Development of a murine animal model of depression for repeated dosing with human interferon alpha

Siddegowda, Nagesh Koregala; Rao, Nisha; Andrade, Chittaranjan

doi:10.4103/0019-5545.86815

Cited by 7 publications

(3 citation statements)

References 14 publications

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“…It is reported that, when administrated with murine IFN-α (60,000 IU/kg for 8 consecutive days, intraperitoneal injection), the mice exhibit subtle behavioral changes in the FST, but not TST 35 . hIFN-α-2b (400–1600 IU/g/day for 5–15 days, subcutaneously) significantly increases the immobility in the FST 36 . A more recent study finds that treatment with murine IFN-α (250 IU/day) for 14 days results in a reproducible depression-like state that can be characterized by increased immobility of C57BL6/J mice in TST and FST 37 .…”

Section: Discussionmentioning

confidence: 99%

“…All mice were maintained with a 12-h light/dark cycle, and food and water were provided ad libitum. For drug treatments, three or four mice were housed per cage and hIFN-α-2b was injected into mice for 10 uninterrupted days (1000 IU/g/day, intraperitoneal injection, total volume = 0.2 mL) 36 . hIFN-α-2b was purchased from Sigma and diluted with PBS.…”

Section: Methodsmentioning

confidence: 99%

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Probable involvement of p11 with interferon alpha induced depression

Guo

Zhang

et al. 2016

Sci Rep

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Depression is one of the major side effects of interferon alpha (IFN-α) treatment, but the molecular mechanism underlying IFN-α-induced depression remains unclear. Several studies have shown that the serotonin receptors 5-HTR1b and 5-HTR4 play key roles in the anti-depression effects associated with p11 (S100A10). We investigated the effects of IFN-α on the regulation of p11, 5-HTR1b and 5-HTR4 in mice and human neuroblastoma cells (SH-sy5y). We found that intraperitoneal injection with IFN-α in Balb/c mice resulted in an increased immobility in FST and TST, and potently lowered the protein levels of p11, 5-HTR1b and 5-HTR4 in the hippocampus or cingulate gyrus. IFN-α significantly down-regulated the protein levels of p11, 5-HTR1b and 5-HTR4 in SH-sy5y cells, in a time- and dose-dependent manner. Our study revealed that over-expression of p11 could prevent the IFN-α-induced down-regulation of 5-HTR1b and 5-HTR4. The results indicated that IFN-α treatment resulted in p11 down-regulation, which subsequently decreased 5-HTR1b and 5-HTR4 in vitro or in vivo. Our findings suggested that p11 might be a potential regulator on 5-HTR1b and 5-HTR4 as well as a predictor of or a therapeutic target for IFN-α-induced depression.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Probable involvement of p11 with interferon alpha induced depression

Guo

Zhang

et al. 2016

Sci Rep

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“…For all mouse studies mice were treated with daily subcutaneous injections of 10 4 IU human recombinant interferon alpha 2b (Intron A; Schering Corporation, Kenilworth, NJ). The dose of interferon alpha 2b was chosen based on a search of the literature [18] , [19] . The interferon was reconstituted using sterile water for injection, USP provided by the manufacturer and was stored at 4°C after reconstitution per the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Recombinant Human Interferon Alpha 2b Prevents and Reverses Experimental Pulmonary Hypertension

et al. 2014

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Pulmonary hypertension (PH) is a progressive and fatal disease with no cure. Vascular remodeling in PH involves intraluminal growth of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Cell growth in these lesions is quasi-neoplastic, with evidence of monoclonality, apoptosis resistance and cancer-like metabolic derangements. Herein we tested the effect of human interferon alpha 2b (IFNα), a pleiotropic cytokine and anti-cancer therapeutic, on the development and progression of PH in the rat SU5416/hypoxia (SUH) model and mouse hypoxia model of the disease. In both models IFNα attenuated the development of PH and reversed established PH as assessed by measuring right ventricular systolic pressure and right ventricular hypertrophy. The effect of IFNα was dependent on the type I interferon receptor (IFNAR) since mice lacking a subunit of the IFNAR were not protected by IFNα. Morphometric analysis of pulmonary aterioles from hypoxic mice or SUH rats showed that IFNα inhibited pulmonary vascular remodeling in both models and that IFNα reversed remodeling in SUH rats with established disease. Immunohistochemical staining revealed that IFNα decreased the number of PCNA and Tunel positive cells in the wall of pulmonary arterioles. In vitro, IFNα inhibited proliferation of human pulmonary artery smooth muscle cells and as well as human pulmonary artery endothelial cell proliferation and apoptosis. Together these findings demonstrate that IFNα reverses established experimental PH and provide a rationale for further exploration of the use of IFNα and other immunotherpies in PH.

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Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression

Fitzgibbon

Kerr

Henry

et al. 2019

Brain, Behavior, and Immunity

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Depression is a well-recognised effect of long-term treatment with interferon-alpha (IFN-α), a widely used treatment for chronic viral hepatitis and malignancy. In addition to the emotional disturbances, high incidences of painful symptoms such as headache and joint pain have also been reported following IFN-α treatment. The endocannabinoid system plays an important role in emotional and nociceptive processing, however it is unknown whether repeated IFN-α administration induces alterations in this system. The present study investigated nociceptive responding in the IFN-α-induced mouse model of depression and associated changes in the endocannabinoid system. Furthermore, the effects of modulating peripheral endocannabinoid tone on inflammatory pain-related behaviour in the IFN-α model was examined. Repeated IFN-α administration (8,000IU/g/day) to male C57/Bl6 mice increased immobility in the forced swim test and reduced sucrose preference, without altering body weight gain or locomotor activity, confirming development of the depressivelike phenotype. There was no effect of repeated IFN-α administration on latency to respond in the hot plate test on day 4 or 7 of treatment, however, formalin-evoked nociceptive behaviour was significantly increased in IFN-α treated mice following 8 days of IFN-α administration. 2-Arachidonoyl glycerol (2-AG) levels in the periaqueductal grey (PAG) and rostroventromedial medulla (RVM), and anandamide (AEA) levels in the RVM, were significantly increased in IFN-α-, but not saline-, treated mice following formalin administration. There was no change in endocannabinoid levels in the prefrontal cortex, spinal cord or paw tissue between saline-or IFNα-treated mice in the presence or absence of formalin. Furthermore, repeated IFN-α and/or formalin administration did not alter mRNA expression of genes encoding the endocannabinoid catabolic enzymes (fatty acid amide hydrolyase or monoacylglycerol lipase) or endocannabinoid receptor targets (CB1, CB2 or PPARs) in the brain, spinal cord or paw tissue. Intra plantar administration of PF3845 (1μg/10μl) or MJN110 (1μg/10μl), inhibitors of AEA and 2-AG catabolism respectively, attenuated formalin-evoked hyperalgesia in IFN-α, but not saline-, treated mice. In summary, increasing peripheral endocannabinoid tone attenuates inflammatory hyperalgesia induced following repeated IFN-α administration. These data provide support for the endocannabinoid system in mediating and modulating heightened pain responding associated with IFNα-induced depression.

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Development of a murine animal model of depression for repeated dosing with human interferon alpha

Cited by 7 publications

References 14 publications

Probable involvement of p11 with interferon alpha induced depression

Probable involvement of p11 with interferon alpha induced depression

Recombinant Human Interferon Alpha 2b Prevents and Reverses Experimental Pulmonary Hypertension

Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression

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