Ginsenosides attenuate kainic acid-induced synaptosomal oxidative stress via stimulation of adenosine A(2A) receptors in rat hippocampus

Treatment with ginsenosides attenuated KA-induced seizures and oxidative stress in the synaptosome, and reduced synaptic vesicles at the presynaptic terminals dose-dependently. The adenosine A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl) xanthine reversed the ginsenoside-mediated pharmacological actions. Neither the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine nor the adenosine A(2B) receptor antagonist alloxazine affected the ginsenoside-mediated pharmacological actions. Our results suggest that ginsenosides block KA-induced synaptosomal oxidative stress, associated with hippocampal degeneration, through activation of adenosine A(2A) receptors.     

Protection against kainate neurotoxicity by ginsenosides: attenuation of convulsive behavior, mitochondrial dysfunction, and oxidative stress

We previously demonstrated that kainic acid (KA)-mediated mitochondrial oxidative stress contributed to hippocampal degeneration and that ginsenosides attenuated KA-induced neurotoxicity and neuronal degeneration. Here, we examined whether ginsenosides affected KA-induced mitochondrial dysfunction and oxidative stress in the rat hippocampus. Treatment with ginsenosides attenuated KA-induced convulsive behavior dose-dependently. KA treatment increased lipid peroxidation and protein oxidation and decreased the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio to a greater degree in the mitochondrial fraction than in the hippocampal homogenate. KA treatment resulted in decreased Mn-superoxide dismutase expression and diminished the mitochondrial membrane potential. Furthermore, KA treatment increased intramitochondrial Ca(2+) and promoted ultrastructural degeneration in hippocampal mitochondria. Treatment with ginsenosides dose-dependently attenuated convulsive behavior and the KA-induced mitochondrial effects. Protection appeared to be more evident in mitochondria than in tissue homogenates. Collectively, the results suggest that ginsenosides prevent KA-induced neurotoxicity by attenuating mitochondrial oxidative stress and mitochondrial dysfunction.     

Age and body weight adjusted warfarin initiation program for ischaemic stroke patients

Background:  Despite its proven effect, anticoagulation is not recommended to the acute ischaemic stroke due to the risk of bleeding complications. The purpose of this study is development of individualized warfarin initiation program for acute or subacute stroke patients.
Methods:  Among stroke patients who regularly visited out-patient clinics, we included patients who have continuously taken the same dose of warfarin as the prothrombin time remained at target International Nomarlized Ratio (INR). We assessed potential variables that affect the maintenance dose of warfarin. Using these variables, we developed an individualized warfarin initiation program.
Results:  The median warfarin maintenance dose (interquartile range) in the 321 included patients was 4 (3–5) mg per day. Age (adjusted R ² = 0.221, P  <   0.001) and body weight (added to age, adjusted R ² = 0.238, P  =   0.008) were significant predicting factors of the dose. We classified the maintenance doses into high (HG), standard, and low group (LG) based on the distribution of maintenance doses. Decision tree analysis categorized younger (≤55 years old) and heavier (≥55 kg) patients into HG, and very old (≥80 years old) or low body weight (<55 kg among those >56 years old) patients into LG. We recommend 7 mg of warfarin as a standard initial dose, but 10 mg was recommended for HG patients and 5 mg for LG.
Conclusion:  We expect that this individualized program may reduce the time to target INR without excessive anticoagulation. Further prospective studies are needed to reveal the efficacy and safety of applying this program for acute stroke patients.     

Effect of Korean red ginseng extract in a steroid-induced polycystic ovary murine model

Experimental induction of polycystic ovary (PCO) in rodent resembling some aspects of human PCO syndrome was produced using the long-acting compound estradiol valerate (EV). Our previous study on the role of Korean red ginseng total saponins in a steroid-induced PCO rat model demonstrated that electro-acupuncture modulates nerve growth factor (NGF) concentration in the ovaries. In fact, the involvement of a neurogenic component in the pathology of PCO-related ovarian dysfunction is preceded by an increase in sympathetic outflow to the ovaries. In the present study, we tested the hypothesis that Korean red ginseng extract (KRGE) administration modulates sympathetic nerve activity in PCO-induced rats. This was done by analyzing NGF protein and NGF mRNA expression involved in the pathophysiological process underlying steroid-induced PCO. EV injection resulted in significantly higher ovarian NGF protein and NGF mRNA expression in PCO-induced rats compared to control rats, and PCO ovaries were counteracted by KRGE administration with significantly lower expression of NGF protein and NGF mRNA compared to EV treated ovaries. These results indicate that EV modulates the neurotrophic state of the ovaries, which may be a component of the pathological process by which EV induces cyst formation and anovulation in rodents. The first two authors contributed equally to this work.     

