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. This study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, animals received ketamine (20 mg/kg per day intraperitoneally or saline for 14 days, and minocycline (25 or 50 mg/kg daily), risperidone or vehicle treatment from days 8 to 14. In the prevention protocol, mice were pretreated with minocycline, risperidone or vehicle prior to ketamine. 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, hippocampus and striatum. Minocycline and risperidone prevented and reversed ketamine-induced alterations in behavioral paradigms, oxidative markers (i.e. ketamine-induced decrease and increase in GSH levels and TBARS content, respectively) as well as nitrite levels in the striatum. These data provide a rationale for evaluating minocycline as a novel psychotropic agent and suggest that its mechanism of action includes antioxidant and nitrergic systems.

No abstract

Oxidative imbalance, alterations in brain-derived neurotrophic factor (BDNF), and mitochondrial dysfunction are implicated in bipolar disorder (BD) pathophysiology and comorbidities, for example, cardiovascular conditions. Carvedilol (CVD), a nonselective beta-blocker widely used for the treatment of hypertension, presents antioxidant and mitochondrial stabilizing properties. Thus, we hypothesized that CVD would prevent and/or reverse mania-like behavioral and neurochemical alterations induced by lisdexamfetamine dimesylate (LDX). To do this, male Wistar rats were submitted to two different protocols, namely, prevention and reversal. In the prevention treatment the rats received daily oral administration (mg/kg) of CVD (2.5, 5 or 7.5), saline, valproate (VAL200), or the combination of CVD5 + VAL100 for 7 days. From the 8th to 14th day LDX was added. In the reversal protocol LDX was administered for 7 days with the drugs being added from the 8th to 14th day of treatment. Two hours after the last administration the behavioral (open field and social interaction) and neurochemical (reduced glutathione, lipid peroxidation, and BDNF) determinations were performed. The results showed that CVD prevented and reversed the behavioral and neurochemical alterations induced by LDX. The administration of CVD5 + VAL100 potentiated the effect of VAL200 alone. Taken together these results demonstrate a possible antimanic effect of CVD in this preclinical model.

Polymorphisms in the human dopamine transporter (DAT) are associated with bipolar endophenotype. Based on this, the acute inhibition of DAT using GBR12909 causes behavioral alterations that are prevented by valproate (VAL), being related to a mania-like model. Herein our first aim was to analyze behavioral and brain oxidative alterations during a 24 h period post-GBR12909 to better characterize this model. Our second aim was to determine the preventive effects of lithium (Li) or VAL 2 h post-GBR12909. For this, adult male mice received GBR12909 or saline being evaluated at 2, 4, 8, 12 or 24 h post-administration. Hyperlocomotion, levels of reduced glutathione (GSH) and lipid peroxidation in brain areas were assessed at all these time-points. GBR12909 caused hyperlocomotion at 2 and 24 h. Rearing behavior increased only at 2 h. GSH levels decreased in the hippocampus and striatum at the time points of 2, 4, 8 and 12 h. Increased lipid peroxidation was detected at the time-points of 2 and 12 h in all brain areas studied. At the time-point of 2 h post-GBR12909 Li prevented the hyperlocomotion and rearing alterations, while VAL prevented only rearing alterations. Both drugs prevented pro-oxidative changes. In conclusion, we observed that the main behavioral and oxidative alterations took place at the time-period of 2 h post-GBR12909, what points to this time-period as the best for the assessment of alterations in this model. Furthermore, the present study expands the predictive validity of the model by the determination of the preventive effects of Li.

The present study was designed to verify whether frutalin (FTL) affords gastroprotection against the ethanol-induced gastric damage and to examine the underlying mechanism(s). Gastric damage was induced by intragastric administration of 0.2 ml of ethanol (96%). Mice in groups were pretreated with FTL (0.25, 0.5 and 1 mg/kg; i.p.), cimetidine (100 mg/kg; p.o.), or vehicle (0.9% of NaCl, 10 mL/kg; p.o.), 30 min before ethanol administration. They were sacrificed 30 min later, the stomachs excised, and the mucosal lesion area (mm²) measured by planimetry. Gastroprotection was assessed in relation to inhibition of gastric lesion area. To study the gastroprotective mechanism(s), its relations to capsaicin-sensitive fibers, endogenous prostaglandins, nitric oxide, sulphydryls, ATP-sensitive potassium channels, adrenoceptors, opioid receptors and calcium channels were analyzed. Treatments effects on ethanol-associated oxidative stress markers GSH and MDA were measured in gastric tissue. FTL afforded a dose-unrelated gastroprotection against the ethanol damage. However, it failed to prevent the ethanol-induced changes in the levels of GSH and MDA. It was observed that the gastroprotection by FTL was greatly reduced in animals pretreated with capsazepine, indomethacin, L-NAME or glibenclamide. Considering the results, it is suggested that the FTL could probably be a good therapeutic agent for the development of new medicine for the treatment of gastric ulcer.

No abstract

Introduction:The Bipolar Disorder (BD), a chronic psychiatric disorder, is highly prevalent and associated with functional disability and with excessive costs to the health system. The renin-angiotensin system (RAS) has been studied concerning neurological diseases, and the role of angiotensin II is being currently recognized as an important factor in anxiety and mood disorders. The deregulation of SRA brain is associated with the formation of reactive oxygen species, activation of pro-inflammatory pathways, reduced neuroplasticity and mitochondrial dysfunction. It is noteworthy that all these events are related to the pathophysiology of BD. Objectives: To evaluate the effect of candesartan (CDS) in an animal model of mania induced by d-amphetamine (AMPH). Methods: Adult male Swiss mice (20-25 g, n=6-8 per group) were submitted to two treatment protocols. In the prevention protocol, animals received CDS (0.1; 0.3; 1 or 3 mg/kg/day), lithium (47.5 mg/kg/day) or vehicle for 14 days and between the 8th and 14th day mice received AMPH (2 mg/kg/day ip) or saline. In the reversal protocol, AMPH or saline was administered for 14 days and between the 8th and 14th day the animals were treated with CDS, lithium or vehicle. The effect of CDS was evaluated on 14th day by examining the exploratory behavior in the open field, a test that is used for pre-clinical study of anti-manic drugs. Neurochemical tests were conducted to evaluate the oxidative stress, assessing reduced glutathione (GSH) in the prefrontal cortex (PF), hippocampus (HPC) and striatum (ST). The statistical analysis was performed by ANOVA followed by Student's-Newman-Keuls's test, considering p<0.05 as significant. Results: In both treatment protocols, there was an increase in locomotor activity in the groups that received only AMPH, which was prevented and reversed by CDS, whose results were similar to the control group and the animals that received AMPH + lithium. AMPH reduced GSH in HPC and PF in prevention and in HPC, PF and ST. GSH brain levels in CDS-treated animals increased in HPC in the prevention and in PF, HPC and ST in the reversal protocol. Conclusions: CDS, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations. The results suggest an anti-maniac action of CDS and propose a novel, safe and highly promising therapeutic approach for the BD.

No abstract