l-Hypaphorine and d-hypaphorine: Specific antiacetylcholinesterase activity in rat brain tissue.

Acetylcholinesterase (AChEis) inhibitors are used to treat neurodegenerative diseases like Alzheimer's disease (AD). l-Hypaphorine (l-HYP) is a natural indole alkaloid that has been shown to have effects on the central nervous system (CNS). The goal of this research was to synthesize l-HYP and d-HYP and test their anticholinesterasic properties in rat brain regions. l-HYP suppressed acetylcholinesterase (AChE) activity only in the cerebellum, whereas d-HYP inhibited AChE activity in all CNS regions studied. No cytotoxic effect on normal human cells (HaCaT) was observed in the case of l-HYP and d-HYP although an increase in cell proliferation. Molecular modeling studies revealed that d-HYP and l-HYP have significant differences in their binding mode positions and interact stereospecifically with AChE's amino acid residues.

S100B protein and neuron-specific enolase as predictors of postoperative cognitive dysfunction in aged dogs: a case-control study.

OBJECTIVE: Postoperative cognitive dysfunction (POCD) may be related to brain injury. S100B protein and neuron-specific enolase (NSE) have been investigated as potential biochemical markers of neural cell injury in animals and humans. This study aimed to investigate the association between POCD, brain injury and serum concentrations of S100B and NSE after periodontal surgery in aged dogs. STUDY DESIGN: Prospective observational animal study. ANIMALS: A total of 24 male and female dogs undergoing periodontal surgery. METHODS: Dogs were separated into two groups based on age: control group, 10 dogs ≤ 8 years and aged group, 14 dogs > 8 years. Cognitive function was measured preoperatively and on the seventh postoperative day using the Canine Cognitive Dysfunction Rating scale and the Age-Related Cognitive and Affective Disorders scale. S100B protein and NSE serum concentrations were measured before and immediately after the surgery. RESULTS: POCD was not observed after surgery in the present study. Serum concentrations of S100B and NSE were increased postoperatively in the control group but not in the aged group (p = 0.04 and 0.03, respectively). Preoperative S100B serum concentrations were significantly higher in the aged group (p = 0.01). CONCLUSIONS: There was no association between POCD and high concentrations of S100B and NSE in dogs. However, increased postoperative serum concentrations of S100B and NSE were found in the control group after surgery, an effect that may indicate neural damage. CLINICAL RELEVANCE: The results suggest that anesthesia and oral surgery are associated with higher postoperative serum concentrations of S100B and NSE in dogs ≤ 8 years old, which may indicate neural damage. Serum concentrations of S100B were elevated in aged dogs before anesthesia, a finding that might be related to chronic preoperative brain damage.

Serum level of nerve growth factor is a potential biomarker of conversion to bipolar disorder in women with major depressive disorder.

AIM: The aim of this study was to identify biomarkers associated with major depressive disorder (MDD) and conversion from MDD to bipolar disorder (BD) in an outpatient sample of women. METHODS: This was a longitudinal study including women diagnosed with MDD and aged 18 to 60 years. The follow-up was 3 years. The diagnosis was performed using the Mini International Neuropsychiatric Interview Plus. Blood collection was just performed in the first phase. Serum interleukin-6, tumor necrosis factor-α, brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and nerve growth factor (NGF) levels were measured using a commercial immunoassay kit. RESULTS: We included 156 women. The conversion rate from MDD to BD was 15.4% (n = 24). NGF serum levels were increased in patients who converted to BD compared to the remitted MDD group and current MDD group (P = 0.013). The Bonferroni post-hoc test for multiple comparisons revealed significant differences for higher NGF levels in patients who converted to BD compared to patients with current MDD (P = 0.037). Interleukin-6, tumor necrosis factor-α, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor serum levels did not differ among the groups. CONCLUSION: Our results suggest that NGF might be a useful biomarker associated with early detection of conversion to BD, helping clinicians in the clinical diagnosis.

S100B protein and neuron-specific enolase as predictors of cognitive dysfunction after coronary artery bypass graft surgery: A prospective observational study.

