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Background: Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. Aim: The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m‐amph). Methods: Wistar rats were given 14 days of m‐amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low‐frequency stimulation (LFS) or continuous high‐frequency stimulation (HFS). Immediately after DBS, manic‐like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open‐field tests and fast‐scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. Results: M‐amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M‐amph increased DA reuptake time post‐sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. Conclusion: These results demonstrate that both VTA LFS and HFS DBS exert anti‐manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti‐manic effects. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate if sepsis sensitizes behavioural and biochemical responses induced by m‐amphetamine. For this, Wistar rats were submitted to the cecal ligation and puncture. After 30 days of cecal ligation and puncture procedure, the animals were submitted to a single intraperitoneal injection of saline or m‐amphetamine (.25,.50, or 1.0 mg/kg). Locomotor behaviour was assessed 2 h after the administration. Interleukin (IL)‐1β, IL‐6, IL‐10, tumour necrosis factor‐α, dopamine‐cAMP‐regulated phosphoprotein of 32,000 kDa (DARPP‐32) and neuronal calcium sensor (NCS‐1) levels were evaluated in the frontal cortex, hippocampus and striatum. Also, brain‐derived neurotrophic factor (BDNF), neuronal growth factor and glial‐derived neurotrophic factor levels were assessed in the hippocampus. M‐amphetamine alone (.25 and 1.0 mg/kg) increased rats' locomotion and exploratory behaviour compared with the Sham + Sal. Animals from the cecal ligation and puncture + m‐amphetamine (.5 and/or 1.0 mg/kg) group showed an increase in locomotion, exploratory and risk‐like behaviour when compared with the Sham + Saline group and with its respective Sham groups. Cecal ligation and puncture increased interleukin levels compared with the Sham + Sal. However, cecal ligation and puncture animals that received m‐amphetamine (1 mg/kg) increased even more, these inflammatory parameters compared with the Sham + Sal and the cecal ligation and puncture + saline group. M‐amphetamine at lower doses increased neurotrophic factors, but higher doses decreased these parameters in the brain of cecal ligation and puncture rats. M‐amphetamine dose‐dependently increased DARPP‐32 and NCS‐1 levels in cecal ligation and puncture rats in some structures. In conclusion, these results demonstrate that sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model. [ABSTRACT FROM AUTHOR]

Background: There has been growing scientific evidence in recent years that bipolar disorder (BD) is associated with alterations in the kynurenine (KYN) pathway. However, many of these studies have been limited by their focus on adults. Thus, this preliminary study investigated differences in the peripheral levels of KYN metabolites in children and adolescents with BD, unaffected offspring of parents with BD, and healthy controls (HCs). Methods: Plasma samples were collected from 49 youths with BD, 19 bipolar offspring, and 31 HCs. Tryptophan (TRP), KYN, and kynurenic acid (KYNA) were separated using electrospray ionization. Results: One‐Way ANCOVA after controlling for age, gender, race, BMI‐for‐age, and smoking status showed that BD had lower levels of KYN, while unaffected high‐risk offspring subjects had lower levels of TRP, KYN, and KYNA when compared to HCs. Moreover, we found that KYN, KYN/TRP, and KYNA/KYN levels predicted the severity of depressive symptoms, while the YMRS score was not associated with any metabolite. Conclusions: In summary, this preliminary study has shown that KYN metabolites are decreased in both affected and unaffected subjects, strengthening the idea that the KYN pathway might underlie the familial risk of BD shown by high‐risk offspring individuals. However, longitudinal studies are needed to examine whether the alterations observed in this study represent early markers of risk for later developing BD. [ABSTRACT FROM AUTHOR]

