Jun-Sub Jung

Protection against β‐amyloid peptide toxicity in vivo with long‐term administration of ferulic acid

β‐Amyloid peptide (Aβ), a 39 – 43 amino acid peptide, is believed to induce oxidative stress and inflammation in the brain, which are postulated to play important roles in the pathogenesis of Alzheimers disease. Ferulic acid is an antioxidant and anti‐inflammatory agent derived from plants; therefore, the potential protective activity of ferulic acid against Aβ toxicity in vivo was examined. Mice were allowed free access to drinking water (control) or water containing ferulic acid (0.006%). After 4 weeks, Aβ1‐42 (410 pmol) was administered via intracerebroventricular injection. Injection of control mice with Aβ1‐42 impaired performance on the passive avoidance test (35% decrease in step‐through latency), the Y‐maze test (19% decrease in alternation behaviour), and the water maze test (32% decrease in percentage time in platform‐quadrant). In contrast, mice treated with ferulic acid prior to Aβ1‐42 administration were protected from these changes (9% decrease in step‐through latency; no decrease in alternation behaviour; 14% decrease in percentage time in platform‐quadrant). Aβ1‐42 induced 31% decrease in acetylcholine level in the cortex, which was tended to be ameliorated by ferulic acid. In addition, Aβ1‐42 increased immunoreactivities of the astrocyte marker glial fibrillary acidic protein (GFAP) and interleukin‐1β (IL‐1β) in the hippocampus, effects also suppressed by pretreatment with ferulic acid. Administration of ferulic acid per se unexpectedly induced a transient and slight increase in GFAP and IL‐1β immunoreactivity in the hippocampus on day 14, which returned to basal levels on day 28. A slight (8%) decrease in alternation behaviour was observed on day 14. These results demonstrate that long‐term administration of ferulic acid induces resistance to Aβ1‐42 toxicity in the brain, and suggest that ferulic acid may be a useful chemopreventive agent against Alzheimers disease.

Therapeutic effects of lysophosphatidylcholine in experimental sepsis.

Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H2O2 production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-α (TNF-α) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections.

Protection against β-amyloid peptide-induced memory impairment with long-term administration of extract of Angelica gigas or decursinol in mice

We investigated the effect of long-term oral administration of ethanolic extract of Angelica gigas Nakai (Umbelliferae) (EAG) or decursinol, a coumarin isolated from A. gigas, on beta-amyloid peptide 1-42 (Abeta(1-42))-induced memory impairment in mice. Mice were allowed free access to drinking water (control) or water containing different concentrations of EAG. After 4 weeks, Abeta(1-42) (410 pmol) was administered via intracerebroventricular injection. Pretreatment of mice with EAG (0.1%) for 4 weeks significantly blocked the Abeta(1-42)-induced impairment in passive avoidance performance. Next, mice were fed with chow mixed with various doses of decursinol for 4 weeks before intracerebroventricular injection of Abeta(1-42) (410 pmol). Pretreatment of mice with decursinol (0.001%, 0.002%, and 0.004%) for 4 weeks significantly attenuated the Abeta(1-42)-induced impairment in passive avoidance performance. Decursinol (0.004%) also significantly blunted the Abeta(1-42)-induced decrease in alternation behavior (spatial working memory) in the Y-maze test without change in general locomotor activity. These findings suggest that EAG or decursinol may have preventive effect against memory impairment related with Abeta of Alzheimers disease.

Effects of ginseng saponin administered intraperitoneally on the hypothalamo-pituitary-adrenal axis in mice.

Intraperitoneal injection of ginseng total saponin (GTS; 5 and 20 mg/kg) raised plasma corticosterone levels in mice. However, interestingly, pretreatment of animals with the same doses of GTS (5 and 20 mg/kg) significantly attenuated the immobilization stress-induced increase in plasma corticosterone levels. Of the ginsenosides Rb(1), Rb(2), Rc, Rd, Re, Rf, Rg(1), 20(S)-Rg(3), and 20(R)-Rg(3) injected intraperitoneally at doses of 0.1-2 mg/kg, Rc (2 mg/kg) significantly inhibited the immobilization stress-induced increase in plasma corticosterone levels. GTS and Rc administered intraperitoneally did not affect the immobilization stress-induced elevation of plasma adrenocorticotropic hormone (ACTH) level. Pretreatment with GTS and Rc significantly attenuated the increase in plasma corticosterone levels induced by intraperitoneal injection of ACTH (30 microg/kg). These results suggest that GTS and Rc inhibit the immobilization stress-induced increase in plasma corticosterone levels by blocking ACTH action in the adrenal gland. Ginseng may be proposed to be useful for treatment of stress related disorders.