BACKGROUND: Postoperative cognitive dysfunction (POCD) may be related to the systemic inflammatory response and an increase in serum markers of brain injury such as S100B protein and neuron-specific enolase (NSE). OBJECTIVE: The study aims to evaluate the association between POCD and serum levels of S100B and NSE after coronary artery bypass grafting surgery (CABG). DESIGN: Prospective observational study. SETTING: Single university teaching hospital. PATIENTS: We investigated 88 patients undergoing CABG. MAIN OUTCOMES MEASURES: Cognitive function was measured preoperatively, and at the 21st and 180th postoperative days (i.e. 6 months after surgery). S100B protein and NSE serum levels were evaluated preoperatively, after induction of anaesthesia, at the end of surgery and at 6 and 24 h after surgery. RESULTS: The incidence of POCD was 26.1% at 21 days after surgery and 22.7% at 6 months after surgery. Increased serum levels of S100B protein and NSE were observed postoperatively and may indicate brain damage. CONCLUSION: Although serum levels of S100B protein and NSE are both significantly increased postoperatively, our findings indicate that serum levels of S100B protein may be more accurate than NSE in the detection of POCD after CABG. TRIAL REGISTRATION: NCT01550159.

Changes in Purines Concentration in the Cerebrospinal Fluid of Pregnant Women Experiencing Pain During Active Labor.

Labor pain has been reported as a severe pain and can be considered as a model of acute visceral pain. It is well known that extracellular purines have an important role in pain signaling in the central nervous system. This study analyzes the relationship between extracellular purines and pain perception during active labor. A prospective observational study was performed. Cerebrospinal fluid (CSF) levels of the purines and their metabolites were compared between women at term pregnancy with labor pain (n = 49) and without labor pain (Caesarian section; n = 47). Control groups (healthy men and women without chronic or acute pain-n = 40 and 32, respectively) were also investigated. The CSF levels of adenosine were significantly lower in the labor pain group (P = 0.026) and negatively correlated with pain intensity measured by a visual analogue scale (r = -0.48, P = 0.0005). Interestingly, CSF levels of uric acid were significantly higher in healthy men as compared to women. Additionally, pregnant women showed increased CSF levels of ADP, GDP, adenosine and guanosine and reduced CSF levels of AMP, GTP, and uric acid as compared to non-pregnant women (P < 0.05). These findings suggest that purines, in special the nucleoside adenosine, are associated with pregnancy and labor pain.

Leptin in depressive episodes: is there a difference between unipolar and bipolar depression?

OBJECTIVE: The present study investigated whether peripheral leptin levels are associated with current depressive episodes in a cross-sectional study nested within a population-based study. METHODS: The Mini-International Neuropsychiatric Interview (MINI) 5.0 was used to assess the presence of current depressive episodes. The sample was composed of 206 subjects (103 controls and 103 subjects with a current depressive episode) paired by gender, BMI and age. Medication use and lifestyle characteristics were self-reported. RESULTS: Serum leptin levels were lower in currently depressive subjects (10.9 ± 12.0 ng/ml) than in the control group (20.3 ± 24.0 ng/ml; p = 0.023). According to the clinical diagnosis, individuals with bipolar depression present lower leptin levels (8.4 ± 8.1 ng/ml) than those with unipolar depression (12.0 ± 13.4 ng/ml) and the control group (20.3 ± 24.0 ng/ml; p = 0.031). In addition, ANCOVA showed that leptin is an independent factor associated with current depressive episodes (p = 0.018). CONCLUSION: A decreased leptin level might be a useful peripheral marker associated with depressive episodes in the context of bipolar disorder.

Immune dysfunction in bipolar disorder and suicide risk: is there an association between peripheral corticotropin-releasing hormone and interleukin-1ß?

