Airam B. de Moura

Quetiapine treatment reverses depressive-like behavior and reduces DNA methyltransferase activity induced by maternal deprivation

ABSTRACT Stress in early life has been appointed as an important phenomenon in the onset of depression and poor response to treatment with classical antidepressants. Furthermore, childhood trauma triggers epigenetic changes, which are associated with the pathophysiology of major depressive disorder (MDD). Treatment with atypical antipsychotics such as quetiapine, exerts therapeutic effect for MDD patients and induces epigenetic changes. This study aimed to analyze the effect of chronic treatment with quetiapine (20 mg/kg) on depressive‐like behavior of rats submitted to maternal deprivation (MD), as well as the activity of histone acetylation by the enzymes histone acetyl transferases (HAT) and deacetylases (HDAC) and DNA methylation, through DNA methyltransferase enzyme (DNMT) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus. Maternally deprived rats had a depressive‐like behavior in the forced swimming test and an increase in the HDAC and DNMT activities in the hippocampus and NAc. Treatment with quetiapine reversed depressive‐like behavior and reduced the DNMT activity in the hippocampus. This is the first study to show the antidepressant‐like effect of quetiapine in animals subjected to MD and a protective effect by quetiapine in reducing epigenetic changes induced by stress in early life. These results reinforce an important role of quetiapine as therapy for MDD.

Antioxidants Reverse the Changes in the Cholinergic System Caused by L-Tyrosine Administration in Rats

Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in the activity of the enzyme tyrosine aminotransferase, leading to tyrosine accumulation in the body. Although the mechanisms involved are still poorly understood, several studies have showed that higher levels of tyrosine are related to oxidative stress and therefore may affect the cholinergic system. Thus, the aim of this study was to investigate the effects of chronic administration of L-tyrosine on choline acetyltransferase activity (ChAT) and acetylcholinesterase (AChE) in the brain of rats. Moreover, we also examined the effects of one antioxidant treatment (N-acetylcysteine (NAC) + deferoxamine (DFX)) on cholinergic system. Our results showed that the chronic administration of L-tyrosine decreases the ChAT activity in the cerebral cortex, while the AChE activity was increased in the hippocampus, striatum, and cerebral cortex. Moreover, we found that the antioxidant treatment was able to prevent the decrease in the ChAT activity in the cerebral cortex. However, the increase in AChE activity induced by L-tyrosine was partially prevented the in the hippocampus and striatum, but not in the cerebral cortex. Our results also showed no differences in the aversive and spatial memory after chronic administration of L-tyrosine. In conclusion, the results of this study demonstrated an increase in AChE activity in the hippocampus, striatum, and cerebral cortex and an increase of ChAT in the cerebral cortex, without cognitive impairment. Furthermore, the alterations in the cholinergic system were partially prevented by the co-administration of NAC and DFX. Thus, the restored central cholinergic system by antioxidant treatment further supports the view that oxidative stress may be involved in the pathophysiology of tyrosinemia type II.

Early Maternal Deprivation Induces Microglial Activation, Alters Glial Fibrillary Acidic Protein Immunoreactivity and Indoleamine 2,3-Dioxygenase during the Development of Offspring Rats

Maternal deprivation (MD) induces behavioral changes and impacts brain circuits that could be associated with the pathophysiology of depression. This study investigated the markers of microglia and astrocyte activation as well as indoleamine 2,3-dioxygenase (IDO) expression in developmental programming after early life MD (on postnatal days (PNDs) 20, 30, 40, and 60). On PND 60, the rats that were subjected to MD displayed depressive-like behavior. On PND 10, it was found that there was a decrease in the level of glial fibrillary acidic protein (GFAP) immunopositive cells, a decrease in the level of IDO expression, and an increase in the level of Iba-1 (microglial marker) in the hippocampus of rats that were subjected to MD. On PND 20, levels of GFAP were also found to have decreased in the hippocampus, and there was an increase in the level of Iba-1 in the hippocampus. AIF-1 (microglial marker) expression was observed in the PFC following MD. On PND 30, the levels of Iba-1 remained elevated. On PND 40, the levels of GFAP were found to have increased in the hippocampus of rats that were subjected to MD. On PND 60, the levels of GFAP and AIF-1 remained elevated following MD. These results suggest that early life stress induces negative developmental programming in rats, as demonstrated by depressive-like behavior in adult life. Moreover, MD increases microglial activation in both early and late developmental phases. The levels of GFAP and IDO decreased in the early stages but were found to be higher in later developmental periods. These findings suggest that MD could differentially affect the expression of the IDO enzyme, astrocytes, and microglial activation depending on the neurodevelopmental period. The onset of an inflammatory state from resident brain cells could be associated with the activation of the kynurenine pathway and the development of depressive behavior in adulthood.

