Antidepressive mechanisms of rhynchophylline in mice with chronic unpredictable stress-induced depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria rhynchophylla ([Mi] Jack) (gouteng) exerts antidepressive effects. Rhynchophylline (RH), a major component of U. rhynchophylla, exerts similar pharmacological effects to those of gouteng. Thus, RH may have antidepressive effects. AIM OF THE STUDY: To investigate the anti-depressive effects of RH in chronic unpredictable mild stress (CUMS)-induced depressive mice. The anti-depressive mechanism of RH determined by measuring the 5-HT levels, the expressions of cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in cortex and hippocampus. MATERIALS AND METHODS: The behaviors of CUMS-induced depressive mice were measured using an open field test (OFT), forced swimming test (FST), and tail suspension test (TST). 5-HT levels were measured using an ELISA kits. The expressions of BDNF and CREB were determined using western blot test. RESULTS: RH increased the frequency of rearing and grooming in the OFT and decreased the immobility time in the FST and TST. RH effectively increased the 5-HT level and BDNF and CREB expressions in the cortex and hippocampus. CONCLUSION: Our findings indicate that the antidepressive mechanism of RH is related to increased levels of 5-HT from regulating CREB and BDNF expressions in cortex and hippocampus.

Gallic Acid Ameliorated Impaired Lipid Homeostasis in a Mouse Model of High-Fat Diet-and Streptozotocin-Induced NAFLD and Diabetes through Improvement of ß-oxidation and Ketogenesis.

Gallic acid (GA) is a simple polyphenol found in food and traditional Chinese medicine. Here, we determined the effects of GA administration in a combined mouse model of high-fat diet (HFD)-induced obesity and low-dose streptozotocin (STZ)-induced hyperglycemia, which mimics the concurrent non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes pathological condition. By combining the results of physiological assessments, pathological examinations, metabolomic studies of blood, urine, liver, and muscle, and measurements of gene expression, we attempted to elucidate the efficacy of GA and the underlying mechanism of action of GA in hyperglycemic and dyslipidemic mice. HFD and STZ induced severe diabetes, NAFLD, and other metabolic disorders in mice. However, the results of liver histopathology and serum biochemical examinations indicated that daily GA treatment alleviated the high blood glucose levels in the mice and decelerated the progression of NAFLD. In addition, our results show that the hepatoprotective effect of GA in diabetic mice occurs in part through a partially preventing disordered metabolic pathway related to glucose, lipids, amino acids, purines, and pyrimidines. Specifically, the mechanism responsible for alleviation of lipid accumulation is related to the upregulation of ß-oxidation and ketogenesis. These findings indicate that GA alleviates metabolic diseases through novel mechanisms.

Improving the Concentrations of the Active Components in the Herbal Tea Ingredient, Uraria crinita: The Effect of Post-harvest Oven-drying Processing.

Uraria crinita is widely used as a popular folk drink; however, little is known about how the post-harvest operations affect the chemical composition and bioactivity of UC. We assessed three drying methods (Oven-drying, Air-drying, Sun-drying), as well as the Oven-drying temperature using metabolomics approaches and bioactivity assays. The samples processed at 40 degree show a greater effect on the levels of estrogen receptor-alpha activity and nuclear factor erythroid 2-related factor 2 activity, anti-oxidative activity, and cyclooxygenase-2 inhibition compared with the other samples. A multivariate analysis showed a clear separation between the 40 degree Oven-dried samples and the other samples, which is consistent with the results of bioactivity assay. These results are ascribed to at least two-fold increase in the concentrations of flavonoids, spatholosineside A and triterpenoids in the oven-dried samples compared with the other groups. The proposed Oven-drying method at 40 degree results in an improved quality of UC.

Ferulic acid reverses the cognitive dysfunction caused by amyloid ß peptide 1-40 through anti-oxidant activity and cholinergic activation in rats.

