Effects of pentoxifylline, 7-nitroindazole, and imipramine on tumor necrosis factor-α and indoleamine 2,3-dioxygenase enzyme activity in the hippocampus and frontal cortex of chronic mild-stress-exposed rats
Authors Mohamed B, Aboul-Fotouh S, Ibrahim EA, Shehata H, Mansour AA, Yassin N, El-Eraky W, Abdel-Tawab AM
Received 1 December 2012
Accepted for publication 7 January 2013
Published 24 May 2013 Volume 2013:9 Pages 697—708
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Bassim MSA Mohamed,1,6 Sawsan Aboul-Fotouh,2,5 Eman A Ibrahim,3 Hanan Shehata,4 Amal A Mansour,4 Nemat AZ Yassin,1 Wafaa El-Eraky,1 Ahmed M Abdel-Tawab2,5
1Department of Pharmacology, National Research Centre, Cairo, Egypt; 2Department of Pharmacology, 3Department of Pathology, 4Department of Medical Biochemistry and Molecular Biology, 5Clinical Pharmacology Unit, Ain Shams University, Cairo, Egypt; 6Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada
Objectives: This study aimed to investigate the role of tumor necrosis factor (TNF)-α and the neuronal nitric oxide synthase enzyme in dysregulation of indoleamine 2,3-dioxygenase (IDO) enzyme, and hence serotonin availability in chronic mild stress (CMS), an animal model of depression.
Methods: Rats were divided into five groups: two control and CMS-exposed for 6 weeks, and another three groups exposed to CMS and administered pentoxifylline 50 mg/kg/day intraperitoneally, 7-nitroindazole 40 mg/kg/day subcutaneously, or imipramine 20 mg/kg/day intraperitoneally for the previous 3 CMS weeks. Rats were assessed for neurochemical and immunohistochemical abnormalities.
Results: Pentoxifylline-, 7-nitroindazole-, and imipramine-treated rats showed amelioration of CMS-induced behavioral deficits that was accompanied by significant reduction in kynurenine/serotonin molar ratio and nitrates/nitrites in frontal cortex and hippocampus. In the pentoxifylline and 7-nitroindazole groups, serum TNF-α was reduced relative to the CMS group (18.54 ± 0.85 and 19.16 ± 1.54 vs 26.20 ± 1.83 pg/mL, respectively; P < 0.05). Exposure to CMS increased TNF-α and IDO immunohistochemical staining scores in both hippocampus and midbrain raphe nuclei. 7-Nitroindazole and pentoxifylline significantly (P < 0.05) reduced TNF-α immunostaining in hippocampus and raphe nuclei, with significant (P < 0.01) reduction of IDO immunostaining in raphe nuclei. Likewise, imipramine reduced TNF-α immunostaining (P < 0.05) in hippocampus.
Conclusion: Neuronal nitric oxide synthase and TNF-α may play a concerted role in modulating IDO enzyme activity in CMS-exposed rats and provide additional evidence for possible alternative approaches to switch the neurobiological processes in depression.
Keywords: chronic mild stress, TNF-α, kynurenine, serotonin, nNOS, immunohistochemistry
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]