Inhibition of neuroinflammation by synthetic androstene derivatives incorporating amino acid methyl esters on activated BV-2 microglia.
Androstene derivatives incorporating amino acid methyl esters were prepared, and their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Several compounds exhibited dose-dependent inhibition. The most active compound, methyl ((3S,10R,13S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl)-L-phenylalaninate (10) significantly suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Mechanistic studies revealed that compound 10 markedly inhibits phosphorylation of p38 mitogen-activated protein kinases (MAPKs) and subsequent transcription factor (NF-κB) and activator protein-1 (AP-1) activation. Furthermore, compound 10 decreased LPS-activated microglial neurotoxicity in a condition medium/HT-22 neuroblastoma co-culture model. Taken together, these results suggest 10 is a potential lead compound for the development of a novel therapeutic agent for neurodegenerative diseases.
Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou, 215123 (PR China).
Jing
J
Wu
Juanjuan
J
Du
Ruinan
R
Gu
Li
L
Zhang
Xuechu
X
Zhen
Yuanchao
Y
Li
Hongli
H
Chen
Biao
B
Jiang
Longtai
L
Zheng
D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D000736:Androstenes / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000276:immunology
D000596:Amino Acids; D000736:Androstenes; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2
androstene derivatives; microglia; neuroinflammation; neuroprotection