Luciano K. Jornada

Lithium and valproate modulate antioxidant enzymes and prevent ouabain-induced oxidative damage in an animal model of mania

In this study, we assessed the oxidative stress parameters in rats submitted to an animal model of mania induced by ouabain (OUA), which included the use of lithium (Li) and valproate (VPA). Li and VPA treatment reversed and prevented the OUA-induced damage in these structures, however, this effect varies depending on the brain region and treatment regimen. Moreover, the activity of the antioxidant enzymes, namely, superoxide dismutase (SOD) and catalase (CAT) was found to be increased and decreased, respectively, in the brain of OUA-administered rats. Li and VPA modulated SOD and CAT activities in OUA-subjected rats in both experimental models. Our results support the notion that Li and VPA exert antioxidant-like properties in the brain of rats submitted to animal model of mania induced by ouabain.

Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain

There is a body of evidence suggesting that BDNF is involved in bipolar disorder (BD) pathogenesis. Intracerebroventricular (ICV) injection of ouabain (OUA), a specific Na(+)/K(+) ATPase inhibitor, induces hyperlocomotion in rats, and has been used as an animal model of mania. The present study aims to investigate the effects of the lithium (Li) and valproate (VPT) in an animal model of mania induced by ouabain. In the reversal model, animals received a single ICV injection of OUA or cerebrospinal fluid (aCSF). From the day following the ICV injection, the rats were treated for 6 days with intraperitoneal (IP) injections of saline (SAL), Li or VPT twice a day. In the maintenance treatment (prevention model), the rats received IP injections of Li, VPT, or SAL twice a day for 12 days. In the 7th day of treatment the animals received a single ICV injection of either OUA or aCSF. After the ICV injection, the treatment with the mood stabilizers continued for more 6 days. Locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus and amygdala by sandwich-ELISA. Li and VPT reversed OUA-related hyperactive behavior in the open-field test in both experiments. OUA decreased BDNF levels in first and second experiments in hippocampus and amygdala and Li treatment, but not VPT reversed and prevented the impairment in BDNF expression after OUA administration in these cerebral areas. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.

DARPP-32 expression in rat brain after electroconvulsive stimulation

Although electroconvulsive therapy (ECT) has been used as a treatment for mental disorder since 1930s, little progress has been made in the mechanisms underlying its therapeutic or adverse effects. The aim of this work was to analyze the expression of DARPP-32 (a protein with a central role in dopaminergic signaling) in striatum, cortex, hippocampus and cerebellum of Wistar rats subjected to acute or chronic electroconvulsive stimulation (ECS). Rats were submitted to a single stimulation (acute) or to a series of eight stimulations, applied one every 48 h (chronic). Animals were killed for collection of tissue samples at time zero, 0.5, 3, 12, 24 and 48 h after stimulation in the acute model and at the same time intervals after the last stimulation in the chronic model. Our results indicated that acute ECS produces smaller changes in the expression of DARPP-32 but, interestingly, chronic ECS increased transient expression of DARPP-32 in several time frames, in striatum and hippocampus, after the last stimulation. Results on the expression of proteins involved in signaling pathways are relevant for neuropsychiatric disorders and treatment, in particular ECT, and can contribute to shed light on the mechanisms related to therapeutic and adverse effects.

Intracerebral Administration of BDNF Protects Rat Brain Against Oxidative Stress Induced by Ouabain in an Animal Model of Mania

Several studies have suggested that alterations in brain-derived neurotrophic factor (BDNF) and increased oxidative stress have a central role in bipolar disorder (BD). Intracerebroventricular (ICV) injection of ouabain (OUA) in rats alters oxidative stress parameters and decreases BDNF levels in the brain. In this context, the present study aims to investigate the effects of BDNF ICV administration on BDNF levels and oxidative stress parameters in brains of rats submitted to animal model of mania induced by OUA. Wistar rats received an ICV injection of OUA, artificial cerebrospinal fluid (ACSF), OUA plus BDNF, or ACSF plus BDNF. Locomotor activity and risk-taking behavior in the rats were measured using the open-field test. In addition, we analyzed the BDNF levels and oxidative stress parameters (TBARS, Carbonyl, CAT, SOD, GR, and GPx) in the frontal cortex and hippocampus of rats. The BDNF was unable to reverse the ouabain-induced hyperactivity and risk-taking behavior. Nevertheless, BDNF treatment increased BDNF levels, modulated the antioxidant enzymes, and protected the OUA-induced oxidative damage in the brain of rats. These results suggest that BDNF alteration observed in BD patients may be associated with oxidative damage, both seen in this disorder.