Cholinergic dysfunction and oxidation stress are the dominant mechanisms of memory deficit in Alzheimer's disease (AD). This study describes how ferulic acid (FA) ameliorates cognitive deficits induced by mecamylamine (MECA), scopolamine (SCOP), central acetylcholinergic neurotoxin ethylcholine mustard aziridinium ion (AF64A) and amyloid ß peptide (Aß1-40). This study also elucidates the role of anti-oxidant enzymes and cholinergic marker acetylcholinesterase (AChE) in the reversal of FA from Aß1-40-induced cognitive deficits in rats. At 100 mg/kg, FA attenuated impairment induced by MECA and SCOP plus MECA; however, this improvement was not blocked by the peripheral muscarinic receptor antagonist scopolamine methylbromide (M-SCOP). At 100 and 300 mg/kg, FA also attenuated the impairment of inhibitory passive avoidance induced by AF64A. Further, FA attenuated the performance impairment and memory deficit induced by Aß1-40 in rats, as did vitamin E/C. FA reversed the deterioration of superoxide dismutase (SOD) and AChE activities, and the glutathione disulfide (GSSG) and glutathione (GSH) levels in the cortex and hippocampus. Vitamin E/C only selectively reversed deterioration in the hippocampus. We suggest that FA reduced the progression of cognitive deficits by activating central muscarinic and nicotinic receptors and anti-oxidant enzymes.

Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice.

Gallic acid (GA), a naturally abundant plant phenolic compound in vegetables and fruits, has been shown to have potent anti-oxidative and anti-obesity activity. However, the effects of GA on nonalcoholic fatty liver disease (NAFLD) are poorly understood. In this study, we investigated the beneficial effects of GA administration on nutritional hepatosteatosis model by a more "holistic view" approach, namely 1H NMR-based metabolomics, in order to prove efficacy and to obtain information that might lead to a better understanding of the mode of action of GA. Male C57BL/6 mice were placed for 16 weeks on either a normal chow diet, a high fat diet (HFD, 60%), or a high fat diet supplemented with GA (50 and 100 mg/kg/day, orally). Liver histopathology and serum biochemical examinations indicated that the daily administration of GA protects against hepatic steatosis, obesity, hypercholesterolemia, and insulin resistance among the HFD-induced NAFLD mice. In addition, partial least squares discriminant analysis scores plots demonstrated that the cluster of HFD fed mice is clearly separated from the normal group mice plots, indicating that the metabolic characteristics of these two groups are distinctively different. Specifically, the GA-treated mice are located closer to the normal group of mice, indicating that the HFD-induced disturbances to the metabolic profile were partially reversed by GA treatment. Our results show that the hepatoprotective effect of GA occurs in part through a reversing of the HFD caused disturbances to a range of metabolic pathways, including lipid metabolism, glucose metabolism (glycolysis and gluconeogenesis), amino acids metabolism, choline metabolism and gut-microbiota-associated metabolism. Taken together, this study suggested that a 1H NMR-based metabolomics approach is a useful platform for natural product functional evaluation. The selected metabolites are potentially useful as preventive action biomarkers and could also be used to help our further understanding of the effect of GA in hepatosteatosis mice.

Antioxidant, Analgesic, Anti-Inflammatory, and Hepatoprotective Effects of the Ethanol Extract of Mahonia oiwakensis Stem.

The aim of this study was to evaluate pharmacological properties of ethanol extracted from Mahonia oiwakensis Hayata stems (MOS(EtOH)). The pharmacological properties included antioxidant, analgesic, anti-inflammatory and hepatoprotective effects. The protoberberine alkaloid content of the MOS(EtOH) was analyzed by high-performance liquid chromatography (HPLC). The results revealed that three alkaloids, berberine, palmatine and jatrorrhizine, could be identified. Moreover, the MOS(EtOH) exhibited antioxidative activity using the DPPH assay (IC(50), 0.743 mg/mL). The DPPH radical scavenging activity of MOS(EtOH) was five times higher that that of vitamin C. MOS(EtOH) was also found to inhibit pain induced by acetic acid, formalin, and carrageenan inflammation. Treatment with MOS(EtOH) (100 and 500 mg/kg) or silymarin (200 mg/kg) decreased the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the CCl(4)-treated group. Histological evaluation showed that MOS(EtOH) reduced the degree of liver injury, including vacuolization, inflammation and necrosis of hepatocytes. The anti-inflammatory and hepatoprotective effect of MOS(EtOH) were found to be related to the modulation of antioxidant enzyme activity in the liver and decreases in malondialdehyde (MDA) level and nitric oxide (NO) contents. Our findings suggest that MOS(EtOH) has analgesic, anti-inflammatory and hepatoprotective effects. These effects support the use of MOS(EtOH) for relieving pain and inflammation in folk medicine.

