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

• Published in: Brain, behavior, and immunity Vol. 64; pp. 285 - 295
• Main Authors: Hedde, Joseph R, Hanks, Ashley N, Schmidt, Christopher J, Hughes, Zoë A
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2017
• Subjects: Aging; Allergy and Immunology; Animals; Anti-Inflammatory Agents - administration & dosage; Brain - drug effects; Brain - metabolism; Encephalitis - chemically induced; Encephalitis - drug therapy; Encephalitis - metabolism; Humans; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - metabolism; Inflammation Mediators - metabolism; Isoenzymes - administration & dosage; Lipopolysaccharides; LPS; Male; Mice, Inbred C57BL; Microglia; Microglia - drug effects; Microglia - metabolism; Motivation - drug effects; Neuroinflammation; Phosphodiesterase 4; Phosphodiesterase 4 Inhibitors - administration & dosage; Psychiatry; Rats, Inbred Lew; TSPO; Phosphodiesterase 4; cAMP; LPS; PDE; interleukin 6; experimental autoimmune encephalomyelitis; tumor necrosis factor alpha; Aging; TSPO; Toll-like receptor 4; EAE; Neuroinflammation; IL-1β; PBMC; IL-6; Microglia; adenosine 3′,5′ cyclic monophosphate; interleukin 1 beta; translocator protein; TNF-α; peripheral blood monocyte; phosphodiesterase; lipopolysaccharide; positron emission tomography; TLR4; PET; COPD; chronic obstructive pulmonary disease
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2017.04.015

Highlights • ABI-4 is a novel brain penetrant PDE4D-sparing PDE4 inhibitor. • ABI-4 inhibited LPS stimulated central and peripheral inflammation. • The LPS-induced deficit in motivation was attenuated by ABI-4 and significantly smaller in PDE4B−/− mice. • Inflammation in normal aging was reduced by ABI-4 and was lower in PDE4B−/− mice. • PDE4B is the subtype of PDE4 implicated in the mechanism of action of ABI-4.