Quercetin Inhibits ��3��4 Nicotinic Acetylcholine Receptor-Mediated Ion Currents Expressed in Xenopus Oocytes

Quercetin mainly exists in the skin of colored fruits and vegetables as one of flavonoids. Recent studies show that quercetin, like other flavonoids, has diverse pharmacological actions. However, relatively little is known about quercetin effects in the regulations of ligand-gated ion channels. In the previous reports, we have shown that quercetin regulates subsets of homomeric ligand-gated ion channels such as glycine, 5-HT_3A and α7 nicotinic acetylcholine receptors. In the present study, we examined quercetin effects on heteromeric neuronal α3β4 nicotinic acetylcholine receptor channel activity expressed in Xenopus oocytes after injection of cRNA encoding bovine neuronal α3 and β4 subunits. Treatment with acetylcholine elicited an inward peak current (I_ACh) in oocytes expressing α3β4 nicotinic acetylcholine receptor. Co-treatment with quercetin and acetylcholine inhibited I_ACh in oocytes expressing α3β4 nicotinic acetylcholine receptors. The inhibition of I_ACh by quercetin was reversible and concentration-dependent. The half-inhibitory concentration (IC₅₀) of quercetin was 14.9±0.8 µM in oocytes expressing α3β4 nicotinic acetylcholine receptor. The inhibition of I_ACh by quercetin was voltage-independent and non-competitive. These results indicate that quercetin might regulate α3β4 nicotinic acetylcholine receptor and this regulation might be one of the pharmacological actions of quercetin in nervous systems.     

Inhibitory Effects of Quercetin on Muscle-type of Nicotinic Acetylcholine Receptor-Mediated Ion Currents Expressed in Xenopus Oocytes

The flavonoid quercetin is a low molecular weight compound generally found in apple, gingko, tomato, onion and other red-colored fruits and vegetables. Like other flavonoids, quercetin has diverse pharmacological actions. However, relatively little is known about the influence of quercetin effects in the regulation of ligand-gated ion channels. Previously, we reported that quercetin regulates subsets of nicotinic acetylcholine receptors such as α3β4, α7 and α9α10. Presently, we investigated the effects of quercetin on muscle-type of nicotinic acetylcholine receptor channel activity expressed in Xenopus oocytes after injection of cRNA encoding human fetal or adult muscle-type of nicotinic acetylcholine receptor subunits. Acetylcholine treatment elicited an inward peak current (I(ACh)) in oocytes expressing both muscle-type of nicotinic acetylcholine receptors and co-treatment of quercetin with acetylcholine inhibited I(ACh). Pre-treatment of quercetin further inhibited I(ACh) in oocytes expressing adult and fetal muscle-type nicotinic acetylcholine receptors. The inhibition of I(ACh) by quercetin was reversible and concentration-dependent. The IC(50) of quercetin was 18.9±1.2 μM in oocytes expressing adult muscle-type nicotinic acetylcholine receptor. The inhibition of I(ACh) by quercetin was voltage-independent and non-competitive. These results indicate that quercetin might regulate human muscle-type nicotinic acetylcholine receptor channel activity and that quercetin-mediated regulation of muscle-type nicotinic acetylcholine receptor might be coupled to regulation of neuromuscular junction activity.     