OBJECTIVE: The aim of the present study was to investigate the relationship between peripheral levels of corticotropin-releasing hormone (CRH) and interleukin-1ß (IL-1ß) in individuals with bipolar disorder (BD) with and without suicide risk (SR), and controls. METHODS: A total of 120 young adults (40 controls, 40 subjects with BD without SR, and 40 subjects with BD with SR) were enrolled from a population-based study carried out in the city of Pelotas, Brazil. BD and SR were assessed through the Mini International Neuropsychiatric Interview (MINI 5.0), and peripheral markers were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Levels of CRH were significantly lower both in subjects with BD without SR (p = 0.04) and subjects with BD with SR (p = 0.02) when compared to controls. However, levels of IL-1ß were increased in subjects with BD with SR (p = 0.05) when compared to controls. Sociodemographic and clinical variables, current mood episode, and use of psychiatric medications were not associated with changes in these markers. No correlation was found between peripheral levels of CRH and IL-1ß (p = 0.60) in the population or in the BD with SR group (p = 0.88). CONCLUSIONS: These results suggest that peripheral mechanisms linking stress hormones and the immune system might be critical patterns involved in suicidal behavior associated with BD.

Dietary omega-3 deficiency reduces BDNF content and activation NMDA receptor and Fyn in dorsal hippocampus: implications on persistence of long-term memory in rats.

Omega-3 (n-3) fatty acids are important for adequate brain function and cognition. The aim of the present study was to evaluate how n-3 fatty acids influence the persistence of long-term memory (LTM) in an aversive memory task and to explore the putative mechanism involved. Female rats received isocaloric diets that included n-3 (n-3 group) or not (D group). The adult litters were subjected to an inhibitory avoidance task (0.7 mA, 1.0 seconds foot shock) to elicit persistent LTM. Twelve hours after the training session, the fatty acid profile and the brain derived neurotrophic factor (BDNF) content of the dorsal hippocampus were assessed. In addition, we measured the activation of the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor and the SRC family protein Fyn. Despite pronounced learning in both groups, the persistence of LTM was abolished in the D group 7 days after the training session. We also observed that the D group presented reductions in hippocampal DHA (22:6 n-3) and BDNF content. Twelve hours after the training session, the D group showed decreased NR2B and Fyn phosphorylation in the dorsal hippocampus, with no change in the total content of these proteins. Further, there was a decrease in the interaction of Fyn with NR2B in the D group, as observed by co-immunoprecipitation. Taken together, these data suggest that n-3 fatty acids influence the persistence of LTM by maintaining adequate levels of DHA and BDNF as well as by influencing the activation of NR2B and Fyn during the period of memory formation.

Lower and higher volumes of physical exercise build up brain reserves against memory deficits triggered by a head injury in mice.

Decreasing neurotrophic support and impaired mitochondrial bioenergetics are key mechanisms for long-term neurodegeneration and cognitive decline after traumatic brain injury (TBI). We hypothesize that preconditioning with lower and higher volumes of physical exercise upregulates the CREB-BDNF axis and bioenergetic capability, which might serve as neural reserves against cognitive impairment after severe TBI. Using a running wheel mounted in the home cage, mice were engaged in lower (LV, 48 h free access, and 48 h locked) and higher (HV, daily free access) exercise volumes for thirty days. Subsequently, LV and HV mice remained for additional thirty days in the home cage with the running wheel locked and were euthanized. The sedentary group had the running wheel always locked. For the same type of exercise stimulus in a given time, daily workout presents higher volume than alternate days workout. The total distance ran in the wheel was the reference parameter to confirm distinct exercise volumes. On average, LV exercise ran 27.522 m and HV exercise ran 52.076 m. Primarily, we investigate whether LV and HV protocols increase neurotrophic and bioenergetic support in the hippocampus thirty days after exercise ceased. Regardless of volume, exercise increased hippocampal pCREBSer133-CREB-proBDNF-BDNF signaling and mitochondrial coupling efficiency, excess capacity, and leak control, that may compose the neurobiological basis for neural reserves. Further, we challenge these neural reserves against secondary memory deficits triggered by a severe TBI. After thirty days of exercise LV and HV, and sedentary (SED) mice were submitted to the CCI model. Mice remained for additional thirty days in the home cage with the running wheel locked. The mortality after severe TBI was approximately 20% in LV and HV, while in the SED was 40%. Also, LV and HV exercise sustained hippocampal pCREBSer133-CREB-proBDNF-BDNF signaling, mitochondrial coupling efficiency, excess capacity, and leak control for thirty days after severe TBI. Corroborating these benefits, the mitochondrial H2O2 production linked to complexes I and II was attenuated by exercise regardless of the volume. These adaptations attenuated spatial learning and memory deficits caused by TBI. In summary, preconditioning with LV and HV exercise builds up long-lasting CREB-BDNF and bioenergetic neural reserves that preserve memory fitness after severe TBI.