The repeated immobilization stress increases IL-1β immunoreactivities in only neuron, but not astrocyte or microglia in hippocampal CA1 region, striatum and paraventricular nucleus

The effect of repeated immobilization stress (RIS) on the expression of interleukin-1beta (IL-1beta) and types of cells that express IL-1beta in hippocampal CA1 region, striatum and paraventricular nucleus (PVN) were investigated in ICR mice. The RIS was induced daily for 2h for 4 consecutive days. In the immunohistochemical study, RIS increased IL-1beta immunoreactivities (IR) in the hippocampal CA1 region and striatum and PVN. The RIS also increased glial fibrillary acidic protein (GFAP) IR and complement receptor type 3 (OX-42) IR in the hippocampal CA1 regions and striatum but not PVN. In confocal immunofluorescence study, the IL-1beta IR increased by RIS were colocalized with only NeuN, but not GFAP or OX-42 in the hippocampal CA1 region, striatum and PVN. Our results indicate that RIS increases IL-1beta IR on neuron, but not astrocyte or microglia in the hippocampal CA1 region, striatum and PVN, suggesting that the IL-1beta IR on neuron may play an important role during RIS. In addition, GFAP and OX-42 increased by RIS may be involved indirectly in playing another role in the hippocampal CA1 region and striatum during RIS.

Behavioral and Neuropathologic Changes Induced by Central Injection of Carboxyl-Terminal Fragment of β-Amyloid Precursor Protein in Mice

Abstract: Expression of the carboxyl‐terminal fragment (CT) of the β‐amyloid precursor protein (APP) in transgenic animals has been linked with neurotoxicity. However, it remains to be clarified whether the neurotoxicity is caused by β‐amyloid proteins (Aβs) derived from CT or by CT itself. To study the in vivo neurotoxicity of CT, mice were given a single intracerebroventricular injection of a recombinant 105‐amino acid CT (CT105; 68.5–685 pmol, intracerebroventricularly), and changes in behavior and in brain histology were examined. Animals given CT105 (410 or 685 pmol, intracerebroventricularly) showed a dose‐dependent impairment in the passive avoidance performance, whereas boiled CT105 had no effect. CT105 (685 pmol, intracerebroventricularly) induced reactive gliosis in neocortex and hippocampus and neurodegeneration in neocortex. These results indicate that centrally administered CT105 induces behavioral impairment and neuropathologic changes, suggesting a direct toxic effect of CT105 per se.

The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock

Compound K (C‐K), a protopanaxadiol ginsenoside metabolite, was previously shown to have immunomodulatory effects. Here, we describe a novel therapeutic role for C‐K in the treatment of lethal sepsis through the modulation of Toll‐like receptor (TLR) 4‐associated signalling via glucocorticoid receptor (GR) binding. In mononuclear phagocytes, C‐K significantly repressed the activation of TLR4/lipopolysaccharide (LPS)‐induced NF‐κB and mitogen‐activated protein kinases (MAPKs), as well as the secretion of pro‐inflammatory cytokines. However C‐K did not affect the TLR3‐mediated expression of interferon‐β or the nuclear translocation of IRF‐3. C‐K competed with the synthetic glucocorticoid dexamethasone for binding to GR and activated glucocorticoid responsive element (GRE)‐containing reporter plasmids in a dose‐dependent manner. In addition, the blockade of GR with either the GR antagonist RU486 or a siRNA against GR substantially reversed the anti‐inflammatory effects of C‐K. Furthermore, TLR4‐dependent repression of inflammatory response genes by C‐K was mediated through the disruption of p65/interferon regulatory factor complexes. Importantly, pre‐ or post‐treatment with C‐K significantly rescued mice from Gram‐negative bacterial LPS‐induced lethal shock by lowering their systemic inflammatory cytokine levels and by reversing the lethal sequelae of sepsis. Collectively, these results demonstrate that C‐K, as a functional ligand of GR, regulates distinct TLR4‐mediated inflammatory responses, and suggest a novel therapy for Gram‐negative septic shock.

