Protective effects of Saiko-ka-ryukotsu-borei-to (Chai-Hu-Jia-Long-Gu-Mu-Li-Tang) against atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits.

We investigated the protective effects of the traditional Japanese herbal medicine Saiko-ka-ryukotsu-borei-to (Chai-Hu-Jia-Long-Gu-Mu-Li-Tang in Chinese) (SRBT) against hypercholesterolemia and atherosclerotic lesions. We focused on atherosclerosis using female heterozygous Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. The total plasma cholesterol levels increased for up to 12 weeks after beginning a diet containing 0.1% cholesterol and then reached a plateau of about 600 mg dl(-1). When SRBT was administered at a dose of 1.0 g kg(-1)per day for 24 weeks, total plasma cholesterol levels were significantly decreased after 20-24 weeks. On the other hand, pravastatin at a dose of 10 mg kg(-1)per day produced a significant decrease in total plasma cholesterol levels from 4 to 24 weeks (about 105-130 mg dl(-1)). Moreover, 1.0 g kg(-1)per day of SRBT significantly decreased plasma low density lipoprotein (LDL) cholesterol levels but did not change either very low density lipoprotein (VLDL), or high density lipoprotein (HDL) cholesterol levels. Animals that received pravastatin had significantly decreased LDL cholesterol levels and VLDL cholesterol levels after 8 weeks and at 24 weeks. We also examined the expression of apoB, E and LDL receptor mRNA levels in the liver at 24 weeks after beginning the administration of 1.0 g kg(-1)per day of SRBT. Both apoE and LDL receptor mRNA levels were significantly increased compared with those in rabbits receiving the 0.1% cholesterol diet. SRBT at a dose of 1.0 g kg(-1)per day significantly depressed the intimal surface area of the thoracic aortae involved with atheromatous plaques. The present results suggest that SRBT may protect against hypercholesterolemia and atheromatous lesions by affecting apoE and LDL receptor mRNA gene expression in the liver.

Antioxidative effects of Choi-oki-to and its ability to inhibit the progression of atheroma in KHC rabbits.

Agents which inhibit the oxidative modification of low density lipoprotein (LDL) have been thought to be helpful in preventing the formation of atherosclerotic lesions; the so called "oxidation hypothesis". To test this hypothesis, we examined the antioxidative activities of 127 Kampo medicines in vitro and their inhibitory effects on the development of atheromatous plaque formation in KHC rabbits, a model of spontaneous familial hypercholesterolemia. Some of the 127 Kampo medicines showed scavenging or antioxidative effects equal to or stronger than those of probucol in vitro. Choi joki to, which had the strongest antioxidative effects on LDL in vitro, was chosen for a study in vivo. After 24 weeks, 1 g/kg of Choi joki to successfully inhibited the progression of atherosclerotic lesions in KHC rabbits (P < 0.01). Further investigations regarding the antioxidative effects of Kampo medicines are expected.

Effects of San'o-shashin-to on the antioxidative mechanism in spontaneous familial hypercholesterolaemic rabbits.

We investigated the effects of the Kampo medicine San'o-shashin-to which showed strong antioxidative effects in vitro on antioxidative mechanism in Kurosawa and Kusanagi- hypercholesterolaemic (KHC) rabbits, which are a good model of spontaneous familial hypercholesterolaemia. A 1-g kg(-1)dose of San'o-shashin-to was administered orally for 24 weeks and changes in plasma lipids, low-density lipoprotein (LDL) oxidation and redox dynamics of alpha-tocopherol in plasma and erythrocyte membrane were measured in a control group and San'o-shashin-to-treated group. A significant prolongation of the lag time was found in the 12th and 24th week of the experiment in San'o-shashin-to-treated group, indicating antioxidative effects on LDL. At the end of the administration period, the alpha-tocopherolquinone/alpha-tocopherol ratio in erythrocyte membrane, which reflects the utilization rate of alpha-tocopherol was significantly higher in San'o-shashin-to-treated group. There were no significant differences in the two groups with regards to plasma lipids. These results indicate that San'o-shashin-to had antioxidative effects on LDL in vivo and beneficial effects on redox dynamics of alpha-tocopherol, which is the strongest endogenous antioxidant.

