness, GJG is comprised of 10 herbs, each of which contains numerous active ingredients. Recently, GJG has been reported to prevent anticancer drug-induced peripheral neuropathy in colorectal cancer. We performed the present prospective randomized study to confirm the effects of GJG and mecobalamin (B12) against docetaxel (DOC)-associated peripheral neurotoxicity in breast cancer patients. Patients and method: Between May 2007 and April 2011, 60 breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG and 27 patients (B12 group) received oral administration of 1500 μg/day B12. The patients were treated with TC (75mg/m2 docetaxel and 600 mg/m2 cyclophosphamide) every 3 weeks for 4 cycles, docetaxel alone (100mg/m2) every 3 weeks for 4 cycles, and XT (900mg/m2 capecitabine administered orally twice a day on days 1–14 plus 60 mg/m2 docetaxel) every 3 weeks for 6 cycles. Peripheral neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (NCI-CTC) ver.3.0, and a visual analogue scale (VAS). Results: The median age of the GJG group was 58 years old (35 to 70 years old), the B12 group was 55 years old (33 to 69 years old), and they were all females. For the regimens, in the GJG group, TC, DOC only, and XT were administered in 19 cases, 13 cases and 1 case, respectively. In the B12 group, they were 15 cases, 11 cases and 12 cases, respectively. The cumulative dose of DOC was 338.5 mg/m2 in the GJG group, and 340 mg/m2 in the B12 group. Peripheral neuropathy occurred significantly less frequently in the GJG group (39.3%) than the B12 group (88.9%) (p &amp;lt; 0.01). In the GJG group, grade 1 DEB-NTC was observed in 2 cases, grade 2 in 5 cases and grade 3 in 5 cases. Grade 1 NCI-CTC was observed in 7 cases, grade 2 in 6 cases. In the B12 group, grades 1, 2 and 3 DEB-NTC were observed in one case, 12 cases and 12 cases, respectively; and grades 1, 2 and 3 NCI-CTC were observed in 11 cases, 12 cases and one case. The mean VAS scores for numbness after chemotherapy were 2.7 in the GJG group and 4.9 in the B12 group (p &amp;lt; 0.01). The incidence of grade 2/3 peripheral neuropathy was lower in the GJG group than the B12 group. Peripheral neuropathy was significantly controlled in the GJG group. Conclusion: The present study is the first prospective control study to prove the efficacy of GJG against docetaxel-induced peripheral neuropathy in breast cancer patients. Our findings suggest that DOC-associated peripheral neurotoxicity can be suppressed by the administration of GJG. It will be necessary to confirm the usefulness of GJG in larger prospective studies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-11.

Effect of goshajinkigan on peripheral neuropathy in breast cancer patients treated with docetaxel.

e11564 Background: Although taxanes have become a key chemotherapeutic drug in breast cancer treatment, one of the side effects is peripheral neuropathy. Goshajinkigan (GJG) is a traditional Japanese medicine that is used for the treatment of several neurological symptoms including pain and numbness. Recently, GJG has been reported to prevent anticancer drug-induced peripheral neuropathy in colorectal cancer in the gynecology field. We investigated the efficacy of GJG and mecobalamin (B12) on peripheral neurotoxicity associated with docetaxel (DOC) in breast cancer patients. Methods: Between 2007 and 2011, 60 breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG every day during DOC therapy and 27 patients (B12 group) received oral administration of 1500 μg/day B12. Peripheral neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0, and a visual analogue scale (VAS). Results: The median age of the GJG group was 58 years old (35 to 70 years old), the B12 group was 55 years old (33 to 69 years old), and they were all females. For the regimens, in the GJG group, TC (DOC and cyclophosphamide), DOC only, and XT (capecitabine and DOC) were administered in 19 cases, 13 cases and 1 case, respectively. In the B12 group, they were 15 cases, 11 cases and 12 cases, respectively. The cumulative dose of DOC was 338.5 mg/m2 in the GJG group, and 340 mg/m2 in the B12 group. The completion rate was 100% in both groups. The incidence of peripheral neuropathy was 39.3% in the GJG group, and 88.9% in the B12 group (p &lt; 0.01). In the GJG group, grade 1 DEB-NTC was observed in 2 cases, grade 2 in 5 cases and grade 3 in 5 cases. Grade 1 CTCAE was observed in 7 cases, grade 2 in 6 cases, and VAS was 2.7 ± 2.2. In the B12 group, grades 1, 2 and 3 DEB-NTC were observed in one case, 12 cases and 12 cases, respectively; and grades 1 and 2 CTCAE were observed in 12 cases each, and VAS was 4.9 ± 2.4. Peripheral neuropathy was significantly controlled in the GJG group. Conclusions: Concomitant administration of GJG is useful in preventing peripheral neuropathy in breast cancer patients treated with DOC regimen.