Antidepressant-Like Activity of the Ethanolic Extract from Uncaria lanosa Wallich var. appendiculata Ridsd in the Forced Swimming Test and in the Tail Suspension Test in Mice.

This study investigated the antidepressant activity of ethanolic extract of U. lanosa Wallich var. appendiculata Ridsd (UL(EtOH)) for two-weeks administrations by using FST and TST on mice. In order to understand the probable mechanism of antidepressant-like activity of UL(EtOH) in FST and TST, the researchers measured the levels of monoamines and monoamine oxidase activities in mice brain, and combined the antidepressant drugs (fluoxetine, imipramine, maprotiline, clorgyline, bupropion and ketanserin). Lastly, the researchers analyzed the content of RHY in the UL(EtOH). The results showed that UL(EtOH) exhibited antidepressant-like activity in FST and TST in mice. UL(EtOH) increased the levels of 5-HT and 5-HIAA in cortex, striatum, hippocampus, and hypothalamus, the levels of NE and MHPG in cortex and hippocampus, the level of NE in striatum, and the level of DOPAC in striatum. Two-week injection of IMI, CLO, FLU and KET enhanced the antidepressant-like activity of UL(EtOH). UL(EtOH) inhibited the activity of MAO-A. The amount of RHY in UL(EtOH) was 17.12 mg/g extract. Our findings support the view that UL(EtOH) exerts antidepressant-like activity. The antidepressant-like mechanism of UL(EtOH) may be related to the increase in monoamines levels in the hippocampus, cortex, striatum, and hypothalamus of mice.

Analgesic and anti-inflammatory activities of the aqueous extracts from three Flemingia species.

I-Tiao-Gung has long been used in the Kinmen area of Taiwan as an anti-inflammatory agent for the treatment of rheumatic illness. The roots of Flemingia lineata (FL), Flemingia macrophylla (FM) and Flemingia prostrata (FP) are also used as I-Tiao-Gung in the Taiwan markets. In the present study, we investigated the analgesic effect of aqueous extracts of Flemingia lineata (FL), Flemingia macrophylla (FM), and Flemingia prostrata (FP) by acetic acid-induced writhing response, formalin test, and the anti-inflammatory effect of FM, FL and FP by lambda-carrageenan-induced paw edema in mice. We also detected the changes in the activities of superoxide dismutase (SOD), glutathione reductase (GRx) and glutathione peroxidase (GPx) of liver in the lambda-carrageenan-induced paw edema in mice to investigate the anti-inflammatory mechanism of FL and FM. The results showed that FL and FM significantly inhibited the acetic acid-induced writhing response and formalin-induced licking time during the late phase (p < 0.001). FL and FM also significantly decreased the lambda-carrageenan-induced paw edema (p < 0.001). FL and FM significantly increased the GRx and GPx activities in the liver and decreased the levels of malondialdehyde (MDA) and nitric oxide (NO) in the edema paw (p < 0.001). These results indicated that FL and FM possessed analgesic and anti-inflammatory effects. The anti-inflammatory mechanism of FL and FM might be related to the decrease in the level of MDA in the edema paw via increasing the activities of GPx and GRx in the liver and decreasing the NO level in the edema paw.

The ameliorating effects of luteolin on beta-amyloid-induced impairment of water maze performance and passive avoidance in rats.

