Fluoxetine reverses behavior changes in socially isolated rats: role of the hippocampal GSH-dependent defense system and proinflammatory cytokines

Abstract

Exposure of an organism to chronic social isolation (CSIS) has been shown to have an important role in depression. Fluoxetine (Flx) is a first-line treatment for depression; however, its downstream mechanisms of action beyond serotonergic signaling remain ill-defined. We investigated the effect of 3 weeks of Flx (15 mg/kg/day) treatment on behavioral changes and protein expression/activity of the GSH-dependent defense system, including reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GLR), and glutathione S-transferase (GST), as well as catalase (CAT), in the hippocampus of rats exposed to 6 weeks of CSIS. The subcellular distributions of nuclear factor-κB (NF-κB), as well as, cytosolic IL-1β and IL-6 protein expression, were also determined. CSIS induced depressive- and anxiety-like behaviors, evidenced by a decrease in sucrose preference and an increase in the number of buried marbles. Moreover, CSIS compromised redox homeostasis, targeting enzymes such as GPx, CAT, GST, and caused NF-κB nuclear translocation with a concomitant increase in IL-6 protein expression, without an effect on IL-1β. Flx treatment reversed CSIS-induced depressive- and anxiety-like behaviors, modulated GSH-dependent defense by increasing GLR and GST activity, and suppressed NF-κB activation and cytosolic IL-6 protein expression in socially isolated rats. The present study suggests that changes in the GSH-dependent defense system, NF-κB activation and increased IL-6 protein expression may have a role in social isolation-induced changes in a rat model of depression and anxiety, and contributes to our understanding of the mechanisms that underlie the antidepressant and anti-inflammatory activity of Flx in socially isolated rats.

Role of Interleukin-6 in Depressive Disorder

“…These findings implicated that baseline plasma IL-6 levels might be a biological marker for antidepressant treatment response. These clinical findings are in line with the rodent depression model that showed SSRI (fluoxetine) treatment reversed isolation-induced depressive-like behaviors and suppressed cytosolic IL-6 protein [104]. It should be noted that the early study by Maes et al did not find any effects of tricyclic antidepressants on serum IL-6 levels in MDD patients [105].…”

Gastroprotective and antioxidant effects of fluvoxamine on stress-induced peptic ulcer in rats

“…However, fluvoxamine, being an SSRI drug, inhibits the enzyme CYP1A2, which is an inhibitor of ROS 25, 27. The neuroprotective effect of fluvoxamine was attributed to its potent antioxidant and anti-inflammatory effects 60 . This action was explained by its ability to inhibit NADPH oxidase and nitric oxide synthase 61 .…”

Therapeutic potential of glutathione-enhancers in stress-related psychopathologies

“…Similarly, exposure of adult rats to chronic social defeat (Solanki, Salvi et al 2017) or a chronic regime of variable stressors, including social isolation (Herbet, Korga et al 2017b) reduced GSR protein levels in the hippocampus and prefrontal cortex, respectively. Interestingly, adult rats treated chronically with the antidepressant fluoxetine exhibited enhanced GSH levels and increased GPx and GSR activity in the hippocampus, both in the absence and presence of stress exposure (Perić, Stanisavljević et al 2017), suggesting that enhanced GSH levels may contribute to the reversal of depressive-like behaviors. In addition to reductions in the GSH system, nearly all these studies also reported the development of depressive-like or anxiety-like symptoms following chronic stress exposure, suggesting a potential link between alterations in the GSH system and stress-induced psychopathologies.…”