Chun-Sik Bae

Protective effect of ginsenosides, active ingredients of Panax ginseng, on kainic acid-induced neurotoxicity in rat hippocampus

Ginsenosides are known to attenuate glutamate-induced cell injuries in vitro. We investigated the in vivo effect of ginsenosides on kainic acid (KA)-induced neurotoxicity in rat hippocampus using the methods of acid fuchsin (AF) staining and heat-shock protein-70 (HSP-70) immunoreactivity to detect neuronal death and stress, respectively. Pretreatment of ginsenosides (50 or 100 mg/kg for 7 days) via intraperitoneal (i.p.) administration significantly attenuated KA (10 mg/kg i.p.)-induced cell death by decreasing AF-positive neurons in both CA1 and CA3 regions of rat hippocampus compared with KA treatment alone. Pretreatment of ginsenosides (50 or 100 mg/kg for 7 days) via i.p. administration also significantly suppressed KA-induced induction of HSP-70 in both regions of rat hippocampus. These results show that ginsenosides are effective in protecting hippocampal CA1 and CA3 cells against KA-induced neurotoxicity.

Neuropharmacological Potential of Gastrodia elata Blume and Its Components

Research has been conducted in various fields in an attempt to develop new therapeutic agents for incurable neurodegenerative diseases. Gastrodia elata Blume (GE), a traditional herbal medicine, has been used in neurological disorders as an anticonvulsant, analgesic, and sedative medication. Several neurodegenerative models are characterized by oxidative stress and inflammation in the brain, which lead to cell death via multiple extracellular and intracellular signaling pathways. The blockade of certain signaling cascades may represent a compensatory therapy for injured brain tissue. Antioxidative and anti-inflammatory compounds isolated from natural resources have been investigated, as have various synthetic chemicals. Specifically, GE rhizome extract and its components have been shown to protect neuronal cells and recover brain function in various preclinical brain injury models by inhibiting oxidative stress and inflammatory responses. The present review discusses the neuroprotective potential of GE and its components and the related mechanisms; we also provide possible preventive and therapeutic strategies for neurodegenerative disorders using herbal resources.

Mechanism for the protective effect of diallyl disulfide against cyclophosphamide acute urotoxicity in rats.

UNLABELLED This study investigated the protective effects of diallyl disulfide (DADS) against cyclophosphamide (CP)-induced acute urotoxicity in rats. CP caused severe hemorrhagic cystitis as shown by significant increases in bladder weight, edema, and hemorrhage as well as increased urinary bladder epithelial cell apoptosis, protein expression of nuclear factor erythroid 2-related factor-2 (Nrf-2) and phase II enzymes (i.e., NAD(P)H quinone oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1)), immunostaining intensity of acrolein-protein adducts, and histopathological changes. The significant decreases in glutathione content and catalase, glutathione-S-transferase, and glutathione reductase activities and a significant increase in malondialdehyde content indicated that CP-induced bladder injury was mediated through oxidative stress. In contrast, pretreatment with DADS significantly attenuated the CP-induced urotoxic effects, including oxidative damage, histopathological lesions, apoptotic changes, and accumulation of acrolein-protein adducts in the bladder. DADS also significantly increased expression of CYP2B1/2, CYP3A1, Nrf-2, NQO-1, and HO-1 and significantly decreased expression of CYP2C11. These results indicate that DADS prevented CP-induced bladder toxicity, in part, by detoxifying acrolein. The protective effects of DADS may be due to its ability to decrease metabolic activation of CP by inhibiting CYP2C11 and inducing CYP3A1, and its potent antioxidant activity and antiapoptotic effects occurred via the Nrf-2-antioxidant response element pathway.

Protective effects of pine bark extract on developmental toxicity of cyclophosphamide in rats

This study investigated the protective effects of pine bark extract (Pycnogenol®, PYC) against cyclophosphamide (CP)-induced developmental toxicity in rats. A total of 44 mated females were randomly assigned to the following four experimental groups: (1) vehicle control, (2) CP, (3) CP&PYC, or (4) PYC. All dams were subjected to a Caesarean section on day 20 of gestation, and fetuses were examined for morphological abnormalities. Oxidative stress analysis was performed on maternal hepatic tissues. CP treatment caused decreased fetal and placental weights and increased embryonic resorptions and fetal malformations. In addition, an increased malondialdehyde (MDA) concentration and decreased reduced glutathione (GSH) content and catalase activity were observed in the hepatic tissues. On the contrary, PYC treatment during pregnancy significantly ameliorated the CP-induced embryo-fetal developmental toxicity in rats. Moreover, MDA and GSH concentrations and catalase activity in hepatic tissues were not affected when PYC was administered in conjunction with CP. These results suggest that repeated administration of PYC has beneficial effects against CP-induced embryo-fetal developmental toxicity in rats, and that the protective effects of PYC may be due to both inhibition of lipid peroxidation and increased antioxidant activity.