The present study investigated the effects of luteolin on Abeta (1-40)-induced impairment of Morris water maze (MWM) spatial performance, reference memory, and passive avoidance (PA) behavior in rats. Luteolin treatment was started 4 days before the initiation of behavioral testing (passive avoidance on treatment day of 4-5; MWM spatial performance memory testing on treatment day of 5-7 and MWM reference memory testing on treatment day of 7) and continued until the end of the study. We also measured the activity of Mn-SOD, copper/zinc (Cu/Zn)-SOD and glutathione (GSH) levels in rat cortex and hippocampus to understand the ameliorating effect of luteolin on Abeta (1-40) induced memory impairment. The present results showed that luteolin (5, 10 mg/kg) has a protective effect on Abeta (1-40)-induced memory dysfunction in spatial performance, reference memory, and inhibitory avoidance response impairment. Finally, luteolin also increases the level of Mn-SOD, (Cu/Zn)-SOD and glutathione (GSH) in the cortex and hippocampus to reduce the oxidative stress by Abeta (1-40). Taken together, the results in this study suggest that luteolin (5, 10 mg/kg) treatment improves the learning and memory in Abeta (1-40)-induced cognition deficit in rats. The ameliorating mechanisms of luteolin on Abeta (1-40)-induced amnesia may be related to activating the anti-oxidation system.

Neuroprotective effect of luteolin on amyloid beta protein (25-35)-induced toxicity in cultured rat cortical neurons.

The present study was carried out to investigate the neuroprotective effect of luteolin on amyloid beta (Abeta) (25-35)-induced neurotoxicity using cultured rat cortical neurons. After exposure of primary cultures of rat cortical cells to 10 muM Abeta (25-35) for 48 h, cortical cell cultures exhibited marked apoptotic death. Pretreatment with luteolin (1, 10 microM) significantly protected cortical cell cultures against Abeta (25-35)-induced toxicity. Luteolin (1, 10 microM) showed a concentration-dependent inhibition on 10 muM Abeta (25-35)-induced apoptotic neuronal death, as assessed by MTT assay. Furthermore, luteolin reduced apoptotic characteristics by DAPI staining. For Western blot analysis, the results showed that the protective effect of luteolin on Abeta (25-35)-induced neurotoxicity was mediated by preventing of ERK-p, JNK, JNK-p, P38-p and caspase 3 activations in rat primary cortical cultures. Taken together, the results suggest that luteolin prevents Abeta (25-35)-induced apoptotic neuronal death through inhibiting the protein level of JNK, ERK and p38 MAP kinases and caspase 3 activations.

Analgesic and anti-inflammatory activities of ethanol root extract of Mahonia oiwakensis in mice.

AIMS OF THE STUDY: This study investigated the anti-inflammatory and analgesic activities, and protoberberine alkaloid contents of ethanol extract of MO roots (MOR(EtOH)). MATERIALS AND METHODS: The analgesic activity of MOR(EtOH) was determined using acetic acid-induced writhing response and formalin test. The anti-inflammatory activity of MOR(EtOH) was determined using the lambda-carrageenan-induced paw oedema model. The protoberberine alkaloid contents of MOR(EtOH) were identified by high-performance liquid chromatography (HPLC). RESULTS: MOR(EtOH) (100 and 500 mg/kg) decreased the acetic acid-induced writhing responses and licking times of the second phase in the formalin test. Moreover, carrageenan-induced paw oedema was significantly reduced in a dose-dependent manner by administering MOR(EtOH) (100 and 500 mg/kg) at 3, 4, and 5h after the carrageenan injection. The serum levels of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) of MOR(EtOH)-treated mice were significantly reduced compared with those in the serum of animals administered carrageenan. Notably, MOR(EtOH) attenuated the expression of cyclo-oxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) and neutrophil infiltration in paw tissues injected with carrageenan. The anti-inflammatory mechanisms of MOR(EtOH) appear to be related to the inhibition of neutrophil infiltration, iNOS and COX-2 protein expression, NO release, and the decreasing TNF-alpha level in serum. The analytical results showed that the contents of berberine, palmatine and jatrorrhizine were 191.45 mg/g extract, 100.15 mg/g extract and 66.45 mg/g extract, respectively. CONCLUSION: These experimental results suggest that MOR(EtOH) produced both analgesic and anti-inflammatory effects in mice and may be a candidate for the development of pharmacological agents used in the treatment of inflammatory disorders.