Neurochemical characteristics and behavioral responses to psychological stress in ovariectomized rats.

The present study was designed to clarify the time-dependent changes in brain monoamine turnover in the frontal cortex, hypothalamus, hippocampus, septum and amygdala after ovariectomy, and the difference in behavioral responses to psychological stress between sham-operated and ovariectomized (OVX) rats. At 2 and 4 weeks after ovariectomy, the turnover rates of dopamine and norepinephrine in all of the brain regions examined did not differ significantly between the sham-operated and OVX rats. However, 5-hydroxytryptamine (5-HT) turnover in all of the brain regions at 2 weeks after OVX was significantly lower than that in sham-operated rats. This difference was greater in the hypothalamus than in other brain regions. At 4 weeks after ovariectomy, 5-HT turnover in all of the brain regions examined was not significantly different between sham-operated and OVX rats. At 2 and 4 weeks after ovariectomy, exploratory behaviour (e.g., locomotor activity, head- dipping, crossing and rearing behaviours) in a non-stressed ovariectomy group did not differ from that in a non-stressed sham-operation group. Locomotor activity and the number of head-dips and crossings significantly (P<0.05) increased after repeated exposure to psychological stress for 5 days in sham-operated rats, but not in those at 2 weeks after OVX. At 4 weeks after ovariectomy, locomotor activity and the number of crossings and rearings in sham-operated and OVX rats were not significantly different in the psychological stress and non-stress groups. However, the number of head-dips significantly (P<0.05) increased with psychological stress in the sham-operated rats, but not in OVX rats. These results suggest that female gonadal hormones may play an important role in the regulation of brain 5-HTergic systems. These interactions between gonadal hormones and 5-HT metabolism may be related to 5-HT-related neuropsychiatric disorders.

Effects of Saiko-ka-ryukotsu-borei-to on irritable characteristics in El mice.

In the present study, we attempted to characterize the circadian rhythm of locomotor activity of El mice and to examine the duration of sodium pentobarbital-induced sleep during the light and dark periods. The effect of Saiko-ka-ryukotsu-borei-to, a representative Kampo medicine used for treating insomnia, was studied on the locomotor activity and on the duration of sodium pentobarbital-induced sleep in El mice. The spontaneous locomotor activity of El mice during the dark period was not so different from that of ddY mice, whereas the activity during the light period was significantly higher in the El mice, and the duration of sodium pentobarbital-induced sleep of El mice was very short during the light period, nearly equal to that during the dark period. The administration of Saiko-ka-ryukotsu-borei-to caused marked reduction in the locomotor activity during the light period, and dose-dependent prolongation in the duration of sodium pentobarbital-induced sleep time during the light period, but that during the dark period was unaffected. These findings suggest that the El mouse is a model with a tendency to be easily excitable during the light period compared to ddY mice. Furthermore, it was confirmed that Saiko-ka-ryukotsu-borei-to reduced the excitation in El mice and might be useful against sleep disorder due to excitation.

Protective effects of Hange-shashin-to on water-immersion restraint stress-induced gastric ulcers.

Hange-shashin-to (HST) is a traditional Chinese herbal prescription (Banxia Xiexin Tang) which has long been used in the therapy of gastric functional disorders. In this report, the effect of HST extract on water-immersion restraint stress-induced gastric ulcer based on the changes in gastric mucin content and the variations of monoamine contents in hypothalamus were investigated. Ulcer index was microscopically measured by the sum total of the lengths of ulcers in glandular stomach. Gastric mucin content was determined by a PAS-staining methods and the monoamine contents were detected by HPLC-ECD method. HST extract was orally administered at 1, 2 and 3 g/kg for three consecutive days before stress exposure. Water-immersion restraint stress decreased the mucin content and produced gastric ulcers in a restraint time-dependent manner. Pretreatment with HST extract markedly inhibited the reduction of gastric mucin content and the development of gastric ulcer with significant differences (p < or = 0.01). The remarkable decrease of NE and 5-HT contents but prominent increases of MHPG and 5-HIAA contents were observed in hypothalamus after water-immersion restraint stress (p < or = 0.01). Those changes in monoamine contests in hypothalamus were also significantly inhibited by the pretreatment with HST extract at higher dosage (p < or = 0.05). These results indicate that the changes in gastric mucin content and the variation of monoamines in hypothalamus relate to the pathogenesis of water-immersion restraint stress-induced gastric ulcers, and it is suggested that the prophylactic effects of HST extract on stress induced gastric ulcers may be associated with an increase in gastric mucin content, although the prevention of HST extract on the extraordinary changes in monoamine contents in hypothalamus due to stress cannot be ruled out.

