Abstract
N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride, was examined for its effect on TNF-α production by human myeloid THP-1 cells stimulated with lipopolysaccharide (LPS). N2733 inhibited LPS-induced release of TNF-α from THP-1 cells with an IC50 of 11 μM. N2733 did not affect the cell viability at the concentration of 50 μM or 100 μM. This indicates that N2733 is a potent inhibitor for TNF-α 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-α within 1 hr. Treatment of these mice with N2733 (100 mg/kg×2, i.p.) decreased the serum level of TNF-α 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-α production, and this response is associated with an improvement in the survival rate of endotoxemic mice.