Analgesic and anti-inflammatory activities of Torenia concolor Lindley var. formosana Yamazaki and betulin in mice.

The present study was intended to examine the analgesic effect of the 70% methanol extract of Torenia concolor Lindley var. formosana Yamazaki (TC(MeOH)) and betulin using models of acetic acid-induced writhing response and formalin test. In addition, we investigated the anti-inflammatory effect of TC(MeOH) and betulin using model of lambda-carrageenan-induced paw edema. We observed the activities of antioxidant enzymes (SOD, GPx and GR) in the liver and the levels of malondialdehyde (MDA) and nitric oxide (NO) in the edema paw. The results showed that TC(MeOH) (1.0 and 2.0 g/kg) and betulin (30 and 90 mg/kg), significantly inhibited the acetic acid-induced writhing response. TC(MeOH) (2.0 g/kg) and betulin (30 and 90 mg/kg) significantly inhibited formalin-induced licking time during both the early and late phases. TC(MeOH) (0.5, 1.0 and 2.0 g/kg) and betulin (30 and 90 mg/kg) also significantly decreased the paw edema at the 4th hour after lambda-carrageenan injection. Furthermore, TC(MeOH) and betulin treatment also significantly increased the activities of SOD, GR and GPx in the liver while decreasing the level of MDA in the edema paw. Finally, betulin (30 and 90 mg/kg) also caused considerable reduction of NO level in the edema paw. Taken together, the present results indicated that TC(MeOH) and betulin possessed analgesic and anti-inflammatory effects. The anti-inflammatory mechanism of TC(MeOH) and betulin may be related to decreasing the levels of MDA and NO in the edema paw by increasing the activities of antioxidant enzymes in the liver.

Ameliorating effect of emodin, a constitute of Polygonatum multiflorum, on cycloheximide-induced impairment of memory consolidation in rats.

The aim of the present study was intended to investigate the ameliorating effects of emodin on memory consolidation via cholinergic, serotonergic and GABAergic neuronal systems in rats. First, we evaluated the ameliorating effects of emodin on cycloheximide (CXM)-induced impairment of passive avoidance response in rats. Secondly, we clarified the role of cholinergic, serotonergic or GABAergic system on the ameliorating effect of emodin by using 5-HT1A receptor partial agonist, 5-HT2 receptor antagonist, GABAB agonist, GABAA antagonist and muscarinic receptor antagonist. Emodin protected the rat from CXM-induced memory consolidation impairment. The beneficial effect of emodin on CXM-induced memory consolidation impairment was amplified by 8-OH-DPAT (5-HT1A receptor partial agonist) and ritanserin (5-HT2 receptor antagonist), but reduced by scopolamine. These results suggested that the beneficial effect of emodin on CXM-induced memory consolidation impairment was amplified by serotonergic 5-HT1A-receptor partial agonist and 5-HT2 receptor antagonist but reduced by muscarinic receptor antagonist.

Actinidia rubricaulis attenuates hepatic fibrosis induced by carbon tetrachloride in rats.

The purpose of this study was to evaluate the antioxidant activity and hepatoprotective effect of ethanol extracts of Actinidia rubricaulis (AR) on chronic liver injury induced by carbon tetrachloride (CCl(4)) in rats. CCl(4) (20%, 0.5 ml/rat) was given twice a week for 8 weeks, and animals received AR throughout the entire experimental period. AR reduced the elevated levels of serum glutamate-oxalate-transaminase (sGOT) and glutamate-pyruvate-transaminase (sGPT) caused by CCl(4) at weeks 1, 3, 6, and 8. The biochemical data were consistent with those of the histological observations. The AR extract recovered the CCl(4)-induced liver injury and showed antioxidant effect in assays of antioxidant enzyme activity, such as SOD, GSH-Px and GSH-Rd. Based on these results, we suggest that the hepatoprotective effect of the AR is related to its antioxidant activity.

Hepatoprotective effect of Phyllanthus in Taiwan on acute liver damage induced by carbon tetrachloride.