Anxiety disorders are associated with quality of life impairment in patients with insulin-dependent type 2 diabetes: a case-control study

OBJECTIVE To assess the presence of anxiety disorders and quality of life in patients with insulin-dependent type 2 diabetes. METHODS Case-control study of 996 patients with type 2 diabetes and 2,145 individuals without diabetes. The sole inclusion criterion for the case group was insulin-dependent type 2 diabetes. We compared the case and control groups for sociodemographic variables, laboratory and clinical data, and presence of anxiety disorders. Quality of life was evaluated using the WHOQOL-BREF instrument, and the prevalence of anxiety disorder was evaluated by the Mini International Neuropsychiatric Interview (MINI). RESULTS Patients with diabetes had a higher prevalence of generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder. The presence of these disorders in combination with type 2 diabetes was associated with worse quality of life in the physical, social, psychological, and environmental domains. CONCLUSIONS This study demonstrates the importance of diagnosing and treating anxiety disorders in patients with diabetes, so as to prevent more serious complications associated with these comorbidities.

Eating disorders among health science students at a university in southern Brazil

Objectives: To analyze eating disorders among female university students and to assess the frequency of bulimia nervosa, anorexia nervosa, and inappropriate weight loss strategies in this population. Methods: The sample comprised 214 female university students attending different health science programs at a university in southern Brazil, aged over 18 years, assessed using self-administered questionnaires. The 26-item version of the Eating Attitudes Test (EAT-26), the Bulimic Investigatory Test, Edinburgh (BITE), and a supplementary questionnaire covering data on weight status and inappropriate weight loss strategies were used to assess dietary abnormalities. Results: Mean age (± standard deviation) was 21±9.93 years, and mean body mass index (BMI) was 21.1±2.59. Among the respondents, 72.9% said they would like to weigh less, 29% reported the use of different weight loss methods (diuretics were the most common, followed by laxatives, amphetamine-derived drugs, and self-induced vomiting). With regard to EAT-26 scores, 22.4% (95%CI 17.7-27.1) revealed abnormal feeding patterns; BITE indicated that 9.8% (95%CI 6.5-13.1) were at risk for developing bulimia and 36.9% (95%CI 31.5-42.3) required clinical evaluation. Mean BMI was lower among students with normal scores on both tests, but no association was found between BMI and satisfaction with own weight. Conclusion: There was a strong trend toward eating disorders in the health science students assessed, as demonstrated by EAT-26 and BITE scores; inadequate weight loss strategies are frequently used as well.

Vitamin B6 prevents cognitive impairment in experimental pneumococcal meningitis

Streptococcus pneumoniae is the relevant cause of bacterial meningitis, with a high-mortality rate and long-term neurological sequelae, affecting up to 50% of survivors. Pneumococcal compounds are pro-inflammatory mediators that induce an innate immune response and tryptophan degradation through the kynurenine pathway. Vitamin B6 acts as a cofactor at the active sites of enzymes that catalyze a great number of reactions involved in the metabolism of tryptophan, preventing the accumulation of neurotoxic intermediates. In the present study, we evaluated the effects of vitamin B6 on memory and on brain-derived neurotrophic factor (BDNF) expression in the brain of adult Wistar rats subjected to pneumococcal meningitis. The animals received either 10 µL of artificial cerebral spinal fluid (CSF) or an equivalent volume of S. pneumoniae suspension. The animals were divided into four groups: control, control treated with vitamin B6, meningitis, and meningitis treated with vitamin B6. Ten days after induction, the animals were subjected to behavioral tests: open-field task and step-down inhibitory avoidance task. In the open-field task, there was a significant reduction in both crossing and rearing in the control group, control/B6 group, and meningitis/B6 group compared with the training session, demonstrating habituation memory. However, the meningitis group showed no difference in motor and exploratory activity between training and test sessions, demonstrating memory impairment. In the step-down inhibitory avoidance task, there was a difference between training and test sessions in the control group, control/B6 group, and meningitis/B6 group, demonstrating aversive memory. In the meningitis group, there was no difference between training and test sessions, demonstrating impairment of aversive memory. In the hippocampus, BDNF expression decreased in the meningitis group when compared to the control group; however, adjuvant treatment with vitamin B6 increased BDNF expression in the meningitis group. Thus, vitamin B6 attenuated the memory impairment in animals subjected to pneumococcal meningitis.

