(S)-tetrahydroisoquinoline alkaloid inhibits LPS-induced arachidonic acid release through downregulation of cPLA2 expression

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 exa...

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Published in:Molecules and cells 2013, 36(5), , pp.400-409
Main Authors: Choi, Jong Min, Choi, Young Hwa, Kim, Seok Kyun, Ahn, Kyong Hoon, Won, Jong Hoon, Lim, Joo Hyuk, Jang, You Jin, Lee, Sungsook, Kim, Dal-Hyun, Kim, Dae Kyong
Format: Article
Language:English
Subjects:
Animals
Arachidonic Acid - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biotechnology
Calcium - metabolism
Cell Biology
Cell Line
Gene Expression Regulation
Life Sciences
Lipopolysaccharides
Mice
Phospholipases A2 - genetics
Phospholipases A2 - metabolism
Phosphorylation - drug effects
Signal Transduction - drug effects
Tetrahydroisoquinolines - chemistry
Tetrahydroisoquinolines - pharmacology
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Summary: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 A 2 (cPLA 2 ) 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 cPLA 2 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 cPLA 2 expression in RAW 264.7 cells.
ISSN:1016-8478
0219-1032
DOI:10.1007/s10059-013-0078-x