The effect of oral administration of Phyllanthus methanolic extracts (PME) (i.e. P. acidus, P. emblica, P. myrtifolius, P. multiflorus, P. amarus, P. debilis, P. embergeri, P. hookeri, P. tenellus, P. urinaria L.s. nudicarpus, P. urinaria L.s. urinaria) or gallic acid (GA) on the progression of acute liver damage induced by CCl(4) in rats was examined by morphological and biochemical methods. P. acidus, P. urinaria L.s. urinaria, GA at a dose of 0.5 g/kg, and P. emblica, P. urinaria L.s. nudicarpus at a dose of 1.0 g/kg attenuated CCl(4)-induced increase in serum glutamate-oxalate-transaminase (GOT). P. acidus, P. urinaria L.s. nudicarpus, P. urinaria L.s. urinaria, GA at a dose of 0.5 g/kg, and P. emblica, P. amarus, P. hookeri, P. tenellus at a dose of 1.0 g/kg attenuated CCl(4)-induced increase in serum glutamate-pyruvate-transaminase (GPT). Concurrently, P. acidus, P. multiflorus, P. embergeri, P. hookeri, P. tenellus and P. urinaria L.s. urinaria elevated the activity of liver reduced glutathione peroxidase (GSH-Px). Since the protective effects of P. acidus, P. emblica, P. myrtifolius, P. embergeri, P. urinaria L.s. nudicarpus, P. urinaria L.s. urinaria and GA correlate with a reduction in liver infiltration and focal necrosis observed using histological methods, these data demonstrate that P. acidus and P. urinaria L.s. urinaria are hepatoprotective and antioxidant agents.

Analgesic and anti-inflammatory activities of [6]-gingerol.

In the present study, the analgesic and anti-inflammatory effects of [6]-gingerol, which is the pungent constituent of ginger, were performed. Intraperitoneal administration of [6]-gingerol (25 mg/kg-50 mg/kg) produced an inhibition of acetic acid-induced writhing response and formalin-induced licking time in the late phase. [6]-Gingerol (50 mg/kg-100 mg/kg) also produced an inhibition of paw edema induced by carrageenin. These results suggested that [6]-gingerol possessed analgesic and anti-inflammatory activities.

Anxiolytic effect of ting-chih-wan in mouse behavior models of anxiety.

The anxiolytic effect of the alcoholic extract of ting-chih-wan (TCWa) was studied using the black and white test (BWT) and the elevated plus-maze (EPM). We further demonstrated the anxiolytic mechanism of TCWa by combining with diazepam (DIZ), serotonin (5-HT) agonists or antagonists, and measuring the levels of monoamines and its metabolites in the brain stem and cortex. In the BWT, TCWa (0.1-1.0 g/kg, p.o.) increased the time spent in the white chamber and total change between the two chambers, and decreased the time spent in the black chamber. TCWa (0.1-0.5 g/kg, p.o.) increased the arm entries and the time spent on the open arms, and decreased the arm entries and the time spent on the closed arms in the EPM. On the other hand, TCWa (1.0 g/kg, p.o.) decreased horizontal activity and prolonged pentobarbital-induced sleeping times. TCWa (0.1, 0.5 g/kg) decreased the levels of norepinephrine (NE), dopamine (DA), 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) and increased the levels of vanillylmandelic acid (VMA) and homovanillic acid (HVA) in the brain stem. TCWa (0.1 and 0.5 g/kg) decreased the levels of NE, DA and increased the levels of VMA and HVA in the cortex. TCWa also attenuated the anxiogenic effect of 5-hydroxytryptophan (5-HTP) and enhanced the anxiolytic effect of 9p-chlorophenylalanine (PCPA), buspirone (BUS) and ritanserin (RIT) in the EPM. From these results, TCWa at 0.1 and 0.5 g/kg possessed an anxiolytic effect T heanxiolytic mechanisms of TCWa might be due to decreased catecholaminergic activity caused by the increase in the turnover rate of catecholamines in the brain and decreased concentrations of 5-HT in the brain stemvia activating somatodendritic 5-HT1A autoreceptors and inhibiting postsynaptic 5-HT receptors.