The anti-inflammatory effects and mechanisms of compound pre-LBK02

• Main Authors: Lung-Yen Kuo, 郭龍彥
• Other Authors: Tur-Fu Huang
• Format: Others
• Language: zh-TW
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/kbjsy6

碩士 === 國立臺灣大學 === 藥理學研究所 === 105 === Inflammation, usually characterized by swelling, redness, pain and heat, is a crucial function of the innate immune system for protecting the host against pathogens. Upon bacteria invasion, mammalian monocytes/ macrophages release a variety of inflammatory mediators such as pro-inflammatory and cytotoxic cytokines, nitric oxide and reactive oxygen species to defense harmful stimuli, but excessive inflammatory reaction leads to extensive tissue damage and manifestation of pathological states such as multiple sclerosis, asthma, arthritis, atherosclerosis, Alzheumer’s disease and cancer. Hence, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-associated diseases. Under the drug screening process of nstpbp5185 derivatives, we discovered that compound pre-LBK02, a synthetic benzimidazole molecule, possessed anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNF-alpha and IL-6, as well as decreased the production of NO, and we also excluded its cytotoxicity by cell viability and LDH assay. Furthermore, we found that pre-LBK02 attenuates some pathological syndromes of LPS-induced endotoxemia in mice, such as decreasing the cytokine release, protecting the mice from tissue injury in septic conditions. These results suggest the beneficial effects of pre-LBK02 in septic animal models. Regarding protein expression of LPS-stimulated RAW264.7 cells, we observed that the molecular mechanism of pre-LBK02-mediated anti-inflammation is associated with decreasing phosphorylation of MAP kinases such as ERK1/2, JNK and p38. pre-LBK02 also inhibited phosphorylation of Ikappa B alpha and reversed Ikappa B alpha degradation and attenuated the expression of NF-kappaB-related downstream inducible enzymes such as iNOS and COX-2. In addition, we also identified that pre-LBK02 might be a potential anti-inflammatory agent by downregulating phosphorylation of some JAKs/STATs associated with inflammation such as JAK2, STAT5, STAT3. Taken together, these results indicate that pre-LBK02 inhibits LPS-induced inflammation by inhibiting phosphorylation of MAP kinases and Ikappa B alpha and downregulating phosphorylation of some JAKs/STATs.