Lithium and valproate act on the GSK-3β signaling pathway to reverse manic-like behavior in an animal model of mania induced by ouabain

&NA; The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on the PI3K/Akt signaling pathway in the brains of rats subjected to the ouabain (OUA)‐induced animal model of mania. In addition, the effects of AR‐A014418, a GSK‐3&bgr; inhibitor, on manic‐like behavior induced by OUA were evaluated. In the first experimental protocol Wistar rats received a single ICV injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li or VPA twice a day. In the second experimental protocol, rats received OUA, aCSF, OUA plus AR‐A014418, or aCSF plus AR‐A014418. On the 7th day after OUA injection, locomotor activity was measured using the open‐field test. In addition, we analyzed the levels of p‐PI3K, p‐MAPK, p‐Akt, and p‐GSK‐3&bgr; in the brain of rats by immunoblot. Li and VPA reversed OUA‐related hyperactivity. OUA decreased p‐PI3K, p‐Akt and p‐GSK‐3&bgr; levels. Li and VPA improved these OUA‐induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. In addition, AR‐A014418 reversed the manic‐like behavior induced by OUA. These findings suggest that the manic‐like effects of ouabain are associated with the activation of GSK‐3&bgr;, and that Li and VPA exert protective effects against OUA‐induced inhibition of the GSK‐3&bgr; pathway. HighlightsOuabain (OUA)‐induced manic‐like behavior in animal model of mania.Mania is clinic march clinical of bipolar disorder; mood stabilizers such as lithium (Li) and valproate (VPA) reversed the manic‐like behavior induced by OUA.Bipolar patients overexpress GSK‐3&bgr;; AR‐A0144818, an inhibitor of GSK‐3&bgr;, reversed the manic‐like behavior induced by OUA.

Neonatal Escherichia coli K1 meningitis causes learning and memory impairments in adulthood

Neonatal Escherichia coli meningitis continues to be an important cause of mortality and morbidity in newborns worldwide. The aim of this study was to investigate the cytokines/chemokines, brain-derived neurotrophic factor (BDNF) levels, blood-brain barrier integrity in neonatal rats following E. coli K1 experimental meningitis infection and subsequent behavioural parameters in adulthood. In the hippocampus, interleukin increased at 96 h, IL-6 at 12, 48 and 96 h, IL-10 at 96 h, cytokine-induced neutrophil chemoattractant-1 at 6, 12, 24, 48 and 96 h, and BDNF at 48 and 96 h. In the cerebrospinal fluid, tumour necrosis factor alpha levels increased at 6, 12, 24, 48 and 96 h. The BBB breakdown occurred at 12 h in the hippocampus, and at 6h in the cortex. We evaluated behavioural parameters in adulthood: habituation to the open-field, step-down inhibitory avoidance, object recognition, continuous multiple-trials step-down inhibitory avoidance and forced swimming tasks. In adulthood, the animals showed habituation and aversive memory impairment. The animals needed a significant increase in the number of training periods to learn and not had depressive-like symptoms.

Decreased BDNF levels in amygdala and hippocampus after intracerebroventricular administration of ouabain

OBJETIVO: O presente estudo tem como objetivo investigar os efeitos da injecao intracerebroventricular de ouabaina sobre os niveis de BDNF na amigdala e no hipocampo de ratos Wistar. METODOS: Os animais receberam uma unica injecao intracerebroventricular de ouabaina (10-3 and 10-2 M) ou fluido cerebroespinhal artificial e, imediatamente, 3h, 24h ou sete dias apos a injecao, os niveis de BDNF foram mensurados na amigdala e hipocampo dos ratos por ELISA sandwich (n = 8 animais por grupo). RESULTADOS: Quando avaliados imediatamente apos a injecao, 3h ou 24h, ouabaina nas doses 10-2 e 10-3 M nao alterou os niveis de BDNF em ambas as estruturas avaliadas. Entretanto, quando avaliados sete dias apos a injecao, ouabaina nas doses 10-2 e 10-3 M mostrou uma significante reducao nos niveis de BDNF em amigdala e hipocampo. CONCLUSAO: Em conclusao, propoe-se que a administracao de ouabaina diminuiu os niveis de BDNF em amigdala e hipocampo quando avaliados sete dias apos a injecao, suportando a hipotese da participacao da Na/K ATPase no transtorno bipolar.