Anti-neuroinflammatory properties of synthetic cryptolepine in human neuroblastoma cells: Possible involvement of NF-¦ÊB and p38 MAPK inhibition

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• 作者：Olumayokun A. Olajide^a ; ^b ; ^{o.a.olajide@hud.ac.uk} ; Harsharan S. Bhatia^b ; Antonio C.P. de Oliveira^b ; ^c ; Colin W. Wright^d ; Bernd L. Fiebich^b ; ^e
• 关键词：Cryptolepis sanguinolenta ; Cryptolepine ; Neuroinflammation ; Cyclooxygenase-2 ; NF-¦ÊB ; p38 MAPK
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：63
• 期：Complete
• 页码：333-339
• 全文大小：708 K

文摘

Cryptolepis sanguinolenta and its bioactive alkaloid, cryptolepine have shown anti-inflammatory activity. However, the underlying mechanism of anti-inflammatory action in neuronal cells has not been investigated. In the present study we evaluated an extract of C.?sanguinolenta (CSE) and cryptolepine (CAS) on neuroinflammation induced with IL-1¦Â in SK-N-SH neuroblastoma cells. We then attempted to elucidate the mechanisms underlying the anti-neuroinflammatory effects of CAS in SK-N-SH cells. Cells were stimulated with 10?U/ml of IL-1¦Â in the presence or absence of different concentrations of CSE (25-200?¦Ìg/ml) and CAS (2.5-20?¦ÌM). After 24?h incubation, culture media were collected to measure the production of PGE₂ and the pro-inflammatory cytokines (TNF¦Á and IL-6). Protein and gene expressions of cyclooxygenase (COX-2) and microsomal prostaglandin synthase-1 (mPGES-1) were studied by immunoblotting and qPCR, respectively. CSE produced significant (p?<?0.05) inhibition of TNF¦Á, IL-6 and PGE₂ production in SK-N-SH cells. Studies on CAS showed significant and dose-dependent inhibition of TNF¦Á, IL-6 and PGE₂ production in IL-1¦Â-stimulated cells without affecting viability. Pre-treatment with CAS (10 and 20?¦ÌM) was also found to inhibit IL-1¦Â-induced protein and gene expressions of COX-2 and mPGES-1. Further studies to determine the mechanism of action of CAS showed inhibition of NF-¦ÊBp65 nuclear translocation, but not I¦ÊB phosphorylation. At 10 and 20?¦ÌM, CAS inhibited IL-1¦Â-induced phosphorylation of p38 MAPK. Studies on the downstream substrate of p38, MAPK-activated protein kinase 2 (MAPKAPK2) showed that CAS produced significant (p?<?0.05) and dose dependent inhibition of MAPKAPK2 phosphorylation in IL-1¦Â-stimulated SK-N-SH cells. This study clearly shows that cryptolepine (CAS) inhibits neuroinflammation through mechanisms involving inhibition of COX-2 and mPGES-1. It is suggested that these actions are probably mediated through NF-¦ÊB and p38 signalling.