It is known that bipolar disorder has a multifactorial aetiology where the interaction between genetic and environmental factors is responsible for its development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzyme alterations in rats or mice submitted to animal models of mania induced by dextro‐amphetamine or sleep deprivation, respectively. Adult male Wistar rats were subjected to 14 days of dextro‐amphetamine administration, and from the eighth to the fourteenth day, the animals were treated with valproate and sodium butyrate in addition to dextro‐amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open‐field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro‐amphetamine and sleep deprivation induced hyperactivity and increased histone deacetylase and DNA methyltransferase activities in the animal's brain. Valproate and sodium butyrate were able to reverse hyperlocomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzyme activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between theirselves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a psychiatric condition that affects a large number of people in the world, and the treatment existents do not work for all individuals affected. Thus, it is believed that other systems or pathways which regulate brain networks involved in mood regulation and cognition are associated with MDD pathogenesis. Studies in humans and animal models have been shown that in MDD there are increased levels of inflammatory mediators, including cytokines and chemokines in both periphery and central nervous system (CNS). In addition, microglial activation appears to be a key event that triggers changes in signaling cascades and gene expression that would be determinant for the onset of depressive symptoms. Recent researches also point out that changes in the gut microbiota would lead to a systemic inflammation that in different ways would reach the CNS modulating inflammatory pathways and especially the microglia, which could influence responses to treatments. Moreover, pre‐ and probiotics have shown antidepressant responses and anti‐inflammatory effects. This review will focus on studies that show the relationship of inflammation with the gut microbiota–brain axis and its relation with MDD. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder that affects branched-chain amino acid (BCAA) catabolism and is associated with acute and chronic brain dysfunction. Recent studies have shown that inflammation may be involved in the neuropathology of MSUD. However, these studies have mainly focused on single or small subsets of proteins or molecules. Here we performed a case-control study, including 12 treated-MSUD patients, in order to investigate the plasmatic biomarkers of inflammation, to help to establish a possible relationship between these biomarkers and the disease. Our results showed that MSUD patients in treatment with restricted protein diets have high levels of pro-inflammatory cytokines [IFN-γ, TNF-α, IL-1β and IL-6] and cell adhesion molecules [sICAM-1 and sVCAM-1] compared to the control group. However, no significant alterations were found in the levels of IL-2, IL-4, IL-5, IL-7, IL-8, and IL-10 between healthy controls and MSUD patients. Moreover, we found a positive correlation between number of metabolic crisis and IL-1β levels and sICAM-1 in MSUD patients. In conclusion, our findings in plasma of patients with MSUD suggest that inflammation may play an important role in the pathogenesis of MSUD, although this process is not directly associated with BCAA blood levels. Overall, data reported here are consistent with the working hypothesis that inflammation may be involved in the pathophysiological mechanism underlying the brain damage observed in MSUD patients. [ABSTRACT FROM AUTHOR]

There is increasing interest in natural antioxidants that are candidates for the prevention of brain damage occurring in major depressive disorders. Cecropia pachystachya is a tropical tree species of Central and South America and a rich source of polyphenols, particularly flavonoids. The aim of this study was to characterize the flavonoid profile of an enriched flavonoid fraction of C. pachystachya (EFF- Cp) and evaluate the antidepressant-like effects of its acute administration in behavior, cytokine levels, oxidative stress and energy metabolism parameters . The EFF- Cp chemical characterization was performed by HPLC/DAD and LC/QTOF. The antidepressant-like effects were performed by the forced swimming test, splash test and open field test. EFF- Cp revealed 15 flavonoids, including seven new glycosyl flavonoids for C. pachystachya. Quantitatively, EFF- Cp showed isoorientin (43.46 mg/g), orientin (23.42 mg/g) and isovitexin (17.45 mg/g) as major C-glycosyl flavonoids. In addition, EFF- Cp at doses 50 and 100 mg/kg reduced the immobility time in the forced swimming test, without changing the locomotor activity and grooming time. In addition, EFF- Cp was able to prevent the oxidative damage in some brain areas. In conclusion, the results of this study suggest that EFF- Cp exerts antidepressant-like effects with its antioxidant properties. [ABSTRACT FROM AUTHOR]

Objectives The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation ( PSD). Methods Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. Results The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. Conclusions Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system − alterations presented in the animal models of mania - is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers. [ABSTRACT FROM AUTHOR]

