The isozyme selective phosphodiesterase-4 inhibitor, ABI-4, attenuates the effects of lipopolysaccharide in human cells and rodent models of peripheral and CNS inflammation

Abstract Inhibitors of phosphodiesterase-4 (PDE4) have been approved for the treatment of inflammatory disorders, but are associated with dose-limiting nausea and vomiting. These side effects are hypothesized to be mediated by inhibition of the PDE4D isozyme. Here we demonstrate the anti-inflammatory effects of the novel brain penetrant PDE4D-sparing PDE4 inhibitor, ABI-4. ABI-4 was a potent (EC 50  ∼ 14 nM) inhibitor of lipopolysaccharide (LPS) induced TNF-α release from mouse microglia and human PBMCs. ABI-4 (0.32 mg/kg) blocked LPS-induced release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in blood and brain of mice. In a rat model of endotoxin induced uveitis, ABI-4 (0.03–0.3 mg/kg) demonstrated steroid-like efficacy in preventing leucocyte infiltration of the aqueous humor when administered 4 h after LPS. LPS (0.32 mg/kg × 5 days) caused a 30% upregulation of translocator protein (TSPO) binding which was prevented by co-administration of ABI-4 (0.32 mg/kg). In a paradigm to assess motivation, LPS (0.32 mg/kg) reduced the number of rewards received, whereas the effect was significantly blunted in mice dosed with ABI-4 (P