Acute treatment with ketamine and chronic treatment with minocycline exert antidepressant-like effects and antioxidant properties in rats subjected different stressful events

Despite decades of research, the fundamental neurochemical and molecular mechanisms underlying the major depressive disorder (MDD) are still poorly understood, and current antidepressant treatments have limited clinical efficacy. In clinical conditions, the rapprochement between the disease and the corrective actions of drugs in laboratory animals is essential for developing effective therapies. Thus, the aim of this study was to evaluate the antidepressant effects of ketamine (N-metil-d-asparte (NMDA) receptor antagonist), minocycline (tetracycline antibiotic), and amitriptyline (classical antidepressant), on behavior and oxidative stress parameters in animals submitted to the chronic mild stress (CMS) and maternal deprivation protocols. For this aim, male Wistar rats were submitted to maternal deprivation or CMS. To induce maternal deprivation, Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, Wistar rats were submitted to the CMS for 40 days. To reverse the effects of stress, treatment was done intraperitoneally with a single dose of ketamine (15 mg/kg), and minocycline (25 mg/kg) and amitriptyline (10 mg/kg) by 20 days. After treatment, the animals were submitted to the forced swimming test and then analyzed oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). Treatment with ketamine, minocycline and amitriptyline were able to exert antidepressant effects in the forced swimming test. However, these antidepressant effects were dependent on the stress model by which the animals were exposed. In certain brain regions some treatment strategies had a pro-oxidant effect. Though, most of the strategies used in this study had antioxidant effects, as reported by a decrease on protein and lipid damage, nitrite/nitrate concentration and myeloperoxidase activity. In addition, an increase in the antioxidant superoxide dismutase (SOD) and catalase (CAT) enzymes activities were also evident after treatments. In conclusion, the antidepressant effects of ketamine and minocycline, in the present study, may be associated, at least in part, with its antioxidant and neuroprotective effects in animals subjected to maternal deprivation or CMS.

Mechanism of synergistic action on behavior, oxidative stress and inflammation following co-treatment with ketamine and different antidepressant classes

BACKGROUND Major depressive disorder (MDD) affects many people in the world. However, around 40% of patients do not respond to any pharmacological drugs. An alternative is to use a combination of different pharmacological groups or the combination of a classical antidepressant with a substance that can potentiate its effect. Thus, this study aimed to investigate the synergistic interactions between different antidepressants, including fluoxetine, quetiapine and lamotrigine in combination with ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist. METHODS Wistar rats were acutely treated with fluoxetine (1.25mg/kg), quetiapine (5mg/kg), and lamotrigine (5.0mg/kg) alone or in combination with ketamine (5.0mg/kg), and then subjected to behavioral tests. In addition, oxidative damage and antioxidant capacity were assessed in the rat brain, and pro-inflammatory cytokines levels were evaluated in the serum. RESULTS It was observed a synergistic effect of ketamine in combination with fluoxetine on the immobility time in the forced swimming test, indicating an antidepressant effect. Other antidepressant did not show effects when administrated alone or joint to ketamine. The combination of ketamine with other antidepressants, particularly quetiapine, in some brain regions induced an increase in damage to lipids and proteins. However, the combination of ketamine with fluoxetine increased the antioxidant activity of superoxide dismutase, and decreased oxidative damage, thus suggesting a neuroprotective effect of the combination of these drugs. The combination of ketamine with fluoxetine or lamotrigine reduced pro-inflammatory cytokines levels. CONCLUSION In conclusion, ketamine induced antioxidant or pro-antioxidant effects dependent of antidepressant classes or brain area.