Karine F. Ribeiro

Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain

A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10mg/kg) and imipramine (10 and 20mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10mg/kg and ketamine at the dose of 5mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.

Maternal Deprivation Induces Depressive-like Behaviour and Alters Neurotrophin Levels in the Rat Brain

The present study was aimed to evaluate the behavioral and molecular effects of maternal deprivation in adult rats. To this aim, male rats deprived and non-deprived were assessed in the forced swimming and open-field tests in adult phase. In addition adrenocorticotrophin hormone (ACTH) levels was assessed in serum and brain-derived-neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) protein levels were assessed in prefrontal cortex, hippocampus and amygdala. We observed that maternal deprivation increased immobility time, and decreased climbing time, without affecting locomotor activity. ACTH circulating levels were increased in maternal deprived rats. Additionally, BDNF protein levels were reduced in the amygdala and NT-3 and NGF were reduced in both hippocampus and amygdala in maternal deprived rats, compared to control group. In conclusion, our results support the idea that behavioral, ACTH circulating levels and neurotrophins levels altered in maternal deprivation model could contribute to stress-related diseases, such as depression.

Imipramine reverses alterations in cytokines and BDNF levels induced by maternal deprivation in adult rats.

A growing body of evidence is pointing toward an association between immune molecules, as well brain-derived neurotrophic factor (BDNF) and the depression. The present study was aimed to evaluate the behavioral and molecular effects of the antidepressant imipramine in maternally deprived adult rats. To this aim, maternally deprived and non-deprived (control group) male rats were treated with imipramine (30mg/kg) once a day for 14 days during their adult phase. Their behavior was then assessed using the forced swimming test. In addition to this, IL-10, TNF-α and IL-1β cytokines were assessed in the serum and cerebrospinal fluid (CSF). In addition, BDNF protein levels were assessed in the prefrontal cortex, hippocampus and amygdala. In deprived rats treated with saline was observed an increase on immobility time, compared with non-deprived rats treated with imipramine (p<0.05). Deprived rats treated with saline presented a decrease on BDNF levels in the amygdala (p<0.05), compared with all other groups. The IL-10 levels were decreased in the serum (p<0.05). TNF-α and IL-1β levels were increased in the serum and CSF of deprived rats treated with saline (p<0.05). Interestingly, imipramine treatment reversed the effects of maternal deprivation on BDNF and cytokines levels (p<0.05). Finally, these findings further support a relationship between immune activation, neurotrophins and the depression, and considering the action of imipramine, it is suggested that classic antidepressants could exert their effects by modulating the immune system.

Synergist effects of n-acetylcysteine and deferoxamine treatment on behavioral and oxidative parameters induced by chronic mild stress in rats

A growing body of evidence has pointed to a relationship between oxidative stress and depression. Thus, the present study was aimed at evaluating the effects of the antioxidants n-acetylcysteine (NAC), deferoxamine (DFX) or their combination on sweet food consumption and oxidative stress parameters in rats submitted to 40days of exposure to chronic mild stress (CMS). Our results showed that in stressed rats treated with saline, there was a decrease in sweet food intake and treatment with NAC or NAC in combination with DFX reversed this effect. Treatment with NAC and DFX decreased the oxidative damage, which include superoxide and TBARS production in submitochondrial particles, and also thiobarbituric acid reactive substances (TBARS) levels and carbonyl proteins in the prefrontal cortex, amygdala and hippocampus. Treatment with NAC and DFX also increased the activity of the antioxidant enzymes, superoxide dismutase and catalase in the same brain areas. Even so, a combined treatment with NAC and DFX produced a stronger increase of antioxidant activities in the prefrontal cortex, amygdala and hippocampus. The results described here indicate that co-administration may induce a more pronounced antidepressant activity than each treatment alone. In conclusion, these results suggests that treatment with NAC or DFX alone or in combination on oxidative stress parameters could have positive effects against neuronal damage caused by oxidative stress in major depressive disorders.

Effects of acute and chronic treatment elicited by lamotrigine on behavior, energy metabolism, neurotrophins and signaling cascades in rats.

The present study was aimed to investigate the behavioral and molecular effects of lamotrigine. To this aim, Wistar rats were treated with lamotrigine (10 and 20 mg/kg) or imipramine (30 mg/kg) acutely and chronically. The behavior was assessed using forced swimming test. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), Proteina Kinase B (PKB, AKT), glycogen synthase kinase 3 (GSK-3) and B-cell lymphoma 2 (Bcl-2) levels, citrate synthase, creatine kinase and mitochondrial chain (I, II, II-III and IV) activities were assessed in the brain. The results showed that both treatments reduced the immobility time. The BDNF were increased in the prefrontal after acute treatment with lamotrigine (20 mg/kg), and the BDNF and NGF were increased in the prefrontal after chronic treatment with lamotrigine in all doses. The AKT increased and Bcl-2 and GSK-3 decreased after both treatments in all brain areas. The citrate synthase and creatine kinase increased in the amygdala after acute treatment with imipramine. Chronic treatment with imipramine and lamotrigine (10 mg/kg) increased the creatine kinase in the hippocampus. The complex I was reduced and the complex II, II-III and IV were increased, but related with treatment and brain area. In conclusion, lamotrigine exerted antidepressant-like, which can be attributed to its effects on pathways related to depression, such as neurotrophins, metabolism energy and signaling cascade.

