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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.

Studies have suggested that the brain renin angiotensin system (RAS) regulates cerebral flow, autonomic and hormonal systems, stress, innate immune response and behavior, being implicated in several brain disorders such as major depression, Parkinson's and Alzheimer's disease. The angiotensin II receptor subtype 1 (AT1R) is distributed in brain regions responsible for the control of stress response through peripheral and central sympathetic hyperactivation as well as in the hypothalamic paraventricular region, areas known for the release of several neurotransmitters related to inflammatory response facilitation. This relationship leads to the assumption that AT1R might be the receptor most related to the central deleterious actions of angiotensin II. New evidences from clinical studies have shown a possible role for RAS in the pathogenesis of bipolar disorder (BD), a multifactorial disorder with acknowledged presence of neuronal damage via oxidative stress in brain areas such as hippocampus, prefrontal cortex and striatum. Given the studies highlighting AT1R activation as a central pro-inflammatory pathway and, conversely, the involvement of inflammatory response in the pathogenesis of BD; this paper hypothesizes the use of AT1R antagonists for BD management and prevention of its neuroprogression, due to their anti-inflammatory and neuroprotective effects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)