The effect of TNFα secreted from macrophages activated by titanium particles on osteogenic activity regulated by WNT/BMP signaling in osteoprogenitor cells

Wear particles are the major cause of osteolysis associated with failure of implant following total joint replacement. During this pathologic process, activated macrophages mediate inflammatory responses to increase osteoclastogenesis, leading to enhanced bone resorption. In osteolysis caused by wear particles, osteoprogenitors present along with macrophages at the implant interface may play significant roles in bone regeneration and implant osteointegration. Although the direct effects of wear particles on osteoblasts have been addressed recently, the role of activated macrophages in regulation of osteogenic activity of osteoblasts has scarcely been studied. In the present study, we examined the molecular communication between macrophages and osteoprogenitor cells that may explain the effect of wear particles on impaired bone forming activity in inflammatory bone diseases. It has been demonstrated that conditioned medium of macrophages challenged with titanium particles (Ti CM) suppresses early and late differentiation markers of osteoprogenitors, including alkaline phosphatase (ALP) activity, collagen synthesis, matrix mineralization and expression of osteocalcin and Runx2. Moreover, bone forming signals such as WNT and BMP signaling pathways were inhibited by Ti CM. Interestingly, TNFα was identified as a predominant factor in Ti CM to suppress osteogenic activity as well as WNT and BMP signaling activity. Furthermore, Ti CM or TNFα induces the expression of sclerostin (SOST) which is able to inhibit WNT and BMP signaling pathways. It was determined that over-expression of SOST suppressed ALP activity, whereas the inhibition of SOST by siRNA partially restored the effect of Ti CM on ALP activity. This study highlights the role of activated macrophages in regulation of impaired osteogenic activity seen in inflammatory conditions and provides a potential mechanism for autocrine regulation of WNT and BMP signaling mediated by TNFα via induction of SOST in osteprogenitor cells.

Effect of Zen Meditation on serum nitric oxide activity and lipid peroxidation.

This study was designed to investigate the effect of Zen Meditation on serum nitric oxide activity (NO) and oxidative stress (lipid peroxidation). The experimental group included 20 subjects who had practiced the Zen Meditation program in Meditation Center located in Seoul, South Korea. The control group included 20 subjects who did not practice any formal stress management technique and were age and sex matched with experimental group. To provide an assessment of nitric oxide production, the serum level of nitrate/nitrite was determined using the Griess reagent. Malondialdehyde (MDA) concentration was measured as a convenient index of lipid peroxidation by thiobarbituric acid (TBA) method. Meditation group showed a significant higher level of serum nitrate+nitrite concentration and a significant reduced level of serum malondialdehyde (MDA) than control group. A comprehensive randomized controlled trial should be performed to prove the causal relationship between meditation and level of nitric oxide or oxidative stress in reducing cardiovascular risk factors.

The inhibitory effect of ginseng saponins on the stress-induced plasma interleukin-6 level in mice.

The effect of ginseng saponins on plasma interleukin-6 (IL-6) in non-stressed and immobilization-stressed mice were investigated. Ginseng total saponins, ginsenosides Rb2, Rg1 and Rd administered intraperitoneally attenuated the immobilization stress-induced increase in plasma IL-6 level. But, intracerebroventricular injection of each ginsenoside did not affect plasma IL-6 level induced by immobilization stress. Ginsenosides Rb2, Rd and Rg1 significantly decreased norepinephrine and/or epinephrine-induced increase of IL-6 level in macrophage cell line (RAW 264.7). Thus, it can be suggested that the inhibitory action of ginseng saponins against the immobilization stress-induced increase of plasma IL-6 level would be in periphery; at least in part, mediated by blocking norepinephrine- and/or epinephrine-induced increase of IL-6 level in macrophage rather than in the brain. Ginseng saponins might be proposed as a possible candidate in the research or therapeutic modulation of stress-related disorders.