Effects of lamotrigine on behavior, oxidative parameters and signaling cascades in rats exposed to the chronic mild stress model

The rats were subjected to 40 days of stress protocol, during which the sucrose consumption was assessed in rats chronically treated with lamotrigine (20mg/kg) or with saline. The signaling cascade and oxidative stress parameters were assessed in the brain rat. Both control and stressed rats treated with lamotrigine showed an increase on malondialdehyde equivalents (MDA) in the prefrontal cortex, and that there was also an increase in the amygdala of the control rats treated with lamotrigine. The carbonyl protein was increased in the prefrontal cortex of the stressed group treated with saline, however, the lamotrigine treatment reversed this effect. The treatment with lamotrigine increased the superoxide dismutase (SOD) and catalase activity (CAT) activities in the amygdala of stressed rats. The protein kinase B (PKB/Akt) was reduced in the amygdala in the stressed group treated with saline or lamotrigine. We suggest that the antidepressant-like effect of lamotrigine on anhedonic behavior may be related at least in part to its effects on the oxidative stress parameters and AKT.

Lamotrigine treatment reverses depressive-like behavior and alters BDNF levels in the brains of maternally deprived adult rats

Lamotrigine is an anticonvulsant and has an antiglutamatergic action, which may contribute to its antidepressant effects, since glutamate has been linked to depression. The purpose of the present study was to investigate the behavioral and molecular effects of lamotrigine treatment in maternally deprived rats. To this aim, deprived and non-deprived male rats were treated with lamotrigine (20 mg/kg) once a day for 14 days during their adult phase. Their behavior was then assessed in the forced swimming and open field tests. In addition to this, the BDNF and NGF levels were assessed in the prefrontal cortex, hippocampus and amygdala. In the course of this study we demonstrated that maternally deprived rats treated with saline and lamotrigine showed an increase in their immobility time and a decrease in the climbing and swimming times when compared with non-deprived rats treated with saline alone. Treatment with lamotrigine reversed the increase in the immobility time in the deprived rats. The BDNF levels were decreased in the amygdala in deprived rats treated with saline, and treatment with lamotrigine reversed this decrease. The NGF levels were decreased in the hippocampus in deprived rats treated with saline, but treatment with lamotrigine did not reverse this decrease. In conclusion, lamotrigine showed antidepressant effects in the forced swimming test, and it presented positive effects on the BDNF protein levels in the amygdala of maternally deprived rats.

Treatment with olanzapine, fluoxetine and olanzapine/fluoxetine alters citrate synthase activity in rat brain

A growing body of evidence has indicated that energy metabolism impairment may be involved in pathophysiology of some neuropsychiatric disorders. In this study, we evaluated the effect of acute and chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on citrate synthase activity in brain of rats. For acute treatment, Wistar rats received one single injection of olanzapine (3 or 6mg/kg) and/or fluoxetine (12.5 or 25mg/kg). For chronic treatment, rats received daily injections of olanzapine (3 or 6mg/kg) and/or fluoxetine (12.5 or 25mg/kg) for 28 days. In the present study we observed that acute administration of olanzapine inhibited citrate synthase activity in cerebellum and prefrontal cortex. The acute administration of olanzapine increased citrate synthase activity in prefrontal cortex, hippocampus and striatum and fluoxetine increased citrate synthase activity in striatum. Olanzapine 3mg/kg and fluoxetine 12.5mg/kg in combination increased citrate synthase activity in prefrontal cortex, hippocampus and striatum. In the chronic treatment we did not observed any effect on citrate synthase activity. Our results showed that olanzapine and fluoxetine increased citrate synthase activity after acute, but not chronic treatment.

Imipramine treatment reverses depressive-like behavior in alloxan-diabetic rats.

A growing body of evidence has shown an association between diabetes and depression, as well a role of brain‐derived neurotrophic factor (BDNF) in diabetes and depression. The present study was designed to evaluate the behavioural and molecular effects of the anti‐depressant imipramine in diabetic rats.

Effects of sodium butyrate in animal models of mania and depression: implications as a new mood stabilizer.

Bipolar disorder is a severe mood disorder with high morbidity and mortality. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on depressive-like and manic-like behaviors. Therefore, the aim of the present study was to evaluate the effects of sodium butyrate (SB) on behavioral changes in animal models of depression and mania. The animals were submitted to protocols of chronic mild stress or maternal deprivation for induction of depressive-like behaviors and subjected to amphetamine, or ouabain administration for induction of manic-like behaviors. SB reversed the depressive-like and manic-like behaviors evaluated in the animal models. From these results we can suggest that SB may be a potential mood stabilizer.