کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5040642 | 1473903 | 2017 | 22 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The isozyme selective phosphodiesterase-4 inhibitor, ABI-4, attenuates the effects of lipopolysaccharide in human cells and rodent models of peripheral and CNS inflammation
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موضوعات مرتبط
علوم زیستی و بیوفناوری
ایمنی شناسی و میکروب شناسی
ایمونولوژی
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چکیده انگلیسی
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 (EC50 â¼Â 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 Ã 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 < 0.05) or in PDE4Bâ/â mice. PDE4B was also shown to modulate brain and plasma levels of TNF-α and IL-1β in aged mice. Aged mice dosed chronically with ABI-4 (0.32 mg/kg) as well as aged PDE4Bâ/â mice, had significantly lower levels of TNF-α and IL-1β in brain and plasma relative to vehicle treated or PDE4+/+ mice. Together these data demonstrate that the PDE4D sparing, PDE4 inhibitor, ABI-4 retains potency and efficacy in exerting anti-inflammatory effects. This mechanism warrants further investigation in human disorders involving neuroinflammation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Brain, Behavior, and Immunity - Volume 64, August 2017, Pages 285-295
Journal: Brain, Behavior, and Immunity - Volume 64, August 2017, Pages 285-295
نویسندگان
Joseph R. Hedde, Ashley N. Hanks, Christopher J. Schmidt, Zoë A. Hughes,