Despite the revolution in recent decades regarding monoamine involvement in the management of major depressive disorder (MDD), the biological mechanisms underlying this psychiatric disorder are still poorly understood. Currently available treatments require long time courses to establish antidepressant response and a significant percentage of people are refractory to single drug or combination drug treatment. These issues, and recent findings demonstrating the involvement of synaptic plasticity in the pathophysiological mechanisms of MDD, are encouraging researchers to explore the molecular mechanisms underlying psychiatric disease in more depth. The discovery of the rapid antidepressant effect exerted by glutamatergic and cholinergic agents highlights the mammalian target of rapamycin (mTOR) pathway as a critical pathway that contributes to the efficacy of these pharmacological agents in clinical and pre-clinical research. The mTOR pathway is a downstream intracellular signal that transmits information after the direct activation of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and neurotrophic factor receptors. Activation of these receptors is hypothesized to be one of the major axes involved in the synthesis of synaptogenic proteins underlying synaptic plasticity and critical to both the rapid and delayed effects exerted by classic antidepressants. This review focuses on the involvement of mTOR in the pathophysiology of depression and on molecular mechanisms involved in the activity of emerging and classic antidepressant agents. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to investigate the effect of subchronic administration of agomelatine on energy metabolism, oxidative stress markers and antioxidant defense in the brains of rats. Methods The animals received daily intraperitoneal injections of agomelatine (10, 30 or 50 mg/kg) or saline for 14 days. The prefrontal cortex, cerebellum, hippocampus, striatum and posterior cortex were analyzed. Results The findings showed that complex I was activated in the prefrontal cortex, cerebellum and striatum and inhibited in the posterior cortex at the 10-mg/kg dose, and inhibited in all brain areas analyzed at the 30-mg/kg and 50-mg/kg doses. Complex II was activated in the posterior cortex at the 50-mg/kg dose. Complex IV was inhibited in the striatum and posterior cortex at the 10-mg/kg dose, inhibited in the striatum at the 30-mg/kg dose and activated in the hippocampus at the 50-mg/kg dose. Creatine kinase activity was inhibited in the striatum at the 10-mg/kg and 30-mg/kg doses. Lipid peroxidation and protein carbonylation levels were not changed after the administration of agomelatine. Superoxide dismutase activity was increased in the striatum at the 10-mg/kg dose, and catalase activity was inhibited in the cerebellum at the 10-mg/kg dose and increased in the posterior cortex at the 30-mg/kg dose. Conclusions Our results are consistent with other studies showing that some antidepressants may influence brain energy metabolism and oxidative stress parameters and expand knowledge about the effects of agomelatine in biochemical parameters in the brains of rats. [ABSTRACT FROM AUTHOR]

Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Duchenne muscular dystrophy (DMD) is a degenerative disease of skeletal, respiratory, and cardiac muscles caused by defects in the dystrophin gene. More recently, brain involvement has been verified. Mitochondrial dysfunction and oxidative stress may underlie the pathophysiology of DMD. In this study we evaluate Krebs cycle enzymes activity in the cerebral cortex, diaphragm, and quadriceps muscles of mdx mice.Methods: Cortex, diaphragm, and quadriceps tissues from male dystrophic mdx and control mice were used.Results: We observed increased malate dehydrogenase activity in the cortex; increased malate dehydrogenase and succinate dehydrogenase activities in the diaphragm; and increased citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase activities in the quadriceps of mdx mice.Conclusion: This study showed increased activity of Krebs cycle enzymes in cortex, quadriceps, and diaphragm in mdx mice. [ABSTRACT FROM AUTHOR]

Objectives Several recent studies have suggested that the physiopathology of bipolar disorder ( BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin ( IL)-1β, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha ( TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d- AMPH). Methods Male Wistar rats were treated with d- AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine ( IL-1β, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid ( CSF), serum, frontal cortex, striatum, and hippocampus. Results The present study showed that d- AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d- AMPH increased the levels of IL-4, IL-6, IL-10, and TNF-α in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). Conclusions Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d- AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy. [ABSTRACT FROM AUTHOR]