Furosemide versus Gosha-Jinki-Gan, a Blended Herbal Medicine, for Nocturnal Polyuria: A Randomized Crossover Trial.

To investigate the efficacy of two types of drugs, furosemide and gosha-jinki-gan (GJG), for treatment of nocturia with nocturnal polyuria using a randomized crossover method. A total of 36 patients with nocturnal polyuria were recruited for this study. We assessed the International Prostate Symptom Score (I-PSS), Pittsburgh Sleep Quality Index (PSQI), frequency volume charts, blood pressure, urine chemistry, serum B-type natriuretic peptide (BNP) and body fluid compartments. Both furosemide and GJG significantly improved the nocturia score in the I-PSS, the I-PSS Quality of Life (QOL) score, actual nocturnal frequency and hours of undisturbed sleep compared with those at baseline. Nocturnal frequency and nocturnal urine volume were more significantly reduced by furosemide treatment than with GJG treatment. The I-PSS total score and nocturnal urine volume significantly improved only by furosemide treatment. Furosemide treatment definitively improved nocturia with nocturnal polyuria. GJG treatment may also induce mild improvement of nocturnal polyuria, although further study is required to confirm its efficacy.

Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents

Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Goshajinkigan (GJG) is a Kampo medicine that is used for the treatments of several neurological symptoms including pain and numbness. More recently, GJG has been reported to prevent the oxaliplatin-induced peripheral neuropathy in clinical studies. No experimental study, however, has been conducted to date to determine the effect of GJG on pain behaviour in a rat model of oxaliplatin-induced neuropathy. Moreover, the impact on the anti-tumour effect of oxaliplatin remains unknown. In the present study, we examined the effects of GJG on the peripheral neuropathy and anti-tumour activity of oxaliplatin in rodents. Repeated administration of oxaliplatin caused cold hyperalgesia from days 3 to 37 and mechanical allodynia from days 21 to 28. Repeated administration of GJG prevented the oxaliplatin-induced cold hyperalgesia but not mechanical allodynia and axonal degeneration in rat sciatic nerve. Single administration of GJG reduced both cold hyperalgesia and mechanical allodynia after the development of neuropathy. In addition, GJG did not affect the anti-tumour effect of oxaliplatin in the tumour cells or tumour cells-implanted mice. These results suggest that GJG relieves the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting anti-tumour activity of oxaliplatin, and, therefore, may be useful for the oxaliplatin-induced neuropathy in clinical practice.

The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen

Oxaliplatin is now considered a standard treatment for advanced or unresectable colorectal cancer, but its main dose-limiting toxicity is sensory neuropathy. The OPTIMOX (stop and go) approach offers a reasonable strategy, but the preventive agent is not established. It is reported that the Kampo medicine, Goshajinkigan (GJG), has recently been considered an effective agent for the neuropathy of taxanes and for vibration sensation in patients with diabetic neuropathy. The aim of this study was to clarify the efficacy of GJG for peripheral neuropathy associated with oxaliplatin therapy. From 2007, 45 patients treated with modified FOLFOX6 for non-resectable or recurrent colorectal cancer participated in the study. Twenty-two patients (GJG group) received oral administration of 7.5g/day of GJG every day during mFOLFOX6 therapy and 23 patients (control group) did not receive GJG. Neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm). The median number of cycles per patient in the GJG group was 13 (range 4-32), and in the control group was 12 (range 4-28). The cumulative dose of oxaliplatin was 1105mg/m(2) (GJG group) and 1120mg/m(2) (control group). The incidence of grade 3 peripheral neuropathy in the GJG group was significantly lower than in the control group (p<0.01, log-rank test). The incidence of grade 3 peripheral neuropathy after 10 courses was 0% in the GJG group and 12% in the control group, and after 20 courses was 33% in the GJG group and 75% in the control group. The percentage of grade 2 and 3 peripheral neuropathy in the GJG group was lower than that in the control group. There were no differences in adverse effects between the two groups except for peripheral neuropathy and influence on tumor response. The Kampo medicine, Goshajinkigan, is useful in preventing neuropathy in non-resectable or recurrent colorectal cancer patients treated with a FOLFOX regimen.

