title: Effect of the p38 MAPK inhibitor SB-239063 on Lipopolysaccharide-induced psychomotor retardation and peripheral biomarker alterations in rats.
abstract: Lipopolysaccharide (LPS) administration in rats induces a characteristic syndrome termed 'sickness behavior', including profound changes on locomotor activity and circulating stress and inflammatory mediators. The aim of the present investigation was to evaluate whether the behavioral and the peripheral biomarker responses induced by LPS could be modified by acute treatment with the p38 mitogen-activated protein kinase inhibitor SB-239063. Male Sprague-Dawley rats were treated orally either with vehicle or SB-239063 (3, 10 and 30 mg/kg) 1h before an intraperitoneal injection of either saline or LPS 125 μg/kg. Two hours after LPS injection, rats were placed in a novel open field arena for locomotion assessment during both the light and dark periods. Inflammation and stress mediators were evaluated in plasma 2, 3, 5 or 14 h into the dark phase. Pre-treatment with SB-239063 significantly reversed the locomotor deficits induced by LPS injection. Interleukin (IL)-1β, IL-6, IL-10, Granulocyte-Macrophage-Colony Stimulating Factor, Interferon-γ, and C-reactive-protein levels were increased significantly by LPS, but not when LPS was preceded by SB-239063 treatment. LPS significantly decreased growth-hormone and Prolactin, and this effect was attenuated by SB-239063. Tumor Necrosis Factor-α, Adrenocorticotropic Hormone and Corticosterone levels were significantly higher in LPS-treated rats and were not normalized by SB-239063. Thus, we demonstrate that acute treatment with SB-239063 may have ameliorating effects in early changes of LPS-induced sickness behavior and alteration in the peripheral cytokines/hormones. As such, our procedure may offer an opportunity to test the activity of novel anti-inflammatory compounds on specific symptoms of sickness associated with neuroimmune dysfunctions.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline S.p.A., Medicines Research Centre, Verona, Italy. silvia.bison@aptuit.com
authors.forename: Silvia
authors.initials: S
authors.lastname: Bison
authors.forename: Maria
authors.initials: M
authors.lastname: Razzoli
authors.forename: Roberto
authors.initials: R
authors.lastname: Arban
authors.forename: Francesca
authors.initials: F
authors.lastname: Michielin
authors.forename: Simone
authors.initials: S
authors.lastname: Bertani
authors.forename: Lucia
authors.initials: L
authors.lastname: Carboni
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006728:Hormones / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011596:Psychomotor Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D015415:Biomarkers; D006728:Hormones; D007093:Imidazoles; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063