ABSTRACT Sepsis is defined as the host's reaction to infection and it is characterized by a systemic inflammatory response with important clinical implications. Central nervous system dysfunction secondary to sepsis is associated with local generation of pro- and anti-inflammatory cytokines, impaired cerebral microcirculation, disturbance of neurotransmitters, apoptosis, and cognitive impairment. It is known that during the process of learning and memory formation several pathways are involved such as dopaminergic and cholinergic systems. Thus, the objective of this study is to evaluate the neuronal calcium sensor (NCS-1) and dopamine-cAMP regulated phosphoprotein of 32,000 kDa (DARPP-32) expression as well as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in prefrontal cortex and hippocampus of rats 12, 24, and 48 h after sepsis induction. To this aim, we used sham-operated Wistar rats or submitted to the cecal ligation and perforation procedure. After 12 and 24 h, there was an increase of NGF levels in hippocampus; and up to 48 h, a decrease of NCS-1 expression in prefrontal cortex, a decrease of BDNF levels in hippocampus and an increase of NGF levels in hippocampus. In conclusion, we believe that the low expression of NCS-1 in prefrontal cortex and low levels of BDNF in hippocampus may be associated with the pathophysiology of cognitive impairment during sepsis and a putative role of the dopaminergic system. Synapse 68:474-479, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Central nervous system (CNS) dysfunction secondary to sepsis is characterized by long-term cognitive impairment. It was observed that oxidative damage, energetic metabolism impairment, and cytokine level alteration seen in early times in an animal model of sepsis may persist for up to 10 days and might be associated with cognitive damage. In order to understand these mechanisms, at least in part, we evaluated the effects of sepsis on cytokine levels in the cerebrospinal fluid (CSF), oxidative parameters, and energetic metabolism in the brain of rats at both 30 and 60 days after sepsis induction by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent CLP with 'basic support' or were sham-operated. Both 30 and 60 days after surgery, the CSF was collected and the animals were killed by decapitation. Then, the prefrontal cortex, hippocampus, striatum, and cortex were collected. Thirty days after surgery, an increase of IL-6 level in the CSF; an increase in the thiobarbituric acid-reactive species (TBARS) in prefrontal cortex and a decrease in hippocampus, striatum, and cortex; a decrease of carbonyl protein formation only in prefrontal cortex and an increase in striatum; and an increase in the complex IV activity only in hippocampus were observed. Sixty days after sepsis, an increase of TNF-α level in the CSF; a decrease of TBARS only in hippocampus; an increase of carbonyl protein formation in striatum; and a decrease of complex I activity in prefrontal cortex, hippocampus, and striatum were observed. These findings may contribute to understanding the role of late cognitive impairment. Further studies may address how these findings interact during sepsis development and contribute to CNS dysfunction. Synapse 67:786-793, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is a neurometabolic disorder that leads to the accumulation of branched-chain amino acids (BCAAs) and their α-keto branched-chain by-products. Because the neurotoxic mechanisms of MSUD are poorly understood, this study aimed to evaluate the effects of chronic administration of a BCAA pool (leucine, isoleucine and valine). This study examined the effects of BCAA administration on spatial memory and the levels of brain-derived neurotrophic factor (BNDF). We examined both pro-BDNF and bdnf mRNA expression levels after administration of BCAAs. Furthermore, this study examined whether antioxidant treatment prevented the alterations induced by BCAA administration. Our results demonstrated an increase in BDNF in the hippocampus and cerebral cortex, accompanied by memory impairment in spatial memory tasks. Additionally, chronic administration of BCAAs did not induce a detectable change in pro-BDNF levels. Treatment with N-acetylcysteine and deferoxamine prevented both the memory deficit and the increase in the BDNF levels induced by BCAA administration. In conclusion, these results suggest that when the brain is chronically exposed to high concentrations of BCAA (at millimolar concentrations) an increase in BDNF levels occurs. This increase in BDNF may be related to the impairment of spatial memory. In addition, we demonstrated that antioxidant treatment prevented the negative consequences related to BCAA administration, suggesting that oxidative stress might be involved in the pathophysiological mechanism(s) underlying the brain damage observed in MSUD. [ABSTRACT FROM AUTHOR]