Fixed dose rate infusion of gemcitabine with oral doxifluridine and leucovorin for advanced unresectable pancreatic cancer: a phase II study

The standard beneficial chemotherapy proven for patients with advanced pancreatic cancer is a regimen containing gemcitabine. In the pregemcitabine era, 5-fluorouracil (5-FU) was the standard agent. Oral 5-FU can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better patient convenience. The possibility to improve efficacy of gemcitabine by fixed dose rate infusion (FDRI) was proposed in addition to combining it with 5-FU. We tried a new chemotherapy combining FDRI of gemcitabine with doxifluridine and leucovorin. Eligibility criteria were pathologically proven, chemotherapy-na?ve, and metastatic or nonoperable advanced pancreatic cancer. Gemcitabine 1,000 mg/m(2) was infused over 100 min (days 1, 8 and 15). Doxifluridine 200 mg/m(2) t.i.d. and leucovorin 15 mg b.i.d. were given orally (days 1-21). Chemotherapy was repeated every 28 days until a patient had received 6 cycles or progression was found. Twenty-nine patients were enrolled from October 2002 to December 2004. A total of 78 cycles were given at a mean of 2.7 cycles per patient. Response could be evaluated in 26 patients. Responses were partial remission in 4/26 patients (15.4%), stable disease in 8/26 (30.8%) and progression in 14/26 (53.8%). All patients progressed except for 2 in partial remission and 2 in stable disease. Toxicities could be assessed in 23 patients. Maximal hematological toxicities greater than grade 2 were leucopenia in 3 patients (11.5%), neutropenia in 2 (7.7%), anemia in 2 (7.7%), thrombocytopenia in 1 (3.8%) and febrile neutropenia in 3 (11.5%). Maximal nonhematological grade 3 or 4 toxicities were asthenia in 1 patient (3.8%), anorexia in 1 (3.8%), vomiting in 1 (3.8%), diarrhea in 2 (7.7%), allergic reaction in 1 (3.8%), hand-foot syndrome in 1 (3.8%) and hyperbilirubinemia in 1 (3.8%). All 29 patients were dead on last follow-up. Median progression-free survival was 3.91 months in 26 evaluable patients and median overall survival was 5.59 months in all patients. Combination chemotherapy including FDRI of gemcitabine seems minimally active for patients with advanced, nonoperable pancreatic cancer. Further research to improve effectiveness of chemotherapy for advanced pancreatic cancer is mandatory.     

Identification of ginsenoside interaction sites in 5-HT3A receptors

We previously demonstrated that 20(S)-ginsenoside Rg(3) (Rg(3)), one of the active components of Panax ginseng, non-competitively inhibits 5-HT(3A) receptor channel activity on extracellular side of the cell. Here, we sought to elucidate the molecular mechanisms underlying Rg(3)-induced 5-HT(3A) receptor regulation. We used the two-microelectrode voltage-clamp technique to investigate the effect of Rg(3) on 5-HT-mediated ion currents (I(5-HT)) in Xenopus oocytes expressing wild-type or 5-HT(3A) receptors harboring mutations in the gating pore region of transmembrane domain 2 (TM2). In oocytes expressing wild-type 5-HT(3A) receptors, Rg(3) dose-dependently inhibited peak I(5-HT) with an IC(50) of 27.6+/-4.3microM. Mutations V291A, F292A, and I295A in TM2 greatly attenuated or abolished the Rg(3)-induced inhibition of peak I(5-HT). Mutation V291A but not F292A and I295A induced constitutively active ion currents with decrease of current decay rate. Rg(3) accelerated the rate of current decay with dose-dependent manner in the presence of 5-HT. Rg(3) and TMB-8, an open channel blocker, dose-dependently inhibited constitutively active ion currents. The IC(50) values of constitutively active ion currents in V291A mutant receptor were 72.4+/-23.1 and 6.5+/-0.7microM for Rg(3) and TMB-8, respectively. Diltiazem did not prevent Rg(3)-induced inhibition of constitutively active ion currents in occlusion experiments. These results indicate that Rg(3) inhibits 5-HT(3A) receptor channel activity through interactions with residues V291, F292, and I295 in the channel gating region of TM2 and further demonstrate that Rg(3) regulates 5-HT(3A) receptor channel activity in the open state at different site(s) from those of TMB-8 and diltiazem.     

Nonexudative morphologic changes of neovascularization on optical coherence tomography angiography as predictive factors for exudative recurrence in age-related macular degeneration

Graefe's Archive for Clinical and Experimental Ophthalmology - To evaluate morphologic changes of choroidal neovascularization (CNV) on optical coherence tomography angiography (OCTA) during...