N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride inhibits LPS-induced TNF-alpha production and improves survival in endotoxemic mice.
N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride, was examined for its effect on TNF-alpha production by human myeloid THP-1 cells stimulated with lipopolysaccharide (LPS). N2733 inhibited LPS-induced release of TNF-alpha from THP-1 cells with an IC50 of 11 microM. N2733 did not affect the cell viability at the concentration of 50 microM or 100 microM. This indicates that N2733 is a potent inhibitor for TNF-alpha production without severe cytotoxicity. N2733 was also studied in two murine endotoxin shock models induced with LPS. One model was DBA/2 mice injected with LPS (5.6 mg/kg, i.v.), which increased the serum level of TNF-alpha within 1 hr. Treatment of these mice with N2733 (100 mg/kg x 2, i.p.) decreased the serum level of TNF-alpha significantly. Another model was DBA/2 mice induced with LPS (30 mg/kg, i.v.), which reduced the survival rate to 30% during 7 days. Administrations of 30 mg/kg and 100 mg/kg N2733 (i.v.) restored the survival rates to 60% and 90% respectively. Our data demonstrate that N2733 inhibits LPS-induced TNF-alpha production, and this response is associated with an improvement in the survival rate of endotoxemic mice.
Katsuyama
K
K
Pharmaceutical Research Center, Nisshin Flour Milling Co., Ltd., Saitama, Japan.
Kojima
R
R
Yokoyama
S
S
Yanai
M
M
Sueda
N
N
Sugita
M
M
Momose
K
K
Yamada
H
H
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D051379:Mice; D008811:Mice, Inbred DBA; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000627:therapeutic use*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*