Bradykinin stimulates glutamate uptake via both B1R and B2R activation in a human retinal pigment epithelial cells

AIMS We were to examine the effect of bradykinin (BK) in the regulation of glutamate transporter and its related signaling molecules in a human retinal pigment epithelial (ARPE) cells, which are important cells to support retina. MAIN METHODS d-[2,3-(3)H]-aspartate uptake, western immunoblotting, reverse transcription polymerase chain reaction, [(3)H]-arachidonic acid release, and siRNA transfection techniques were used. KEY FINDINGS BK stimulated glutamate uptake as well as the mRNA expression of excitatory amino acid transporter 4 (EAAT4) and excitatory amino acid carrier 1 (EAAC1), which was blocked by treatment with bradykinin 1 receptor (B1R) and bradykinin 2 receptor (B2R) siRNA, suggesting the role of B1R and B2R in this process. The BK-induced stimulation of glutamate uptake was also blocked by [des-Arg(10)]-HOE 140, a B1R antagonist, and HOE 140, a B2R antagonist, as well as by the tyrosine kinase inhibitors genistein and herbimycin A. In addition, the BK-induced stimulation of glutamate uptake was blocked by treatment with the phospholipase A(2) inhibitors mepacrine and AACOCF(3), the cyclooxygenase (COX) inhibitor indomethacin, and the COX-2 inhibitor Dup 697. Furthermore, the BK-induced increase in COX-2 expression was blocked by the PI-3 kinase inhibitors wortmannin and LY294002, Akt inhibitor, and the protein kinase C (PKC) inhibitors staurosporine and bisindolylmaleimide I, suggesting the role of PI-3 kinase and PKC in this process. BK stimulated Akt activation and the translocation of PKC activation via the activation of B1R and B2R. SIGNIFICANCE BK stimulates glutamate uptake through a PKC-Akt-COX-2 signaling cascade in ARPE cells.

Correlation of immunohistochemical characteristics of the craniomandibular joint with the degree of mandibular lengthening in rabbits

PURPOSE This study examined immunohistochemical changes in the craniomandibular joints of rabbits after distraction osteogenesis following mandibular corticotomy. MATERIALS AND METHODS The experimental animals (n = 8) were divided into 3 groups that underwent 2, 3.5, and 5 mm of unilateral distraction osteogenesis (groups 1, 2, and 3, respectively). After corticotomy of the left mandibular body and a 7-day healing period, a second operation was performed to expose the device. Distraction was then performed at the rate of 0.5 mm/d. A 14-day consolidation period was allowed after the distraction was complete. Changes in cartilage, osteoblast activity, and osteoclast activity were then examined. RESULTS The differentiation and proliferation of cartilage increased in groups 1 and 2, were highest in group 2, and decreased in group 3. Group 2 also showed the greatest increase in the width of the hypertrophic chondrocyte layer. Relative to the control group, osteoclast activity was only somewhat higher in groups 1 and 2 but was significantly higher in group 3. Osteoblast activity was significantly higher in groups 1 and 2 than in the control group. However, the osteoblast activity in group 3 was slightly lower than that in group 2. At the time of unilateral mandibular distraction, no degenerative changes of the temporomandibular joint were observed in groups 1 or 2, but bone resorption was observed in group 3. CONCLUSIONS The unilateral mandibular distraction of 2 or 3.5 mm was acceptable in that no degenerative changes of the temporomandibular joint were observed on either the distraction or the nondistraction sides. Five millimeters of distraction might be beyond physiologic limits.

Protective effect of morin on the imipenem-induced nephrotoxicity in rabbits

The present study investigated the protective effect of morin, a natural flavonoid, on the imipenem-induced nephrotoxicity in rabbits. Nephrotoxicity of imipenem was examined after the intravenous administrations of imipenem (200 mg/kg) to rabbits in the presence and the absence of morin (12, 25, 50 mg/kg, p.o.). Cytotoxicity of imipenem was also examined in the presence and the absence of morin (100 μM) by using MDCK cells overexpressing human organic anion transporter 1 and 3 (MDCK/hOAT1 or MDCK/hOAT3). Intravenous dosing of imipenem alone induced severe proximal tubular necrosis in rabbits, however, the concurrent use of morin (25 or 50 mg/kg, p.o.) significantly suppressed the histopathological damage in the kidney induced by imipenem. While imipenem was not cytotoxic in MDCK/hOAT1 cells over the tested concentrations up to 10 mM, it showed significant cellular toxicity with CC50 of 0.77 mM in MDCK/hOAT3 cells, implying that OAT3 may involve more actively in the imipeneminduced nephrotoxicity. In addition, the cellular toxicity of imipenem decreased by approximately 20 folds in the presence of morin in MDCK/hOAT3 cells. In conclusion, the present study suggests that morin might be beneficial to reduce the nephrotoxicity of imipenem, at least in part, via the inhibition of OAT3-mediated renal excretion of imipenem.