Probucol Protects Neuronal Cells Against Peroxide-Induced Damage and Directly Activates Glutathione Peroxidase-1.

Experimental evidence has shown that probucol, a hypocholesterolemic agent, is also able to increase glutathione peroxidase (GPx) activity. However, there is a lack of knowledge about the mechanism(s) involved in this event. In this study, in vitro experiments with purified GPx1 from bovine erythrocytes and cultured SH-SY5Y neuroblastoma cells, as well as in silico studies with GPx1, were performed in order to elucidate mechanisms mediating the stimulatory effect of probucol on GPx activity and to investigate the relevance of this event in terms of susceptibility against peroxide-induced cytotoxicity. In vitro experiments with purified GPx1 showed a direct stimulatory effect of probucol on the activity of GPx1, which was related to an increase in Vmax with no changes in KM. Probucol also increased GPx activity in cultured SH-SY5Y neuroblastoma cells, while the levels of GPx1 expression were not changed, corroborating the results found with the purified enzyme. In addition, probucol rendered SH-SY5Y cells more resistant to hydroperoxide-induced cytotoxicity, and this event was abolished in GPx1 knocked-down cells. In silico studies with GPx1 pointed to a potential binding site for probucol at the close vicinity of the GSH pocket. Collectively, the results presented herein indicate that GPx1 plays a central role in the probucol-induced protective effects against peroxide toxicity. This highlights a novel target (GPx1) and a new mechanism of action (direct activation) for an "old drug." The relevance of such results for in vivo conditions deserves further investigation.

Intradialytic exercise with blood flow restriction: Something to add to hemodialysis adequacy? Findings from a crossover study.

INTRODUCTION: Hemodialysis (HD) increases the lifespan of chronic kidney disease (CKD) patients. However, HD is only partially effective in replacing renal function. The aim of this study is to compare HD adequacy between sessions with intradialytic exercise with or without blood flow restriction (BFR) with sessions without exercise. METHODS: A crossover study including 22 adult CKD patients on HD. The patients were assigned to BFR (n = 11) or exercise alone group (n = 11). Each patient was submitted to four HD sessions (two with exercise and two control sessions). HD adequacy was assessed by equilibrated Kt/V-urea (eKT/V), single-pool Kt/V-urea (sp-Kt/V), urea and phosphorus rebound, urea reduction ratio (URR) and removal of urea and phosphorus in dialysate. FINDINGS: BFR exercise improved eKt/V and sp-Kt/V (1.32 ± 0.21 vs. 1.10 ± 0.16 for control, P < 0.001; 1.53 ± 0.26 vs. 1.27 ± 0.19 for control, P < 0.001, respectively) and URR (72.5 ± 5.4% vs. 66.1 ± 7.7% for control, P < 0.001). No difference in eKt/V, sp-Kt/V or URR could be detected between exercise alone and control HD sessions. Urea rebound was lower in BFR exercise vs. control sessions (-8.9 ± 9.1% vs. 30.7 ± 12.8%, P < 0.01) and exercise alone vs. control sessions (13.3 ± 29.0% vs. 42.4 ± 15.3%, P < 0.01). Phosphorus rebound was marginally lower in exercise vs. control sessions (14.4 ± 19.1% vs. 28.4 ± 22.1%, P = 0.18). Urea and phosphorus mass removal in dialysate were marginally higher in exercise vs. control sessions (42.2 ± 19.4 g vs. 35.7 ± 12.5 g, P = 0.24; 912.1 ± 360.9 mg vs. 778.6 ± 245.1 mg, P = 0.28). CONCLUSIONS: Intradialytic exercise with BFR was more effective than standard exercise in increasing HD adequacy.

BDNF Val66Met polymorphism and resilience in major depressive disorder: the impact of cognitive psychotherapy.

