N2733, 1-[3-(3-Pyridyl)-acryloyl]-2-pyrrolidinone Hydrochloride Inhibits LPS-induced TNF-α Production and Improves Survival in Endotoxemic Mice

Abstract

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.

Suppression of the TRIF-dependent signaling pathway of toll-like receptors by (E)-isopropyl 4-oxo-4-(2-oxopyrrolidin-1-yl)-2-butenoate

“…Several studies have reported that pyrrolidinone derivatives have anti-inflammatory activities (9-11). Rolipram, a type 4 phosphodiesterase inhibitor, and N2733, a pyridyl acryloyl pyrrolidinone, inhibits LPS-induced NF-κB activation (9)(10)(11). Previously, we also demonstrated that the fumaryl pyrrolidinone derivate, IPOP, inhibits TLR2 and TLR4 agonist-induced NF-κB activation and COX-2 expression (8).…”

Suppression of cyclooxygenase-2 expression induced by Toll-like receptor 2 or 4 agonists by (E)-isopropyl 4-oxo-4-(2-oxopyrrolidin-1-yl)-2-butenoate

“…Activation of this transcription factor then induces the expression of pro-inflammatory gene products including COX-2 13 . It has been reported that pyrrolidinone derivatives have anti-inflammatory activities [14][15][16] . Rolipram, a type 4 phosphodiesterase inhibitor, inhibits LPS-induced NF-κB activation and E-selectin, TNF-α, and IL-6 expression 14 .…”

“…Rolipram, a type 4 phosphodiesterase inhibitor, inhibits LPS-induced NF-κB activation and E-selectin, TNF-α, and IL-6 expression 14 . N2733, a pyridyl acryloyl pyrrolidinone, inhibits LPS-induced TNF-α production and IL-1β-induced NF-κB activation and iNOS expression 15,16 . These results suggest that pyrrolidinone derivatives exert their anti-inflammatory activity by regulating the TLR4 signaling pathway.…”

Prostaglandin F2 receptor (FP) signaling regulates Bmp signaling and promotes chondrocyte differentiation

“…They are expressed in variable levels among different tissues and their expression is regulated by various physiological and pathological stimuli [5], providing an additional level of regulation in prostaglandin signaling. For example, LPS treatment highly induced the expressions of EP2 and EP4 receptors [6, 7] in macrophages and these inductions were suggested to be involved in the regulation of TNF-α [8]. In addition, the overexpression of the EP2 receptor in the epidermis of EP2 transgenic mice resulted in enhanced skin tumor formation, proliferation, and blood vessel formation [9].…”