Efficacy of Goshajinkigan for Peripheral Neurotoxicity of Oxaliplatin in Patients with Advanced or Recurrent Colorectal Cancer

Peripheral neurotoxicity is the major limiting factor for oxaliplatin therapy. Goshajinkigan (GJG), a traditional Japanese herbal medicine, was recently shown to be effective in protecting against the neurotoxicity of taxanes in Japan. We retrospectively investigated the effect of GJG on peripheral neurotoxicity associated with oxaliplatin therapy. Ninety patients with metastatic colorectal cancer that received FOLFOX4 or modified FOLFOX6 therapy were assigned to receive one of the following adjuncts: oral GJG at 7.5 g day−1 (Group A, n = 11), intravenous supplementation of calcium gluconate and magnesium sulfate (1 g each before and after FOLFOX) (Group B, n = 14), combined GJG and calcium gluconate and magnesium sulfate therapies (Group C, n = 21), or no concomitant therapy (Group D, n = 44). The incidence of peripheral neurotoxicity was investigated when the cumulative dose of oxaliplatin exceeded 500 mg m−2. When the cumulative dose of oxaliplatin exceeded 500 mg m−2, the incidence of neuropathy (all grades) in Groups A–D was 50.0%, 100%, 78.9%, and 91.7%, respectively. It was lowest in the group that received GJG alone. Concomitant administration of GJG reduced the neurotoxicity of oxaliplatin in patients that received chemotherapy for colorectal cancer.

Effects of Gosha-jinki-gan (Chinese herbal medicine: Niu-Che-SenQi-Wan) on hyperinsulinemia induced in rats fed a sucrose-rich diet

We investigated the effects of a Chinese herbal medicine, Gosha-jinki-gan (GJG), on the regulation of insulin levels in rats fed a sucrose-rich diet (SRD). Normal Wistar rats in the SRD group were fed an SRD for 4 weeks. Increased dietary sucrose did not alter plasma glucose levels but it increased plasma insulin levels at 2 and 4 weeks in the SRD-fed rats relative to control rats that were fed standard chow. GJG treatment significantly suppressed the SRD-induced elevation in plasma insulin levels. These results suggest that GJG improves hyperinsulinemia caused by an SRD.

Gosha jinki gan appears to prevent acute oxaliplatin-induced neurotoxicity,

Gosha jinki gan appears to prevent acute oxaliplatin-induced neurotoxicity,

Goshajinkigan (Chinese herbal medicine niu-che-sen-qi-wan) improves insulin resistance in diabetic rats via the nitric oxide pathway.