Macêdo DS, Medeiros CD, Cordeiro RC, Sousa FC, Santos JV, Morais TA, Hyphantis TN, McIntyre RS, Quevedo J, Carvalho AF. Effects of alpha-lipoic acid in an animal model of mania induced by d-amphetamine. Bipolar Disord 2012: 14: 707-718. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S Objectives: Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha-lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine-induced model of mania. Methods: In the reversal protocol, adult mice were first given d-amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open-field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid-reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain-derived neurotrophic factor (BDNF) levels were measured in the HC. Results: ALA and Li prevented and reversed the AMPH-induced increase in locomotor activity. Prevention model: ALA and Li co-administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. Reversal model: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH-induced decreases in BDNF and GSH in the HC. Conclusions: Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA's possible antimanic effect. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: To this aim, after induction of diabetes by alloxan (150 mg/kg), Wistar rats were treated with imipramine (30 mg/kg) once a day for 14 days and then subjected to behavioural tests. BDNF was then assessed in the prefrontal cortex, hippocampus and amygdala.Results: In diabetic rats treated with saline, we observed an increase in the immobility time, compared with control rats treated with saline. Treatment with imipramine decreased the immobility time in nondiabetic and diabetic rats, compared with both nondiabetic and diabetic rats treated with saline. In the open-field test, it was observed that treatment with imipramine reduced the number of crossings the diabetic rats performed, compared with nondiabetic rats treated with saline. The number of rearings did not alter in any of the groups. Diabetic rats injected with saline did not show altered BDNF levels in the prefrontal cortex, hippocampus or amygdala, but interestingly, the treatment with imipramine in diabetic animals increased BDNF levels in the prefrontal cortex.Conclusions: In conclusion, this study demonstartes a link between diabetes and depression in rats and that imipramine exerted antidepressant effects in diabetic animals. [ABSTRACT FROM AUTHOR]

Abstract: Obesity is a chronic disease of multiple etiologies, including genetic, metabolic, environmental, social, and other factors. Pharmaceutical strategies in the treatment of obesity include drugs that regulate food intake, thermo genesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine. Studies suggest that amphetamine induces neurotoxicity through generation of free radicals and mitochondrial apoptotic pathway by cytochrome c release, accompanied by a decrease of mitochondrial membrane potential. Mitochondria are intracellular organelles that play a crucial role in ATP production. Thus, in the present study we evaluated the activities of some enzymes of Krebs cycle, mitochondrial respiratory chain complexes and creatine kinase in the brain of young rats submitted to acute and chronic administration of fenproporex. In the acute administration, the animals received a single injection of fenproporex (6.25, 12.5 or 25mg/kg i.p.) or tween. In the chronic administration, the animals received a single injection daily for 14 days of fenproporex (6.25, 12.5 or 25mg/Kg i.p.). Two hours after the last injection, the rats were sacrificed by decapitation and the brain was removed for evaluation of biochemical parameters. Our results showed that the activities of citrate synthase, malate dehydrogenase and succinate dehydrogenase were increased by acute and chronic administration of fenproporex. Complexes I, II, II–III and IV and creatine kinase activities were also increased after acute and chronic administration of the drug. Our results are consistent with others reports that showed that some psychostimulant drugs increased brain energy metabolism in young rats. [Copyright &y& Elsevier]

Abstract: Intracerebroventricular (ICV) injection of ouabain (a potent Na+/K+-ATPase inhibitor) in rats resulted in manic-like effects. There is an emerging body of data indicating that major neuropsychiatric disorders, such as bipolar disorder and schizophrenia, are associated with increased oxidative stress. In this study, we investigated the effects of ICV ouabain injection on oxidative stress parameters in total tissue of rat brain. Our findings demonstrated that ICV injection increased thiobarbituric acid reactive species levels and protein carbonyl generation in the prefrontal cortex and hippocampus of rats. Moreover, the activity of the antioxidants enzymes catalase and superoxide dismutase was altered in several areas of the rat brain and cerebrospinal fluid of ICV ouabain-subjected rats. These results showed that Na+/K+-ATPase inhibition can lead to oxidative stress in the brain of rats. [Copyright &y& Elsevier]

In this study we investigated energy metabolism in the mdx mouse brain.To this end, prefrontal cortex, cerebellum, hippocampus, striatum, and cortex were analyzed. There was a decrease in Complex I but not in Complex II activity in all structures. There was an increase in Complex III activity in striatum and a decrease in Complex IV activity in prefrontal cortex and striatum. Mitochondrial creatine kinase activity was increased in hippocampus, prefrontal cortex, cortex, and striatum. Our results indicate that there is energy metabolism dysfunction in the mdx mouse brain. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