OBJECTIVE: Clinical and biological correlates of resilience in major depressive disorder are scarce. We aimed to investigate the effect of the Val66Met polymorphism in the BDNF gene on resilience scores in major depressive disorder patients and evaluate the polymorphism's moderation effect on resilience scores in response to cognitive therapy. METHOD: A total of 106 major depressive disorder patients were enrolled in this clinical randomized study. The Resilience Scale and the Hamilton Rating Scale for Depression were applied at baseline, post-treatment, and at six months of follow-up. Blood samples were obtained at baseline for molecular analysis. RESULTS: The baseline resilience scores were higher in patients with the Met allele (114.6±17.6) than in those with the Val/Val genotype (104.04±21.05; p = 0.037). Cognitive therapy treatment increased resilience scores (p ≤ 0.001) and decreased depressive symptoms (p ≤ 0.001). In the mixed-effect model, the Val/Val genotype represented a decrease in resilience scores (t218 = -1.98; p = 0.048), and the Val66Met polymorphism interacted with sex to predict an increase in total resilience scores during cognitive treatment (t218 = 2.69; p = 0.008). CONCLUSION: Our results indicate that cognitive therapy intervention could improve resilience in follow-up, considering that gender and genetic susceptibility are predicted by the Val66Met polymorphism.

The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia.

Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes. In addition, the IDO inhibitor prevented lipid peroxidation, and decreased the levels of protein carbonyl in the prefrontal cortex (PFC), hippocampus and striatum. It also increased the activity of superoxide dismutase (SOD) in the hippocampus, as well as increasing the levels of catalase activity in the PFC and hippocampus. The TDO inhibitor prevented lipid damage in the striatum and reduced the levels of protein carbonyl in the hippocampus and striatum. Also, the TDO inhibitor increased the levels of SOD activity in the striatum and CAT activity in the hippocampus of ketamine-induced pro-oxidant effects. Lipid damage was not reversed by the KMO inhibitor. The KMO inhibitor increased the levels of SOD activity in the hippocampus, and reduced the levels of protein carbonyl while elevating the levels of CAT activity in the striatum of rats that had been injected with ketamine. Our findings revealed that the KP pathway could be a potential mechanism by which a schizophrenia animal model induced by ketamine could cause interference by producing behavioral disturbance and inducing oxidative stress in the brain, suggesting that the inhibition of the KP pathway could be a potential target in treating schizophrenia.

Effects of cognitive-behavioral therapy on neurotrophic factors in patients with major depressive disorder.

OBJECTIVE: To correlate neurotrophic factors - brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and beta-nerve growth factor (beta-NGF) - and severity of depressive symptoms in patients diagnosed with major depressive disorder (MDD) undergoing cognitive-behavioral therapy (CBT). METHODS: In this quasi-experimental study, participants were selected by convenience and received 16 sessions of CBT. The outcomes of interest were severity of depressive symptoms and changes in neurotrophic factor levels after CBT. The differences between variables before and after treatment (deltas) were analyzed. RESULTS: Patients had significant changes in symptom severity after treatment. No significant associations were found between Beck Depression Inventory II (BDI-II) scores and any independent variable. No correlations were observed between BDNF or GDNF levels and BDI scores before or after treatment, although there was a trend toward significant differences in beta-NGF levels. CONCLUSION: BDNF, beta-NGF, and GDNF were not influenced by the effects of CBT on depressive symptoms.

Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation.

