Prevention effects of ND-07, a novel drug candidate with a potent antioxidative action and anti-inflammatory action, in animal models of severe acute pancreatitis
| Autor: | Ki Baik Hahm, Sung Ig Cho, Byoung Joo Gwag, Kum Suk Kang, Jin Hwan Lee, Chun San An, Bok Sun Yun, Sun Mi Won, Young Ae Lee |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Lipopolysaccharides
Male medicine.medical_specialty Anti-Inflammatory Agents Inflammation Nitric Oxide medicine.disease_cause Benzoates Antioxidants Dinoprostone Cell Line Nitric oxide Mice chemistry.chemical_compound Cell Line Tumor Malondialdehyde Internal medicine Lactate dehydrogenase In Situ Nick-End Labeling medicine Animals Humans Rats Wistar Ceruletide Pharmacology Mice Inbred BALB C L-Lactate Dehydrogenase Pancreatitis Acute Necrotizing Tumor Necrosis Factor-alpha business.industry Lipase medicine.disease Rats Disease Models Animal Endocrinology medicine.anatomical_structure chemistry Amylases Pancreatitis Acute pancreatitis Female medicine.symptom business Pancreas Oxidative stress |
| Zdroj: | European Journal of Pharmacology. 687:28-38 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2012.04.048 |
| Popis: | Oxidative stress and inflammation both play major roles in the development of the acute pancreatitis. Currently, a pancreatic enzyme inhibitor with limited efficacy is only clinically available in a few countries, and antioxidants or non-steroidal anti-inflammatory drugs (NSAIDs) provide only partial tissue protection in acute pancreatitis animal models. Here, we introduce a new drug candidate for treating acute pancreatitis named ND-07 [chemical name: 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid] that exhibits both potent antioxidative and anti-inflammatory activities. In an electron spin resonance (ESR) study, ND-07 almost blocked hydroxyl radical generation as low as 0.05 μM and significantly suppressed DNA oxidation and cell death in a lipopolysaccharide (LPS)-stimulated pancreatic cell line. In a cerulein plus LPS-induced acute pancreatitis model, ND-07 pretreatment showed significant tissue protective effects, with reductions of serum amylase and lipase levels and pancreatic wet weights. ND-07 not only diminished the plasma levels of malondialdehyde (MDA) and nitric oxide but also significantly decreased prostaglandin E₂ (PGE₂) and expression of tumor necrotizing factor-alpha (TNF-α) in the pancreatic tissue. In a severe acute necrotizing pancreatitis model induced by a choline deficient, ethionine-supplemented (CDE) diet, ND-07 dramatically protected the mortality even without any death, providing attenuation of pancreas, lung, and liver damages as well as the reductions in serum levels of lactate dehydrogenase (LDH), amylase and lipase, MDA levels in the plasma and pancreatic tissues, plasma levels of TNF-α, and interleukin-1 (IL-1β). These findings suggest that current dual synergistic action mechanisms of ND-07 might provide a superior protection for acute pancreatitis than conventional drug treatments. |
| Databáze: | OpenAIRE |
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