Goshajinkigan (GJG), an aqueous extract of a combination of 10 herbal medicines, is widely used for the treatment of diabetic neuropathy in Japan. In this study, the effect of GJG on insulin-induced glucose disposal in normal and streptozotocin (STZ) diabetic rats was analyzed using the euglycemic clamp technique. Male Wistar rats, aged 9 weeks, were randomly assigned to six groups: group NS, normal rats receiving saline; group NG, normal rats receiving GJG (800 mg x kg(-1) x day(-1), p.o.); group NGL, normal rats receiving GJG + N(G)-monomethyl-L-arginine (L-NMMA, 1 mg x kg(-1) x min(-1), i.v.); group DS, diabetic rats receiving saline; group DG, diabetic rats receiving GJG; group DGL, diabetic rats receiving GJG + L-NMMA. After daily oral administrations of saline or GJG for one week, euglycemic clamp experiments were performed. The metabolic clearance rates of glucose (MCR) in the DS, DG, and DGL groups (8.7 +/- 2.9, 18.2 +/- 2.5, and 8.1 +/- 1.8 ml x kg(-1) x min(-1), respectively) were significantly lower than those in the NS, NG, and NGL groups (24.1 +/- 4.5, 24.5 +/- 3.1, and 22.2 +/- 2.1 ml x kg(-1) x min(-1), respectively). In addition, the MCR in the DG group was significantly higher than that in the DS and DGL groups, while no significant difference was detected among the NS, NG, and NGL groups. Furthermore, the amelioration of insulin resistance by GJG in diabetic rats was hampered by L-NMMA infusion. These results suggest that daily GJG administrations ameliorate insulin resistance in STZ-diabetic rats, and that the nitric oxide pathway may mediate the effect of GJG.

Preventive Effect of Goshajinkigan on Peripheral Neurotoxicity of FOLFOX Therapy: A Placebo-controlled Double-blind Randomized Phase II Study (the GONE Study)

We conducted a controlled double-blind randomized study in patients with advanced/recurrent colorectal cancer to investigate the efficacy of Goshajinkigan (GJG) for peripheral neurotoxicity induced by FOLFOX therapy. The primary endpoint is the incidence of peripheral neurotoxicity > or = Grade 2 after eight cycles of chemotherapy. The secondary endpoints are the incidence of peripheral neurotoxicity of each grade after each cycle, the psychometric properties of the FACT/GOG-Ntx, time to occurrence of neurotoxicity, time to treatment failure, progression-free survival, response rate and toxicity. Eighty patients are required in the study (40 patients per group).

Effects of hPTH (1-34) and Gosha-jinki-gan on the Trabecular Bone Microarchitecture in Ovariectomized Rat Tibia

Although human parathyroid hormone (1-34) [hPTH (1-34)] was reported to improve osteoporotic bone loss, little is known about the anti-osteoporotic effect of the traditional Chinese medicine, Gosha-jinki-gan (GJG). The purpose of this present study was to clarify and compare the effects of hPTH (1-34) and GJG on trabecular bone microarchitecture in ovariectomized (OVX) rat tibia by using microcomputed tomography (micro-CT). Thirty 12-week-old Sprague-Dawley female rats were underwent ovariectomy (OVX) or sham operation. Four weeks later, the ovariectomized rats were further divided into OVX, OVX + PTH, and OVX + GJG groups. hPTH (1-34) was administered subcutaneously at a dose of 20 microg/kg, 3 times/week, and OVX + GJG group received 0.05% aqueous solution of GJG as the only drinking fluid for 8 weeks respectively. The three-dimensional (3D) trabecular microarchitecture of the bone in the proximal tibial metaphysis was evaluated by micro-CT. In the OVX + PTH group, trabecular bone volume (BV/ TV), number (Tb.N) and thickness (Tb.Th) were significantly increased, structure model index (SMI) and trabecular bone pattern factor (TBPf) decreased when compared with the OVX group. In comparison to the OVX group, BV/TV and Tb.N were significantly greater, while SMI and TBPf had no marked changes in the OVX + GJG group. These results suggest that the administration of hPTH (1-34) restore the trabecular bone volume and improve the microstuctural property as well, while GJG reduce the bone loss without affecting its microstructural property in ovariectomized rats.