Despite the characteristic etiologies and phenotypes, different brain disorders rely on common pathogenic events. Glutamate-induced neurotoxicity is a pathogenic event shared by different brain disorders. Another event occurring in different brain pathological conditions is the increase of the extracellular ATP levels, which is now recognized as a danger and harmful signal in the brain, as heralded by the ability of P2 receptors (P2Rs) to affect a wide range of brain disorders. Yet, how ATP and P2R contribute to neurodegeneration remains poorly defined. For that purpose, we now examined the contribution of extracellular ATP and P2Rs to glutamate-induced neurodegeneration. We found both in vitro and in vivo that ATP/ADP through the activation of P2Y1R contributes to glutamate-induced neuronal death in the rat hippocampus. We found in cultured rat hippocampal neurons that the exposure to glutamate (100 µM) for 30 min triggers a sustained increase of extracellular ATP levels, which contributes to NMDA receptor (NMDAR)-mediated hippocampal neuronal death through the activation of P2Y1R. We also determined that P2Y1R is involved in excitotoxicity in vivo as the blockade of P2Y1R significantly attenuated rat hippocampal neuronal death upon the systemic administration of kainic acid or upon the intrahippocampal injection of quinolinic acid. This contribution of P2Y1R fades with increasing intensity of excitotoxic conditions, which indicates that P2Y1R is not contributing directly to neurodegeneration, rather behaving as a catalyst decreasing the threshold from which glutamate becomes neurotoxic. Moreover, we unraveled that such excitotoxicity process began with an early synaptotoxicity that was also prevented/attenuated by the antagonism of P2Y1R, both in vitro and in vivo. This should rely on the observed glutamate-induced calpain-mediated axonal cytoskeleton damage, most likely favored by a P2Y1R-driven increase of NMDAR-mediated Ca2+ entry selectively in axons. This may constitute a degenerative mechanism shared by different brain diseases, particularly relevant at initial pathogenic stages.

Enhanced cholinergic-tone during the stress induce a depressive-like state in mice.

Major depressive disorder has a heterogeneous etiology, since it arises from the interaction of multiple factors and different pathophysiological mechanisms are involved in the symptomatology. This study aimed to investigate the role of the cholinergic system in the susceptibility to stress and, consequently, in the depression-like behavior. C57BL/6 mice were treated with Physostigmine (PHYS), an acetylcholinesterase (AChE) inhibitor, and were submitted to the social defeat stress. For the behavioral evaluation of the locomotor activity, anxiety-like and depression-like behaviors the open field, elevated plus maze, sucrose preference, social interaction and forced swim were used. Hippocampus and prefrontal cortex samples were collected for evaluation of AChE activity, as well as blood samples for analysis of serum cortisol levels. Our results showed that 15 min after the injection of PHYS there was a significant inhibition of AChE activity in the hippocampus and in the prefrontal cortex. On the other hand, in the end of the experimental design, day 12, there was no difference in AChE activity levels. Inhibition of AChE and exposure to the stress led to an increase in cortisol levels. Animals that received PHYS and were exposed to stress showed less social interaction and greater learned helplessness, anhedonia and anxious-like behavior. Taken together, our findings suggest that increasing the cholinergic tone shortly before stress induction impacts on the ability to cope with upcoming stressful situations, leading to a depressive-like state.

Mood disorder, anxiety, and suicide risk among subjects with alcohol abuse and/or dependence: a population-based study.

OBJECTIVE: To evaluate the prevalence of alcohol abuse and/or dependence in a population-based sample of young adults and assess the prevalence of comorbid mood disorders, anxiety, and suicide risk in this population. METHODS: This cross-sectional, population-based study enrolled 1,953 young adults aged 18-35 years. The CAGE questionnaire was used to screen for alcohol abuse and/or dependence, with CAGE scores ≥ 2 considered positive. Psychiatric disorders were investigated through the structured Mini International Neuropsychiatric Interview (MINI). RESULTS: Alcohol abuse and/or dependence was identified in 187 (9.60%) individuals (5.10% among women and 15.20% among men). Alcohol abuse and/or dependence were more prevalent among men than women, as well as among those who used tobacco, illicit drugs or presented with anxiety disorder, mood disorder, and suicide risk. CONCLUSION: These findings suggest that alcohol abuse and/or dependence are consistently associated with a higher prevalence of psychiatric comorbidities, could be considered important predictors of other psychiatric disorders, and deserve greater public heath attention, pointing to the need for alcohol abuse prevention programs.

Ketamine potentiates oxidative stress and influences behavior and inflammation in response to lipolysaccharide (LPS) exposure in early life.