Vimang is an aqueous extract of Mangifera indica L, used in Cuba for the treatment of immunopathological disorders. Increasing evidence from preclinical studies indicates that Vimang displays antioxidant, antiallergic, analgesic and antiinflammatory actions. The present study investigated the effects of systemic administration of Vimang on behavioural outcomes of neurological function in rats. A single oral administration of Vimang produced an impairment of short- and long-term retention of memory for aversive training when given either 1 h pretraining or immediately posttraining, but not 8 h posttraining. Vimang did not affect open field behaviour or habituation. The results indicate that Vimang might induce deficits of emotionally motivated memory without affecting nonassociative memory, locomotion, exploratory behaviour or anxiety. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine may alter the phosphorylation state of DARPP-32 that plays a central role in the dopaminergic neurons biology. Studies have shown that DARPP-32/protein phosphatase 1 cascade is a major target for psychostimulants drugs. Methylphenidate is a psychostimulant that acts blocking the dopamine transporter has been used as an effective treatment for Attention Deficit Hyperactivity Disorder. We investigated if methylphenidate could alter DARPP-32 expression in five brain regions (striatum, hippocampus, prefrontal cortex, cortex and cerebellum) in young and adult rats. Our results showed that methylphenidate treatment is able to alter DARPP-32 expression in rat brain. Acute methylphenidate treatment has reduced hippocampal DARPP-32 protein levels in old rats, while chronic methylphenidate treatment has decreased them in old rat hippocampus and young rat cerebellum. It was found an increased cortical expression after chronic methylphenidate administration in old rats. Our results provide the first experimental demonstration that methylphenidate induces changes in total DARPP-32 expression that are posology- and age-related in some rat brain areas, although further studies are needed to shed more light on the mechanisms behind these findings. [Copyright &y& Elsevier]

A growing body of evidence has pointed to the blockade of the N-methyl-d-aspartate (NMDA) receptor signaling as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with ketamine and imipramine in rats. To this aim, rats were 14 days treated once a day with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. Ketamine and imipramine, at the all doses tested, reduced immobility time, and increased both climbing and swimming time of rats compared to the saline group, without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA sandwich assay. Chronic administration of both drugs, ketamine and imipramine, did not modify BDNF protein levels in the rat hippocampus. In conclusion, our findings demonstrate for the first time that chronic administration of acute inactive doses of ketamine (5 mg/kg) becomes active after chronic treatment, while no signs of tolerance to the behavioural effects of ketamine were observed after chronic administration of acute active doses (10 and 15 mg/kg). Finally, these findings further support the hypothesis that NMDA receptor could be a new pharmacological target for the treatment of mood disorders. [ABSTRACT FROM AUTHOR]

Typical and atypical antipsychotic drugs have different clinical and behavioural profiles. It is well described that inhibition of creatine kinase activity has been implicated in the pathogenesis of a number of diseases, especially in the brain. In this work, we evaluate the effect of haloperidol, clozapine, olanzapine or aripiprazole chronic administration on creatine kinase activity in brain of rats. Adult male Wistar rats received daily injections of haloperidol (1.5 mg/kg), clozapine (25 mg/kg), olanzapine (2.5, 5 or 10 mg/kg) or aripiprazole (2, 10 or 20 mg/kg). Our results demonstrate that haloperidol did not affect the enzyme activity in brain of rats. Clozapine inhibited the enzyme activity only in cerebellum and prefrontal cortex of rats. Aripiprazole did not affect creatine kinase in hippocampus, cerebellum and prefrontal cortex. The administration of 2.0 mg/kg aripiprazole did not alter creatine kinase activity, but 10.0 and 20.0 mg/kg aripiprazole activated the enzyme in striatum and cerebral cortex. Finally, the higher dose of olanzapine (10.0 mg/kg) activated the enzyme in striatum of rats. In hippocampus and cerebral cortex, we could not verify any effect of olanzapine on creatine kinase activity. The inhibitory effect of clozapine and olanzapine on creatine kinase activity in cerebellum and prefrontal cortex suggest that these drugs may impair energy metabolism in these brain areas. [ABSTRACT FROM AUTHOR]

