Open AccessThe Synthetic Curcumin Derivative CNB-001 Attenuates Thrombin-Stimulated Microglial Inflammation by Inhibiting the ERK and p38 MAPK Pathways
Author(s) -
Tatsuhiro Akaishi,
Shohei Yamamoto,
Kazuho Abe
Publication year - 2020
Publication title -
biological and pharmaceutical bulletin
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.635
H-Index - 117
eISSN - 1347-5215
pISSN - 0918-6158
DOI - 10.1248/bpb.b19-00699
Subject(s) - mapk/erk pathway , p38 mitogen activated protein kinases , thrombin , kinase , microglia , pharmacology , protein kinase a , signal transduction , chemistry , nitric oxide synthase , curcumin , lipopolysaccharide , microbiology and biotechnology , nitric oxide , inflammation , biology , biochemistry , endocrinology , immunology , platelet
We have recently found that the synthetic curcumin derivative CNB-001 suppresses lipopolysaccharide (LPS)-induced nitric oxide (NO) production in cultured microglia, demonstrating that it exerts anti-neuroinflammatory effects by regulating microglial activation. To explore the molecular mechanisms underlying the anti-inflammatory effect of CNB-001, the present study investigated whether CNB-001 is also effective for microglial NO production induced by other stimulants than LPS. Treatment of primary cultured rat microglia with thrombin, a serine protease that has been proposed as a mediator of cerebrovascular injuries, caused the expression of inducible NO synthase (iNOS) and the production of NO. The thrombin-induced NO production was completely blocked by the presence of SCH-79797, a selective protease-activated receptor 1 (PAR-1) antagonist, suggesting that the effect of thrombin is mediated by PAR-1. CNB-001 (1-10 µM) attenuated the thrombin-induced iNOS expression and NO production without affecting the PAR-1 expression. In addition, thrombin treatment caused rapid phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). The changes in ERK and p38 MAPK were significantly suppressed by the presence of CNB-001. These results demonstrate that CNB-001 suppresses thrombin-stimulated microglial activation by inhibiting the ERK and p38 MAPK pathways.