Role of paroxetine in interferon-α-induced immune and behavioural changes in male Wistar rats

Abstract

Treatment with pro-inflammatory cytokine, IFNalpha was documented to result in neuropsychiatric complications including depression and treatment with antidepressant, paroxetine could improve the depressive symptoms. Therefore, the effects of IFNalpha on behaviour and cytokine changes in the whole blood culture and in the prefrontal cortex, hypothalamus and hippocampus areas of the brain in wistar rats were investigated with emphasis on the role of paroxetine in the prevention of depressive behaviour induced by pro-inflammatory cytokines. The group of rats treated with IFNalpha (s.c. 50,000 IU/kg for 3 days/week for 5 weeks) was compared with three other groups; 1) saline control group (s.c. normal saline 0.2 ml/kg/day for 7 weeks), 2) paroxetine control group (paroxetine suspension orally 10 mg/kg/day for 7 weeks) and 3) group treated with paroxetine for 2 weeks followed by IFNalpha for 5 weeks. In open filed, the IFNalpha treated rats showed anxiety behaviour compared to the rats from the other groups. There was no significant difference in home cage emergence test, Morris water maze and object recognition test. There is no significant difference in plasma corticosterone between groups. The pro-inflammatory cytokines (TNFalpha, IL1beta and IFNgamma), were significantly higher whereas the anti-inflammatory cytokine, IL10 was lower in the stimulated whole blood culture of IFNalpha treated rats. In the brain, both pro-inflammatory cytokine IL1beta and anti-inflammatory cytokine IL10 were higher in hypothalamus of the IFNalpha treated rats; by contrast the concentration of IL10 was lowest in hippocampus region of this group compared to the other groups. The paroxetine pretreated rats did not show these cytokine changes following IFNalpha treatment. Thus it appears that paroxetine pretreatment prevents the pro-inflammatory changes in blood and brain following IFNalpha treatment in turn prevents the anxiety behaviour.

Effect of the COX-2 Inhibitor Celecoxib on Behavioural and Immune Changes in an Olfactory Bulbectomised Rat Model of Depression

“…Whole blood was cultured in 24-well Costar plates and for each rat, 2 stimulated culture wells and 2 unstimulated culture wells were prepared. In each well, 250 l of whole blood was incubated at 37 ° C for 48 h with 750 l of RPMI-1640 medium containing 50 g/ml lipopolysaccharide (Sigma) and 10 g/ml concanavalin A (Sigma) for the stimulated cultures [36,37] . RPMI-1640 without mitogens was used for unstimulated cultures.…”

Disruption of Type I-IFN Signaling Decreases Autoimmune Development and Kidney Damage, But Not Anxiety-Like Behaviors in Lupus NZB Mice

“…Such findings are supported by elevated anxiety profile following chronic IFN-α treatments in humans [21], mice [10] and rats [22]. The reasoning for the observed discrepancy for the role of type I-IFN signaling in behavioral deficits in lupus-prone mice is unknown.…”

“…However, a number of factors may contribute to the opposite observations. These include 1) different anxiety paradigms were used in different studies [22]; 2) in addition to type I-IFN, other innate immune mediators such as tumor necrosis factor-α and interleukin-1, which can also contribute to development of anxiety in autoimmune lupus mice [21]. On the other hand, conventional transgenic mice with brain-targeted expression of transgene may change programmed brain development that results in behavioral alterations.…”

Administration of Interferon-Alpha in Mice Provokes Peripheral and Central Modulation of Immune Cells, Accompanied by Behavioral Effects

“…In our experiment, IFN-␣ administration did not induce anxiety-like behavior in this task. However, a coexistence of anxiety with depression has been reported in IFN-␣ -treated patients [10,61] and anxiogenic effects of acute administration of mouse IFN-␣ in rodents have also been observed [50,62] . Here, we used BALB/c mice, which present a naturally high anxiety level [56] .…”

“…IFN-␣ would thus interfere with brain function via secondary effectors such as humoral or cellular peripheral immune components which can in term penetrate the BBB. Regarding the humoral components, IFN-␣ has been shown to induce the secretion of proinflammatory cytokines, which have also been found to be increased in depressed patients [46][47][48] and in rodents [49,50] . Here, we hypothesized that IFN-␣ may have an additional indirect effect by inducing a migratory potential of circulating immune cells into the brain, particularly through increasing expression of adhesion molecules.…”