Minociclina na prevenção e reversão dos sintomas tipo esquizofrenia induzidos por cetamina em camundongos : possível envolvimento do estresse oxidativo e da via nitrérgica

Abstract

Schizophrenia is a serious mental disorder that affects approximately 1 % of the population over the age of 18 and is able to compromise the thought, will, perception, social interaction and affection. The insufficient effect of current pharmacotherapy on negative symptoms and cognitive deficits reflects our poor understanding of the etiology of schizophrenia. It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a role in the neurobiology of schizophrenia. Preliminary evidence suggests that adjunctive minocycline treatment is efficacious for cognitive and negative symptoms of schizophrenia. Thus, this study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, different groups of animals received ketamine (20 mg/kg) or DMSO (vehicle used in controls) for 14 days, and, from the 8th to 14th day, additionally received minocycline (25 or 50mg/kg), risperidone (0.5 mg / kg) or DMSO 30 minutes after. In the prevention protocol, mice were pre-treated with both doses of minocycline, risperidone or DMSO for 14 days, from the 8th to 14th day, additionally received ketamine 30 minutes later. All drugs were administered intraperitoneally and once a day. Behaviors related to positive (locomotor activity and prepulse inhibition of startle), negative (social interaction) and cognitive (Y maze) symptoms of schizophrenia were also assessed. Glutathione (GSH), thiobarbituric acid-reactive substances (TBARS) and nitrite levels were measured in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). The result of behavioral tests showed that ketamine promoted a deficit in sensorimotor filter, increased locomotor activity, decreased social interaction and prejudice in working memory. Virtually all of these parameters were prevented and reversed by the administration of minocycline (25 and 50 mg/kg) and risperidone. Ketamine also promoted changes in oxidative markers by increasing lipid peroxidation and antioxidant GSH levels decrease, in addition to increased levels of nitrite in the ST. Following the same line of the behavioral results, minocycline and risperidone were able to prevent and reverse such changes.These data provide a rationale for evaluating minocycline as a novel psychotropic agent and suggest that its mechanism of action includes antioxidant and nitergic systems.