(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: Jong Min Choi, Young Hwa Choi, Seok Kyun Kim, Kyong Hoon Ahn, Jong Hoon Won, Joo Hyuk Lim, You Jin Jang, Sungsook Lee, Dal-Hyun Kim, Dae Kyong Kim
• Journal: Molecules and cells (Mol Cells) Vol. 36 Issue 5 Pg. 400-9 (Nov 2013) ISSN: 0219-1032 [Electronic] Korea (South)
• PMID: 24293010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• Tetrahydroisoquinolines
• YS 49
• Arachidonic Acid
• Phospholipases A2
• Calcium

Topics

• Animals
• Arachidonic Acid (metabolism)
• Calcium (metabolism)
• Cell Line
• Gene Expression Regulation
• Lipopolysaccharides
• Mice
• Phospholipases A2 (genetics, metabolism)
• Phosphorylation (drug effects)
• Signal Transduction (drug effects)
• Tetrahydroisoquinolines (chemistry, pharmacology)