T-5224

Resume

Background

Sepsis is a potentially fatal syndrome mediated by an early [eg, tumor necrosis factor-alpha (TNF-α)] and late [high-mobility group box 1 (HMGB-1)] cytokine response to infection. Sepsis-induced acute kidney injury (ARI) is associated with high mortality.

C-Fos / activator protein-1 (AP-1) controls the transactivation of pro-inflammatory cytokines through the binding of AP-1 in the promoter region. T-5224 is a de novo small molecule c-Fos / AP-1 inhibitor that controls the gene expression of multiple pro-inflammatory cytokines. We investigated whether T-5224, a selective c-Fos / AP-1 inhibitor, improves survival in lethal lipopolysaccharide (LPS) -induced AKI by inhibiting early (TNF-α) and late (HMGB-) pro-inflammatory cytokine responses. 1).

Methods

The mice were divided into four groups (control, LPS, LPS + T-5224, and T-5224 only). Control mice were administered a polyvinylpyrrolidone (PVP) solution orally, immediately after intraperitoneal (i.p.) injection of saline. LPS mice were administered a PVP solution orally immediately after i.p. Injection of LPS (10 mg/kg). LPS + T-5224 mice were administered T-5224 orally (300 mg / kg) immediately after i.p. LPS injection.

T-5224 mice were administered T-5224 orally (300 mg/kg) after i.p. saline injection. Serum concentrations of TNF-α, HMBG-1, and interleukin (IL) -10 were measured by an enzyme-linked immunosorbent assay (ELISA). Serum blood urea nitrogen (BUN) and creatinine concentrations were commercially analyzed. Finally, a histological examination of the kidney was performed.

Results

Treatment with T-5224 decreased serum levels of TNF-α and HMGB-1 and increased survival after LPS injection. In addition, treatment with T-5224 decreased serum BUN and creatinine levels, but increased serum IL-10 levels. LPS-induced pathological changes in the kidney were attenuated by treatment with T-5224.

Conclusions

These results suggest that T-5224, a selective c-Fos / AP-1 inhibitor, inhibits the expression of early and late pro-inflammatory cytokines, protecting mice from LPS-induced lethality. T-5224 is a potential approach to decrease lethality in sepsis-induced ARF.

Keywords:

T-5224, C-Fos / activator protein-1, Lipopolysaccharide (LPS), Tumor necrosis factor-alpha (TNF-α), Interleukin-10 (IL-10), High mobility group chart-1 (HMGB-1)

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