New mouse model mimicking IFN-related depression in HCV patients

Background: We have previously identified 15 genes (DRIIs) that are associated with the development of severe depressive side effects during the standard therapy with interferon alpha (IFN-α) and ribavirin in the peripheral blood of hepatitis C virus (HCV) infected patients. In the present work, through the direct intracerebroventricular application of IFN and poly(I:C), we developed an animal model mimicking the depression conditions affecting HCV patients, as well as the genetic response in terms of DRIIs and cytokine expression.

Methods: 10 – 12 weeks old C57Bl6/j mice were anesthetized with 1% isoflurane and the cannulae linked to miniosmotic pumps (Alzet 1002, U.S.A.) were implanted into the left lateral ventricle (1 mm lateral to bregma/2.5 mm below brain surface) for administration of normal saline (used as vehicle), recombinant mouse IFN-α (mIFNα) and/or poly(I:C) during 14 days (N = 12 mice/group). After this period, in order to check the depression-like behavior, animals underwent three behavioral tests (open field test to during 20 minutes, tail suspension for test 6 minutes and forced swim test during 6 minutes/session). Then, animals were reanesthetized and decapitated and hippocampus (HP) and prefrontal cortex (PC) were dissected and use to measure the expression of nine of the DRIIs and the pro-inflammatory chemokines Ccl5, Cxcl1 and Timp-1 by RT-PCR.

Results: As depicted by the results of the tail suspension and the forced swim tests, concomitant administration of mIFNα and poly(I:C) promoted a depression-like behavior which was not detectable with the single treatments. In the open field test, a strong tendency to anxious-like behavior was seen. With the exception of Mef2A, the rest of the checked DRIIs (Gch1, Psmb9, Stat1, Ube2l6, Tnfsf10, Dynlty1, Rtp4, Gbp1) showed a significant or strong upregulation, especially with the costimulation treatment and in HP. Similar results were observed in the measurement of the chemokine expression.

Conclusion: Subchronic intracerebroventricular administration of mIFNαA and poly(I:C) in mice may at least partially mimic the neural environment present in depressed-HCV patients undergoing IFN therapy. As suggested by our previous ex vivo studies, the upregulation of selective DRIIs and production of inflammatory cytokines may be involved in the pathophysiological mechanisms underlying IFN-associated depression.