title: (S)-tetrahydroisoquinoline alkaloid inhibits LPS-induced arachidonic acid release through downregulation of cPLA2 expression.
abstract: Sepsis, a systemic inflammatory response syndrome, remains a potentially lethal condition. (S)-1-α-Naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) is noted as a drug candidate for sepsis. Many studies have demonstrated its significant anti-inflammatory effects. Here we first examined whether CKD712 inhibits lipopolysaccharide (LPS)-induced arachidonic acid (AA) release in the RAW 264.7 mouse monocyte cell line, and subsequently, its inhibitory mechanisms. CKD712 reversed LPS-associated morphological changes in the RAW 264.7 cells, and inhibited LPS-induced release of AA in a concentrationdependent manner. The inhibition was apparently due to the diminished expression of a cytosolic form of phospholipase A2 (cPLA2) by CKD712, resulting from reduced NF-κB activation. Furthermore, CKD712 inhibited the activation of ERK1/2 and SAP/JNK, but not of p38 MAPK. CKD712 had no effect on the activity or phosphorylation of cPLA2 and on calcium influx. Our results collectively suggest that CKD712 inhibits LPS-induced AA release through the inhibition of a MAPKs/NF-κB pathway leading to reduced cPLA2 expression in RAW 264.7 cells.
authors.affiliation: Department of Environmental and Health Chemistry, College of Pharmacy, Chung-Ang University, Seoul, 156-756, Korea.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Choi
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Choi
authors.forename: Seok Kyun
authors.initials: SK
authors.lastname: Kim
authors.forename: Kyong Hoon
authors.initials: KH
authors.lastname: Ahn
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Won
authors.forename: Joo Hyuk
authors.initials: JH
authors.lastname: Lim
authors.forename: You Jin
authors.initials: YJ
authors.lastname: Jang
authors.forename: Sungsook
authors.initials: S
authors.lastname: Lee
authors.forename: Dal-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Dae Kyong
authors.initials: DK
authors.lastname: Kim
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides; D051379:Mice; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008070:Lipopolysaccharides; D044005:Tetrahydroisoquinolines; C090309:YS 49; D016718:Arachidonic Acid; D054467:Phospholipases A2; D002118:Calcium