Effects of Toki-shakuyaku-san on electric footshock stress in ovariectomized mice.

In the present study, ovariectomized mice were exposed to electric footshock stress for 7 days, and the duration of sodium pentobarbital-induced sleep was measured on the day following the last stress exposure. In ovariectomized mice, the duration of sodium pentobarbital-induced sleep before exposure to stress did not differ markedly from that in the sham-operation group. After exposure to stress, however, the duration of sodium pentobarbital-induced sleep in ovariectomized mice was shortened significantly, compared to the ovariectomized mice without stress. When the effect of Toki-shakuyaku-san on the stress-induced shortening of sleep time was studied, it was found that the shortening of the sleep time was suppressed by treatment with Toki-shakuyaku-san. In ovariectomized mice, the increase in hypothalamic noradrenaline (NA) turnover in response to stress was significantly greater than that in mice with intact ovaries. The stress-induced enhancement of NA turnover was suppressed significantly by Toki-shakuyaku-san in a dose-dependent manner, beginning with a low dose level. When effect of 17Beta-estradiol on the stress induced-shortening of sleep time was examined in ovariectomized mice, by high doses of 17Beta-estradiol the shortening of the sleep time was prolonged. A major difference between 17Beta-estradiol and Toki-shakuyaku-san was the marked uterine weight gain observed following 17Beta-estradiol treatment despite no effect of Toki-shakuyaku-san on uterine weight. The results in this study suggest that Toki-shakuyaku-san may reduce menopausal symptoms by a mechanism different from that of estrogen.

Further pharmacological study on Sho-seiryu-to as an antiallergic.

Examination was made of the pharmacological characteristics of Sho-seiryu-to, an antiallergic kampo medicine. Sho-seiryu-to suppressed histamine release from rat peritoneal mast cells, but failed to inhibit the binding of [3H]-mepyramine to histamine H1 receptors in guinea pig cerebral cortex and lung. Sho-seiryu-to had no effect on cutaneous reactions induced by serotonin, platelet-activating factor (PAF), leukotriene (LT) C4 or LTD4. Ketotifen prolonged electrically induced convulsions, while Sho-seiryu-to did not. Sho-seiryu-to did not affect salivation induced by pilocarpine. Sho-seiryu-to thus does not appear to inhibit histamine H1 receptors or inflammation induced by serotonin, PAF, LTC4 and LTD4, but suppresses mast cell activity. Sho-seiryu-to would thus have only a few side effects such as dry mouth and convulsions due mainly to the blockage of the action of muscarinic in salivary glands and histamine in the brain.

Pharmacological characteristics of Sho-seiryu-to, an antiallergic Kampo medicine without effects on histamine H1 receptors and muscarinic cholinergic system in the brain.

The pharmacological characteristics of Sho-seiryu-to, an antiallergic Kampo medicine, were investigated. Forty-eight-hour passive cutaneous anaphylactic (PCA) reaction was significantly inhibited in rats orally administered Sho-seiryu-to (1000 mg/kg). Sho-seiryu-to significantly inhibited increase in vascular permeability induced by histamine. These data confirm previous findings that Sho-seiryu-to has antiallergic activity in animals and suggest that the antagonism of histamine may be an antiallergic mechanism of Sho-seiryu-to. Sho-seiryu-to did not affect locomotor activity or motor coordination in mice. Although ketotifen prolonged sleeping time induced by pentobarbital, Sho-seiryu-to had no such effect. Nor was there any effect on oxotremorine-induced tremor and [3H]-mepyramine binding to histamine H1 receptors in rat brain. Thus, Sho-seiryu-to appears to be useful for treating type I allergy, with relatively few side effects such as sedation and drowsiness due mainly to blockade of histamine H1 and muscarinic receptors in the brain.