Efeito antidepressivo da Riparina IV sobre padrões comportamentais e neuroquímicos de camundongos expostos ao modelo de estresse crônico induzido pela administração de corticosterona.

Abstract

Mental disorders have a multifactorial etiology and stress presents as one of the causal factors. In depression, it is suggested that high cortisol concentration contributes directly to the pathology of this disease. Based on these findings, the study aimed to investigate the potential antidepressant effect of Riparin IV (Rip IV) in mice submitted to chronic stress model by repeated corticosterone administration. Female Swiss mice were divided into four groups: control (Control), corticosterone (Cort), Riparin IV (Cort + Rip IV) and fluvoxamine (Cort + Flu). Three groups were administrated with corticosterone (20 mg/kg, subcutaneous) during the 21-day study, while the control group received only saline vehicle. After the 14th day, the groups were administrated the following tested drugs: Riparin IV (50 mg/kg), fluvoxamine (50 mg/kg) or distilled water vehicle, by gavage, one hour after the subcutaneous injections. At the end of dosing schedule, neurobehavioral tests were conducted such as the forced swimming test (FST), the tail suspension test (TST), the open field test (OFT), the elevated plus maze (EPM), the sucrose preference test (SPT), the Y-maze test (YMT), the step-down inhibitory avoidance test (SDIT), the social interaction test (SIT), and the prepulse inhibition test (PPI). Behavioral tests were followed by neuroinflammation, through oxidative stress (malondialdehyde, nitrite/nitrate and reduced glutathione levels, and superoxide dismutase and catalase activities) and cytokine content (TNF-, IFN-, IL-2, IL-4, IL-6 e IL-10), and neuroplasticity (brain-derived neurotrophic factor – BDNF - levels) evaluation through biochemical analysis in the prefrontal cortex, the striatum and the hippocampus. Behavioral tests revealed the development of anxiety/depressive-like behavior with an cognitive deficit in Cort mice as compared to the control. Cort treatment also induced to oxidative stress and neuroinflammation, leading to a decrease of brain-derived neurotrophic factor (BDNF) and neuronal cell death. Rip IV treatment, in a similar manner to the antidepressant Flu, showed an antidepressant-like effect improving cognitive function, reveling its neuroprotective effect regarding oxidative stress, neurogenesis and pro-inflammatory and anti-inflammatory cytokine profile. This antioxidant and anti-inflammatory effect observed indicates Riparin IV as a possible drug in the antidepressant treatment of non-responsive patients related to severe and cognitive symptoms.