Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Aβ) has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD.</p> <p>Methods</p> <p>In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS) using immunohistochemistry, ELISA, behavioral tests and Western blotting.</p> <p>Results</p> <p>Intraperitoneal injection of LPS, (250 μg/kg) induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 μg/kg, 3 or 7 times) resulted in an accumulation of Aβ_1–42in the hippocampus and cerebralcortex of mice brains through increased β- and γ-secretase activities accompanied with the increased expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and generation of Aβ_1–42as well as activation of astrocytes <it>in vivo</it>. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally), an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death <it>in vivo</it>. Sulindac sulfide (12.5–50 μM) also suppressed LPS (1 μg/ml)-induced amyloidogenesis in cultured neurons and astrocytes <it>in vitro</it>.</p> <p>Conclusion</p> <p>This study suggests that neuro-inflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.</p

A multicenter, prospective, randomized, controlled trial evaluating the safety and efficacy of intracoronary cell infusion mobilized with granulocyte colony-stimulating factor and darbepoetin after acute myocardial infarction: study design and rationale of the 'MAGIC cell-5-combination cytokine trial'

<p>Abstract</p> <p>Background</p> <p>Bone marrow derived stem/progenitor cell transplantation after acute myocardial infarction is safe and effective for improving left ventricular systolic function. However, the improvement of left ventricular systolic function is limited. This study will evaluate novel stem/progenitor cell therapy with combination cytokine treatment of the long-acting erythropoietin analogue, darbepoetin, and granulocyte colony-stimulating factor (G-CSF) in patients with acute myocardial infarction.</p> <p>Methods</p> <p>The 'MAGIC Cell-5-Combination Cytokine Trial' is a multicenter, prospective, randomized, 3-arm, controlled trial with blind evaluation of the endpoints. A total of 116 patients will randomly receive one of the following three treatments: an intravenous darbepoetin infusion and intracoronary infusion of peripheral blood stem cells mobilized with G-CSF (n = 58), an intracoronary infusion of peripheral blood stem cells mobilized with G-CSF alone (n = 29), or conventional therapy (n = 29) at phase I. Patients with left ventricular ejection fraction < 45% at 6 months, in the patients who received stem cell therapy at phase I, will receive repeated cell therapy at phase II. The objectives of this study are to evaluate the safety and efficacy of combination cytokine therapy with erythropoietin and G-CSF (phase I) and repeated progenitor/stem cell treatment (phase II).</p> <p>Discussion</p> <p>This is the first study to evaluate the safety and efficacy of combination cytokine based progenitor/stem cell treatment.</p> <p>Trial registration</p> <p><url>http://www.ClinicalTrials.gov</url> identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00501917">NCT00501917</a>.</p

Polymorphisms in Genes That Regulate Cyclosporine Metabolism Affect Cyclosporine Blood Levels and Clinical Outcomes in Patients Who Receive Allogeneic Hematopoietic Stem Cell Transplantation

In patients who received allogeneic hematopoietic stem cell transplantation (HSCT), we investigated the correlations between single nucleotide polymorphisms (SNPs) in genes that regulate cyclosporine metabolism and clinical outcomes. All patients received sibling-matched HSCT. DNA samples of patients and donors were analyzed for 4 SNPs: MDR1 +1236C>T (rs1128503), +2677G>T>A (rs2032582), +3435C>T (rs1045642), and CYP3A5 +6986G>A (rs776746). A total of 156 patients (median age 40 years) were analyzed. Nineteen patients received HSCT for nonmalignant disease. The CYP3A5 +6986AA genotype was associated with a high cyclosporine blood level after transplantation. However, this genotype was not related to any particular clinical outcome. In contrast, the MDR1 +1236C>T SNP was correlated with specific clinical outcomes. When neither the donor nor the recipient had the CC genotype of MDR1 +1236, patients had lower creatinine levels (P < .001) and less transplantation-related mortality (TRM) (P = .012). These patients also showed longer overall survival (OS) in both univariate (P = .003) and multivariate (P = .003) analyses. Although the CYP3A5 +6986AA genotype was correlated with a high blood cyclosporine concentration, lack of the MDR1 +1236CC genotype in both the donor and recipient was correlated with less TRM and a longer OS in patients who received allogeneic HSCT

Study design and rationale of 'Influence of Cilostazol-based triple anti-platelet therapy on ischemic complication after drug-eluting stent implantation (CILON-T)' study: A multicenter randomized trial evaluating the efficacy of Cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease

<p>Abstract</p> <p>Background</p> <p>Current guidelines recommend dual anti-platelet therapy, aspirin and clopidogrel, for patients treated with drug-eluting stent for coronary heart disease. In a few small trials, addition of cilostazol on dual anti-platelet therapy (triple anti-platelet therapy) showed better late luminal loss. In the real-world unselected patients with coronary heart disease, however, the effect of cilostazol on platelet reactivity and ischemic vascular events after drug-eluting stent implantation has not been tested. It is also controversial whether there is a significant interaction between lipophilic statin and clopidogrel.</p> <p>Methods/Design</p> <p>CILON-T trial was a prospective, randomized, open-label, multi-center, near-all-comer trial to demonstrate the superiority of triple anti-platelet therapy to dual anti-platelet therapy in reducing 6 months' major adverse cardiovascular/cerebrovascular events, composite of cardiac death, nonfatal myocardial infarction, target lesion revascularization and ischemic stroke. It also tested whether triple anti-platelet therapy is superior to dual anti-platelet therapy in inhibiting platelet reactivity in patients receiving percutaneous coronary intervention with drug-eluting stent. Total 960 patients were randomized to receive either dual anti-platelet therapy or triple anti-platelet therapy for 6 months and also, randomly stratified to either lipophilic statin (atorvastatin) or non-lipophilic statin (rosuvastatin) indefinitely. Secondary endpoints included all components of major adverse cardiovascular/cerebrovascular events, platelet reactivity as assessed by VerifyNow P2Y12 assay, effect of statin on major adverse cardiovascular/cerebrovascular events, bleeding complications, and albumin-to-creatinine ratio to test the nephroprotective effect of cilostazol. Major adverse cardiovascular/cerebrovascular events will also be checked at 1, 2, and 3 years to test the 'legacy' effect of triple anti-platelet therapy that was prescribed for only 6 months after percutaneous coronary intervention.</p> <p>Discussion</p> <p>CILON-T trial will give powerful insight into whether triple anti-platelet therapy is superior to dual anti-platelet therapy in reducing ischemic events and platelet reactivity in the real-world unselected patients treated with drug-eluting stent for coronary heart disease. Also, it will verify the laboratory and clinical significance of drug interaction between lipophilic statin and clopidogrel.</p> <p>Trial Registration</p> <p>National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier# NCT00776828).</p