Abstract: Central nervous system dopaminergic mechanisms have been implicated in the cytokine response to stress and sepsis. We here describe the effects of haloperidol or clozapine in the treatment of sepsis induced by cecal ligation and puncture. Male Wistar rats were subjected to the CLP procedure were treated with haloperidol or clozapine and plasma cytokines, myeloperoxidase activity, markers of organ injury and survival was analyzed. The addition of haloperidol or clozapine to basic support did not diminished hepatic, renal, pancreatic or muscular damage observed after sepsis. Neither haloperidol, nor clozapine, modulates pro and antiinflammatory cytokines after sepsis induction. In addition, haloperidol treatment did not diminished myeloperoxidase activity in the kidney, lung or liver, or altered BALF markers of lung damage or inflammatory infiltration. Our data did not support a role of haloperidol or clozapine as an immunomodulator agent in the treatment of sepsis in an animal model of peritonitis. [Copyright &y& Elsevier]

Abstract: Methylphenidate is frequently prescribed for the treatment of attention deficit/hyperactivity disorder. Psychostimulants can cause long-lasting neurochemical and behavioral adaptations. The exact mechanisms underlying its therapeutic and adverse effects are still not well understood. In this context, it was previously demonstrated that methylphenidate altered brain metabolic activity, evaluated by glucose consumption. Most cell energy is obtained through oxidative phosphorylation, in the mitochondrial respiratory chain. Tissues with high energy demands, such as the brain, contain a large number of mitochondria. In this work, our aim was to measure the activities of mitochondrial respiratory chain complexes II and IV and succinate dehydrogenase in cerebellum, prefrontal cortex, hippocampus, striatum, and cerebral cortex of young rats (starting on 25th post-natal day and finishing on 53rd post-natal day) chronically treated with methylphenidate. Our results showed that mitochondrial respiratory chain enzymes activities were increased by chronic administration of this drug. Succinate dehydrogenase was activated in cerebellum, prefrontal cortex and striatum, but did not change in hippocampus and brain cortex. Complex II activity was increased in cerebellum and prefrontal cortex and was not affected in hippocampus, striatum and brain cortex. Finally, complex IV activity was increased in cerebellum, hippocampus, striatum and brain cortex, and was not affected in prefrontal cortex. These findings suggest that chronic exposure to methylphenidate in young rats increases mitochondrial enzymes involved in brain metabolism. Further research is being carried out in order to better understand the effects of this drug on developing nervous system and the potential consequences in adulthood resulting from early-life drug exposure. [Copyright &y& Elsevier]

Background: Acute mania can be modeled in animals using D-amphetamine (AMPH). Acute AMPH injections are associated with monoamine depletion, loss of neurofilaments and neurite degeneration. However, the precise mechanisms underlying AMPH-induced neurotoxicity are still unclear. Several studies have demonstrated that oxidative stress may play a role in the behavioral and neurochemical changes observed after AMPH administration. Methods: The effects of a single and repeated injections (seven daily injections) of AMPH administered intraperitonially on locomotion and the production of lipid and protein oxidative markers in rat cortex, striatum and hippocampus were assessed. Locomotion was assessed in an open-field task and markers of oxidative stress were assessed in brain tissue. Results: Both single and repeated injections of AMPH increased protein carbonyl formation in rat brain. Repeated exposure to AMPH induced an additional increase in thiobarbituric acid reactive species in brain tissue. Conclusions: Longer periods of exposure to AMPH were associated with increased oxidative stress in rat brain. This adds to the notion that repeated manic episodes may be associated with greater brain damage and, therefore, poorer outcomes. [ABSTRACT FROM AUTHOR]

The Passiflora extracts have been used in folk medicine because of its reputed sedative and anxiolytic properties. The present study aimed to compare the potential anxiolytic activity of two Passiflora spray-dried powders obtained from P. alata and P. edulis, known in Brazil as 'maracujá'. Male adult Swiss rats were treated with 200, 400 and 800 mg/kg of spray-dried powders p.o. and anxiolytic activity was evaluated using the elevated plus-maze test. The spray-dried powders showed anxiolytic activity in doses of 400 and 800 mg/kg. Our results support the potential anxiolytic effect of Passiflora spray-dried powders ( P. alata and P. edulis). Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]