Efeito do resveratrol per se e associado à cetamina: avaliação comportamental e de marcadores bioquímicos em camundongos

Abstract

Schizophrenia is a serious and chronic mental illness, which affects approximately 1% of the world's population. It is characterized by positive, negative and cognitive symptoms, which are associated to hyperactivation of the dopaminergic mesolimbic pathway and hypoactivation of the mesocortical pathway, respectively. The conventional treatment for schizophrenia consists of the use of typical and atypical antipsychotics, which are not always effective for all symptoms of the disease and around 20-30% of patients do not respond adequately to this treatment. Then, it is important to search for new treatments and/or therapeutic adjuvants that can be used clinically. Ketamine, a non-competitive NMDA receptor antagonist, is used as a pharmacological agent to cause schizophrenia-like behavior in preclinical models. Literature data demonstrate that the resveratrol (3,5,4′-trihydroxy-transstilbene), a polyphenol found in grapes and red wine, antioxidant, anti-inflammatory and neuroprotective effects. Studies demonstrate that resveratrol modifies dopaminergic markers in rodents increasing the availability of monoamines including dopamine. However, little is known about its effects in experimental models of pathologies where the dopaminergic pathways are altered, such as in schizophrenia. This study aimed to investigate if resveratrol (at different doses) could potentiate the effects of a low dose of ketamine in schizophrenialike symptoms in mice. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30 or 100 mg/kg) from day 8 to day 14 of the experimental period, both intraperitoneally. Stereotyped behavior, locomotor activity, social interaction, special (Y-maze) and non-spatial (novel object recognition test – NORT) memory were quantified, as well as ex vivo analysis of MAO activity, IL-6 levels and oxidative markers (TBARS and total thiol) in brain tissues. Resveratrol (100 mg/kg) alone reduced locomotor activity in the open field, new object exploration time in NORT and MAO-A activity in the striatum. All of these effects were not maintained when resveratrol was associated with ketamine. In mice treated with ketamine+resveratrol 100 mg/kg, there was a decrease in MAO-A activity in the cortex and ketamine reduced the number of stereotyped behavior attacks on the 8th day of the experimental period. No significant changes were found in IL-6 levels or oxidative markers. In conclusion, resveratrol does not appear to produce significant changes in the ketamine-induced model of schizophrenia-like symptoms in mice, however, the effects of resveratrol per se on locomotion and NORT should be further studied.