Fast neutron irradiation deteriorates hippocampus-related memory ability in adult mice

Object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice exposed to cranial fast neutron irradiation (0.8 Gy) were examined to evaluate hippocampus-related behavioral dysfunction following acute exposure to relatively low doses of fast neutrons. In addition, hippocampal neurogenesis changes in adult murine brain after cranial irradiation were analyzed using the neurogenesis immunohistochemical markers Ki-67 and doublecortin (DCX). In the object recognition memory test and contextual fear conditioning, mice trained 1 and 7 days after irradiation displayed significant memory deficits compared to the sham-irradiated controls. The number of Ki-67- and DCX-positive cells decreased significantly 24 h post-irradiation. These results indicate that acute exposure of the adult mouse brain to a relatively low dose of fast neutrons interrupts hippocampal functions, including learning and memory, possibly by inhibiting neurogenesis.

Transplacental pharmacokinetics of the new fluoroquinolone DW-116 in pregnant rats

DW-116 is a newly developed fluoroquinolone antibacterial with a broad spectrum against both gram-positive and gram-negative bacteria. Recently, we have reported that DW-116 induces a significant developmental toxicity in rat. The present study was undertaken to characterize the placental transfer and pharmacokinetics of DW-116 in Sprague-Dawley rats. Pregnant females were given a single oral dose of 500-mg [14C]DW-116/kg on gestational day 18. Maternal and fetal tissues were collected at 0.17, 0.5, 1, 2, 4, 8 and 24 h after dosing. The [14C]DW-116-derived radioactivity was rapidly distributed to the fetus and slowly eliminated from the tissue. The radioactivity in both maternal plasma and fetal tissue reached its peak within 1 h and maintained the level of radioactivity up to 16-28% of the peak level until 24 h after dosing. Radioactivity in whole fetus was higher than those in the maternal plasma and placenta. The T(1/2)abs, T(1/2)beta, AUC, Tmax and Cmax in the maternal plasma were approximately 6 min, 13.3 h, 1620 microg h/ml, 0.5 h and 136 microg/ml, respectively. Those in the placenta were approximately 20 min, 12.3 h, 2150 microg h/ml, 1.0 h and 172 microg/ml, respectively. Those in the whole fetus were 13 min, 12.8 h, 2549 microg h/ml, 1 h and 191 microg/ml, respectively. In the amniotic fluid of maternal uterus, the T(1/2)abs, T(1/2)beta, AUC, Tmax and Cmax were approximately 1.3 h, 9.3 h, 2508 microg h/ml, 4.4 h, and 135 microg/ ml, respectively. While DW-116 disappeared biphasically from maternal plasma, whole fetus and placenta, it was eliminated monophasically from amniotic fluid. These results indicate that (1) total radioactivity appeared rapidly in maternal plasma and fetuses; (2) the elimination of total radioactivity is slow; and (3) DW-116 or relevant metabolites could cross the blood-placenta barrier in pregnant rats.

HPLC Analysis, Optimization of Extraction Conditions and Biological Evaluation of Corylopsis coreana Uyeki Flos

A method for the separation and quantification of three flavonoids and one isocoumarin by reverse-phase high performance liquid chromatography (HPLC) has been developed and validated. Four constituents present in a crude ethanolic extract of the flowers of Coryloposis coreana Uyeki, were analyzed. Bergenin, quercetin, quercitrin and isosalipurposide were used as calibration standards. In the present study, an excellent linearity was obtained with an r2 higher than 0.999. The chromatographic peaks showed good resolution. In combination with other validation data, including precision, specificity, and accuracy, this method demonstrated good reliability and sensitivity, and can be conveniently used for the quantification of bergenin, quercetin, quercitrin and isosalipurposide in the crude ethanolic extract of C. coreana Uyeki flos. Furthermore, the plant extracts were analyzed with HPLC to determine the four constituents and compositional differences in the extracts obtained under different extraction conditions. Several extracts of them which was dependent on the ethanol percentage of solvent were also analyzed for their antimicrobial and antioxidant activities. One hundred % ethanolic extract from C. coreana Uyeki flos showed the best antimicrobial activity against the methicillin-resistant Staphylococcus aureus (MRSA) strain. Eighty % ethanolic extract showed the best antioxidant activity and phenolic content. Taken of all, these results suggest that the flower of C. coreana Uyeki flos may be a useful source for the cure and/or prevention of septic arthritis, and the validated method was useful for the quality control of C. coreana Uyeki.