Maintaining the Redox-Balance Intact: Gosha-Jinki-Gan but Not Insulin Activates Retinal Soluble Guanylate Cyclase in Diabetic Rats

Strategies to prevent hyperglycemia-induced cytotoxic reactive oxygen species in the retina include the prevention of free radical production, activation of radical-scavenging capacities and inhibition of aldose reductase. This study examined the effect of the standardized Japanese herbal extract product gosha-jinki-gan (GJG) in comparison to insulin treatment in the rat retina. Diabetes was induced in male Wistar rats by single injection of streptozotocin (50 mg/kg i.p.). At 6 and 12 weeks, eyecups were removed for immunohistochemistry. At 12 weeks, lipid peroxidation (tested with the antiacrolein antibody, Ab5F6) was enhanced significantly in the untreated diabetic group. This effect was absent in both treatment groups, notably in the outer retina. A similar result was obtained for nitrotyrosine overproduction. As an early treatment effect, GJG – but not insulin – enhanced soluble guanylate cyclase (sGC) activation (using the function-sensing antibody, MoAb 3221). GJG not only reduces nitroxidative stress and lipid peroxidation in the retina, it also ameliorates glucose metabolism within the cells. We propose that the high glucose turnover in the insulin-treated model disturbs the intracellular redox equilibrium, one result of which might be the impaired sGC activation.

Effects of Goshajinkigan on insulin resistance in patients with type 2 diabetes

We investigated the effects of Goshajinkigan (GJG), a Chinese herbal medicine, on insulin sensitivity in patients with type 2 diabetes using the homeostasis model assessment of insulin resistance (HOMA-R) and the euglycemic insulin clamp procedure. Daily oral administration of GJG (7.5 g/day) was performed for 1 month in 71 type 2 diabetes patients: the GJG treatment group. HOMA-Rs were calculated before and after 1 month of GJG treatment and compared with those of 44 controls who were matched in terms of sex, age, body mass index (BMI) and HbA1c levels with the experimental group. In 64 patients out of the GJG treatment group, HOMA-R was calculated 1 month after discontinuation of treatment. In addition, euglycemic clamp was conducted in eight patients before and after the GJG treatment. HOMA-R was 4.78 ± 0.37 (means ± S.E.) before GJG treatment and significantly decreased to 4.02 ± 0.25 after GJG treatment ( P = 0.019). No significant change was observed in the control group. HOMA-R returned to the pre-treatment level ( P = 0.018) 1 month after GJG treatment discontinuation. Glucose infusion rates and metabolic clearance rates determined by the high-dose euglycemic clamp increased after 1 month of GJG treatment (from 9.6 ± 1.1 to 11.1 ± 0.7 mg/kg/min, P = 0.045 and from 7.9 ± 0.8 to 9.1 ± 0.8 ml/kg/min, P = 0.046, respectively). These results indicate that GJG administration might be useful for improving insulin resistance in patients with type 2 diabetes.

Gosha-jinki-gan (a Herbal Complex) Corrects Abnormal Insulin Signaling.

Previous studies have shown that the traditional herbal complex Gosha-jinki-gan (GJG) improves diabetic neuropathy and insulin resistance. The present study was undertaken to elucidate the molecular mechanisms related with the long-term effects of GJG administration on insulin action in vivo and the early steps of insulin signaling in skeletal muscle in streptozotocin (STZ) diabetes. Rats were randomized into five subgroups: (1) saline treated control, (2) GJG treated control, (3) 2-unit insulin + saline treated diabetic, (4) saline + GJG treated diabetic and (5) 2-unit insulin + GJG treated diabetic groups. After seven days of treatment, euglycemic clamp experiment at an insulin infusion rate of 6 mU/kg/min was performed in overnight fasted rats. Despite the 2-unit insulin treatment, the metabolic clearance rates of glucose (MCR, ml/kg/min) in diabetic rats were significantly lower compared with the controls (11.4 ± 1.0 vs 44.1 ± 1.5; P < 0.001), and were significantly improved by insulin combined with GJG or GJG alone (26 ± 3.2 and 24.6 ± 2.2, P < 0.01, respectively). The increased insulin receptor (IR)-β protein content in skeletal muscle of diabetic rats was not affected by insulin combined with GJG administration. However, the decreased insulin receptor substrate-1 (IRS-1) protein content was significantly improved by treatment with GJG. Additionally, the increased tyrosine phosphorylation levels of IR-β and IRS-1 were significantly inhibited in insulin combined with GJG treated diabetes. The present results suggest that the improvement of the impaired insulin sensitivity in STZ-diabetic rats by administration of GJG may be due, at least in part, to correction in the abnormal early steps of insulin signaling in skeletal muscle.