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

• Published in: Neuropsychiatric disease and treatment Vol. 9; no. default; pp. 697 - 708
• Main Authors: Mohamed, Bassim Msa, Aboul-Fotouh, Sawsan, Ibrahim, Eman A, Shehata, Hanan, Mansour, Amal A, Yassin, Nemat Az, El-Eraky, Wafaa, Abdel-Tawab, Ahmed M
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01-01-2013; Dove Press; Dove Medical Press
• Subjects: Antidepressants; chronic mild stress; Enzymes; immunohistochemistry; kynurenine; Necrosis; Nitric oxide; nNOS; Original Research; Rodents; serotonin; TNF-α; Tumor necrosis factor-TNF; serotonin; kynurenine; immunohistochemistry; TNF-α; chronic mild stress; nNOS
• ISSN: 1176-6328; 1176-6328; 1178-2021
• DOI: 10.2147/NDT.S41020

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.
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.
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.
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.