Immune activation (IA) during the early neonatal period is a risk factor for the development of schizophrenia. Lipopolysaccharide (LPS) injected in neonates lead to behavioral and brain changes that persist to adult life. We investigated oxidative stress, levels of cytokines, and the locomotor activity of IA in a schizophrenia animal model in which neonatal male Wistar rats were administered with an injection of LPS (50µg/kg) on postnatal day 3 and different doses of ketamine (5, 15 and 25mg/kg) for 7days during adulthood. Rats LPS-induced did not have locomotor activity alterations. Locomotor activity was elevated in neonatally saline-injected in the higher dose ketamine-treated animals. Carbonyl protein in the prefrontal cortex (PFC), hippocampus and striatum were increased in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Lipid damage occurred in the PFC, striatum and hippocampus in the LPS- and saline-induced in the ketamine (15 and 25mg/kg) -treated animals. In the hippocampus the superoxide dismutase (SOD) was decreased in the LPS- and saline-induced in the ketamine-treated with the dose of 25mg/kg. In the PFC SOD was reduced in the LPS-induced in the ketamine (25mg/kg)-treated animals. Catalase in the PFC and hippocampus was reduced in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Pro- and anti-inflammatory cytokines were lower in the brains of LPS-induced in the higher dose ketamine-treated rats. IA influences the locomotor activity and cytokine levels induced by ketamine, and it has a negative effect in potentiating the oxidative stress by higher doses of ketamine in the brain.

Elevated glutamate and lactate predict brain death after severe head trauma.

OBJECTIVE: Clinical neurological assessment is challenging for severe traumatic brain injury (TBI) patients in the acute setting. Waves of neurochemical abnormalities that follow TBI may serve as fluid biomarkers of neurological status. We assessed the cerebrospinal fluid (CSF) levels of glutamate, lactate, BDNF, and GDNF, to identify potential prognostic biomarkers of neurological outcome. METHODS: This cross-sectional study was carried out in a total of 20 consecutive patients (mean [SD] age, 29 [13] years; M/F, 9:1) with severe TBI Glasgow Coma Scale ≤ 8 and abnormal computed tomography scan on admission. Patients were submitted to ventricular drainage and had CSF collected between 2 and 4 h after hospital admission. Patients were then stratified according to two clinical outcomes: deterioration to brain death (nonsurvival, n = 6) or survival (survival, n = 14), within 3 days after hospital admission. CSF levels of brain-derived substances were compared between nonsurvival and survival groups. Clinical and neurological parameters were also assessed. RESULTS: Glutamate and lactate are significantly increased in nonsurvival relative to survival patients. We tested the accuracy of both biomarkers to discriminate patient outcome. Setting a cutoff of >57.75, glutamate provides 80.0% of sensitivity and 84.62% of specificity (AUC: 0.8214, 95% CL: 54.55-98.08%; and a cutoff of >4.65, lactate has 100% of sensitivity and 85.71% of specificity (AUC: 0.8810, 95% CL: 54.55-98.08%). BDNF and GDNF did not discriminate poor outcome. INTERPRETATION: This early study suggests that glutamate and lactate concentrations at hospital admission accurately predict death within 3 days after severe TBI.

Polymorphism in CRHR1 gene affects the IL-1ß levels in suicidal attempters.

Approximately one million people commit suicide every year, being suicide attempts and ideation even more common. Changes in stress response and activation of the immune system have been associated with suicide risk. Here we investigated the interaction between immune system and HPA axis alterations in the suicide risk, looking for the influence of rs110402 CRHR1 SNP in the IL-1ß levels according to suicide ideation and attempt. This study evaluated 171 subjects of which 15 had suicidal ideation, 20 had suicide attempt and 136 were controls. Genotyping was performed by real-time PCR and IL-1ß levels were measured by ELISA. Our data showed that for each point increase in IL-1ß levels the risk of suicide attempt increased 5% [relative risk = 1.05 (95% CI: 1.0-1.10)]. After sample stratification by rs110402 SNP genotypes, we observed that in subjects carrying the A allele the risk raised to 15% [relative risk = 1.15 (95% CI: 1.03-1.28)], suggesting an apparent effect modification. Thus, this study showed that alterations in CRHR1 gene were associated with higher levels of IL-1ß, and increased risk for suicide, reinforcing the importance of multifactorial interactions of biological markers for psychiatric disorders.