1 b-Amyloid peptide (Ab), a 39 ± 43 amino acid peptide, is believed to induce oxidative stress and in¯ammation in the brain, which are postulated to play important roles in the pathogenesis of Alzheimer's disease. Ferulic acid is an antioxidant and anti-in¯ammatory agent derived from plants; therefore, the potential protective activity of ferulic acid against Ab toxicity in vivo was examined. 2 Mice were allowed free access to drinking water (control) or water containing ferulic acid (0.006%). After 4 weeks, Ab1-42 (410 pmol) was administered via intracerebroventricular injection. 3 Injection of control mice with Ab1-42 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 Ab1-42 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). Ab1-42 induced 31% decrease in acetylcholine level in the cortex, which was tended to be ameliorated by ferulic acid. 4 In addition, Ab1-42 increased immunoreactivities of the astrocyte marker glial ®brillary acidic protein (GFAP) and interleukin-1b (IL-1b) in the hippocampus, eects also suppressed by pretreatment with ferulic acid. 5 Administration of ferulic acid per se unexpectedly induced a transient and slight increase in GFAP and IL-1b 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. 6 These results demonstrate that long-term administration of ferulic acid induces resistance to Ab1-42 toxicity in the brain, and suggest that ferulic acid may be a useful chemopreventive agent against Alzheimer's disease.

No abstract

This study showed that cognitive dysfunction independently predicted mortality in the elderly. Cognitive dysfunction should be considered part of identifying the elderly at high risk for mortality.

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.

Material

No abstract

We previously reported the protective effects of long-term administration of ferulic acid against the in vivo toxicity of β-amyloid peptide administered intracerebroventricularly in mice. In the present study, we investigated the effects of ferulic acid in transgenic amyloid precursor protein (APP)swe/presenilin 1 (PS1)dE9 (APP/PS1) mouse model of Alzheimer disease (AD). Chronic (for 6 months from the age of 6 to 12 months) oral administration of ferulic acid at a dose of 5.3 mg/kg/day significantly enhanced the performance in novel-object recognition task, and reduced amyloid deposition and interleukin-1 beta (IL-1β) levels in the frontal cortex. These results suggest that ferulic acid at a certain dosage could be useful for prevention and treatment of AD.Key words β-amyloid peptide; Alzheimer disease; amyloid precursor protein; presenilin 1; ferulic acid Abnormal accumulation of β-amyloid peptide (Aβ) in the brain is regarded to be important in the pathogenesis of Alzheimer disease (AD), a progressive neurodegenerative disorder.1,2) Thus, continuing efforts have been made to develop strategies targeting Aβ for prevention and treatment of AD. activities. We previously reported that long-term (4 weeks) administration of ferulic acid protects against intracerebroventricularly (i.c.v.) administered Aβ1→42-induced learning and memory impairment 8) and astrocyte and microglial activation [8][9][10] in mice. Furthermore, ferulic acid ethyl ester was reported to protect against Aβ1→42-induced oxidative stress both in vitro 11) and in vivo. 12) Ferulic acid was also reported to destabilize preformed Aβ fibrils in vitro. 13)In addition to the i.c.v. injection of Aβ1→42, 8) amyloid precursor protein (APP) transgenic 14) or APP/presenilin 1 (PS1) double transgenic 15) mice have been very useful for evaluation of beneficial effects of substances targeting Aβ in vivo. Thus, in the present study, we wanted to examine the effects of ferulic acid on the APP/PS1 double transgenic mice, extending our previously study on the protective effects of ferulic acid against the i.c.v. administered Aβ toxicity. 8-10) MATeRIAlS AND MeTHODSMice and Ferulic Acid Female APP/PS1 (APPswe/ PS1de9) transgenic mice were obtained from Jackson laboratory (Bar Harbor, Me, U.S.A.). Procedures for animal experiments were approved by the Animal experimentation Committee at Hallym University. Ferulic acid was obtained from Sigma Chemical Co. (St. louis, MO, U.S.A.). Because 0.004% and 0.006% of ferulic acid in the drinking water (with the average water intake per mouse per day of about 6-8 ml) found to be effective in our previous study on the the protective effects of long-term administration of ferulic acid against the in vivo toxicity of β-amyloid peptide administered intracerebroventricularly in mice [8][9][10] was approximately 9-13 mg/kg/d (for 0.004%) and 14-19 mg/kg/d (for 0.006%), we chose the ferulic acid doses of 5.3 and 16 mg/kg/d in the present study. Ferulic acid was administered from 6 months of age for 6 months at 2 different doses (5.3 ...

on behalf of the TOSS-2 InvestigatorsBackground and Purpose-Our goal was to investigate whether initial ischemic lesion pattern can predict stroke recurrence in patients with symptomatic intracranial arterial stenosis. Methods-Of the Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis (TOSS)-2 trial participants, we included patients who underwent diffusion-weighted imaging and fluid attenuation inversion recovery imaging at baseline with a follow-up fluid attenuation inversion recovery imaging at 7 months. Based on the diffusion-weighted imaging findings, we classified the initial ischemic lesion patterns according to location (subcortical versus cortical versus subcorticocortical) and multiplicity (single versus multiple). We also evaluated the occurrence of new ischemic lesions on follow-up fluid attenuation inversion recovery as well as clinical stroke in the symptomatic intracranial arterial stenosis territory. Results-Of 353 patients included in this study, 44 (12.5%) and 13 (3.7%) patients had new ischemic lesions and clinical recurrent stroke in the initial symptomatic intracranial arterial stenosis territory, respectively. On multivariable analysis, the initial lesion patterns of subcorticocortical and multiple lesions were independent predictors of new ischemic lesions in the symptomatic intracranial arterial stenosis territory (OR, 3.01; 95% CI, 1.33-7.01; Pϭ0.03; OR, 2.81; 95% CI, 1.34 -5.9; Pϭ0.006). These patterns also predicted clinical recurrent stroke. Conclusion-Subcorticocortical lesions and multiple lesions are radiological predictors of recurrent ischemic stroke in symptomatic patients with intracranial arterial stenosis. Clinical Trial Registration-URL: www.clinicaltrials.gov. Unique identifier: NCT00130039.