Combination therapy with cilostazol, aripiprazole, and donepezil protects neuronal cells from β-amyloid neurotoxicity through synergistically enhanced SIRT1 expression

Alzheimer’s disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aβ accumulation, GSK-3β, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased β-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, β-catenin and a7-nicotinic cholinergic receptors in neuronal cells in the presence of Aβ1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole.

Combination therapy with cilostazol, aripiprazole, and donepezil protects neuronal cells from β-amyloid neurotoxicity through synergistically enhanced SIRT1 expression

Alzheimer’s disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aβ accumulation, GSK-3β, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased β-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, β-catenin and a7-nicotinic cholinergic receptors in neuronal cells in the presence of Aβ1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole.

Docosahexaenoic Acid Inhibits Expression of Fibrotic Mediators in Mice With Chronic Pancreatitis

BACKGROUND: Chronic pancreatitis (CP) is an irreversible progressive disease that destroys exocrine parenchyma, which are replaced by fibrous tissue. As pancreatic fibrosis is a key feature of CP, reducing fibrotic protein content in the pancreas is crucial for preventing CP. Studies suggest that NF-κB facilitates the expression of fibrotic mediators in pancreas and protein kinase C-δ (PKC-δ) regulates NF-κB activation in stimulated pancreatic acinar cells. Docosahexaenoic acid (DHA) is an omega-3 fatty acid having anti-inflammatory and anti-fibrotic effects. It has been shown to inhibit NF-κB activity in cerulein-stimulated pancreatic acinar cells which is a cellular model of CP. In the present study, we investigated if DHA inhibits expression of fibrotic mediators by reducing PKC-δ and NF-κB expression in mouse pancreatic tissues with CP.METHODS: For six weeks, mice were weekly induced for acute pancreatitis to develop CP. Furthermore, acute pancreatitis was induced by hourly intraperitoneal injections of cerulein (50 μg/kg × 7). Mice were administered DHA (10 μM) via drinking water before and after CP induction.RESULTS: Cerulein-induced pancreatic damages like decreased pancreatic weight/total body weight, leukocyte infiltration, necrosis of acinar cells, and vacuolization were found to be inhibited by DHA. Additionally, DHA inhibited cerulein-induced fibrotic mediators like alpha-smooth muscle actin and fibronectin in pancreas. DHA reduced expression of PKC-δ and NF-κB p65 in pancreatic tissues of cerulein-treated mice.CONCLUSIONS: DHA may be beneficial in preventing CP by suppressing pancreatic expression of fibrotic mediators.

The Effects of (66)Ho-Loaded Radioactive Stent in a Porcine Model

BACKGROUND AND OBJECTIVES: Vascular brachytherpy known to be an effective method in the prevention of restenosis following percutaneous coronary intervention (PCI). In this study we observed the effects of a radioisotope-loaded stent in a porcine model. MATERIALS AND METHODS: Holmium-166 ((166)Ho) was loaded onto the stent surface using impregnated polyurethane, and placed the stents into 7 porcine coronary arteries. Four weeks after stent overdilation injury, histopathological examination was performed. RESULTS: The absorbed dose of (166)Ho to the coronary artery, from the 158.5+/-140.9 microCi (166)Ho stent, was about 141 Gy at a depth of 0.5 mm, which was calculated by Monte Carlo EGS 4 Code. The mean external, and internal elastic lamina areas, the luminal and neointimal areas and the histopathological area stenosis in the 7 porcine coronary arteries were 7.6+/-2.8 mm2, 4.7+/-1.6 mm2, 2.4+/-1.4 mm2, 2.3+/-1.6 mm2 and 49.4+/-24.9%, respectively. The histopathological findings revealed remarkable inflammatory reactions and thrombosis in two of the porcine coronary arteries. CONCLUSION: (166)Ho radioactive loaded stents, using impregnated polyurethane, may inhibit neointimal hyperplasia, but the problems of stent thrombosis and inflammation should be solved.

A Clinical Investigation of Community-Acquired Pneumonia in Mokpo Area / 결핵

BACKGROUND: Community-acquired pneumonia(CAP) remains a leading cause of morbidity and mortality worldwide. Recently, the evolution of drug-resistant microorganisms has become a serious problem in CAP management. Specific antimicrobial therapy is the cornerstone of CAP management. However, obtaining an accurate etiologic diagnosis clinically is not easy and empirical antimicrobial treatment is usually administered prior to the correct microbiologic diagnosis. In this study, the clinical usefulness of empirical CAP treatment was investigated. METHODS: A total 35 cases were studied prospectively over a 16-month period in Mokpo Catholic Hospital from Dec. 1995 to Mar. 1997. The microbiologic diagnosis was made by sputum, blood culture, a specific serum antibody test and an immunologic study. RESULTS: The causative organisms were isolated in 10 (30%) out of 33 cases: 8 cases and 1 case on the sputum culture and blood culture respectively, and 1 case by an indirect hemagglutinin test. 12 cases had underlying diseases: pulmonary tuberculosis 4, alcoholism 4, diabetes mellitus 3, and liver cirrhosis 1. Antimicrobial treatment was given empirically and all cases recovered. CONCLUSION: A definite microbiologic diagnosis before commencing the appropriate treatment in CAP is not straightforward. Empirical therapy according to a clinical assessment is important and helpful. However, every effort to make the correct etiologic diagnosis should be taken.