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      Behavioral despair associated with a mouse model of Crohn's disease: Role of nitric oxide pathway.

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          Abstract

          Crohn's disease (CD) is associated with increased psychiatric co-morbidities. Nitric oxide (NO) is implicated in inflammation and tissue injury in CD, and it may also play a central role in pathogenesis of the accompanying behavioral despair. This study investigated the role of the NO pathway in behavioral despair associated with a mouse model of CD. Colitis was induced by intrarectal (i.r.) injection of 2,4,6-trinitrobenzenesulfonic acid (10mg TNBS in 50% ethanol). Forced swimming test (FST), pharmacological studies and tissues collection were performed 72 h following TNBS administration. To address a possible inflammatory origin for the behavioral despair following colitis induction, tumor necrosis factor-alpha (TNF-α) level was measured in both the hippocampal and colonic tissue samples. In parallel, hippocampal inducible nitric oxide synthase (iNOS) and nitrite level were evaluated. Pharmacological studies targeting the NO pathway were performed 30-60 min before behavioral test. Colitis was confirmed by increased colonic TNF-α level and microscopic score. Colitic mice demonstrated a significantly higher immobility time in the FST associated to a significant increase of hippocampal TNF-α, iNOS expression and nitrite content. Acute NOS inhibition using either Nω-nitro-l-arginine methyl ester (a non-specific NOS inhibitor) or aminoguanidine hydrochloride (a specific iNOS inhibitor) decreased the immobility time in colitic groups. Moreover, acute treatment with both NOS inhibitors decreased the TNF-α level and nitrite content in the hippocampal samples. This study suggests that the NO pathway may be involved in the behavioral effects in the mouse TNBS model of CD. These findings endow new insights into the gut-brain communication during the development of colonic inflammation, which may ultimately lead to improved therapeutic strategies to combat behavior changes associated with gastrointestinal disorders.

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          Author and article information

          Journal
          Prog. Neuropsychopharmacol. Biol. Psychiatry
          Progress in neuro-psychopharmacology & biological psychiatry
          Elsevier BV
          1878-4216
          0278-5846
          Jan 04 2016
          : 64
          Affiliations
          [1 ] Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran; Brain and Spinal Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
          [2 ] Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran; Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, 1050, avenue de la Médecine, Québec City, Québec, Canada.
          [3 ] Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, 1050, avenue de la Médecine, Québec City, Québec, Canada; Institut universitaire en santé mentale de Québec, 2601, Chemin de la Canardière, Québec City, Québec, Canada.
          [4 ] Brain and Spinal Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
          [5 ] Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
          [6 ] Department of Pathology, Urmia University of Medical Science, Urmia, Iran.
          [7 ] Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
          [8 ] Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Internal Medicine section of Gastroenterology, and Inflammatory Bowel Disease Clinical & Research Center, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: jean-eric.ghia@umanitoba.ca.
          Article
          S0278-5846(15)30024-5
          10.1016/j.pnpbp.2015.08.004
          26268932
          2d58c899-064d-4805-a143-6b2b0de6670b
          History

          TNF-α,Behavioral despair,Inflammatory bowel disease,Nitric oxide

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