Long-lasting recognition memory impairment and alterations in brain levels of cytokines and BDNF induced by maternal deprivation: effects of valproic acid and topiramate.

Exposure to stressful events early in life may have permanent deleterious consequences on nervous system function and increase the susceptibility to psychiatric conditions later in life. Maternal deprivation, commonly used as a source of neonatal stress, impairs memory in adult rats and reduces hippocampal brain-derived neurotrophic factor (BDNF) levels. Inflammatory cytokines, such as interleukins (IL) and tumor necrosis factor-α (TNF-α) have been shown to be increased in the peripheral blood of patients with psychiatric disorders. The aim of the present study was to investigate the effects of maternal separation on the levels of IL-10 and TNF-α, and BDNF in the hippocampus and prefrontal cortex of adult rats. We also evaluated the potential ameliorating properties of topiramate and valproic acid on memory deficits and cytokine and BDNF changes associated with maternal deprivation. The results indicated that, in addition to inducing memory deficits, maternal deprivation increased the levels of IL-10 in the hippocampus, and TNF-α in the hippocampus and in the cortex, and decreased hippocampal levels of BDNF, in adult life. Neither valproic acid nor topiramate were able to ameliorate memory deficits or the reduction in BDNF induced by maternal separation. The highest dose of topiramate was able to reduce IL-10 in the hippocampus and TNF-α in the prefrontal cortex, while valproate only reduced IL-10 levels in the hippocampus. These findings may have implications for a better understanding of the mechanisms associated with alterations observed in adult life induced by early stressful events, and for the proposal of novel therapeutic strategies.

Correlation between Peripheral Levels of Brain-Derived Neurotrophic Factor and Hippocampal Volume in Children and Adolescents with Bipolar Disorder.

Pediatric bipolar disorder (PBD) is a serious mental disorder that affects the development and emotional growth of affected patients. The brain derived neurotrophic factor (BDNF) is recognized as one of the possible markers of the framework and its evolution. Abnormalities in BDNF signaling in the hippocampus could explain the cognitive decline seen in patients with TB. Our aim with this study was to evaluate possible changes in hippocampal volume in children and adolescents with BD and associate them to serum BDNF. Subjects included 30 patients aged seven to seventeen years from the ProCAB (Program for Children and Adolescents with Bipolar Disorder). We observed mean right and left hippocampal volumes of 41910.55 and 41747.96 mm(3), respectively. No statistically significant correlations between peripheral BDNF levels and hippocampal volumes were found. We believe that the lack of correlation observed in this study is due to the short time of evolution of BD in children and adolescents. Besides studies with larger sample sizes to confirm the present findings and longitudinal assessments, addressing brain development versus a control group and including drug-naive patients in different mood states may help clarify the role of BDNF in the brain changes consequent upon BD.

Increase in brain-derived neurotrophic factor expression in early crack cocaine withdrawal.

Recent reports suggest that brain-derived neurotrophic factor (BDNF) could be a biomarker for relapse, drug craving and withdrawal severity. In particular, elevated BDNF levels among former cocaine users have been associated with higher rates of relapse in 90 d. However, no data are available on BDNF levels at baseline and during crack cocaine withdrawal. This study evaluated BDNF among crack cocaine users during inpatient treatment, before and after withdrawal, vs. healthy controls. Clinical correlates with changes in BDNF levels were also assessed. Serum BDNF was evaluated in 49 male crack users on the first and last days of hospitalization and in 97 healthy controls. Serum BDNF was assayed using a sandwich ELISA kit. BDNF levels were significantly lower upon admission when compared to controls, even after adjustment for age, length of inpatient treatment, number of crack rocks used in the last 30 d, years of crack use and interaction between the latter two variables. At discharge, BDNF levels between patients and controls were similar. Number of crack rocks used in the last 30 d and years of crack use were inversely correlated with the outcome. Our findings show that BDNF levels increase during early crack cocaine withdrawal, at an inverse correlation with number of crack rocks used in the last 30 d and years of crack use.

Inflammation and internalizing disorders in adolescents.

Serum inflammatory markers have been studied in adults with anxiety and depression, but little is known about cytokine levels in young adolescents with emotional disorders. The objective of this study is to compare serum levels of interleukin-6 (IL-6) and interleukin-10 (IL-10) between adolescents with internalizing disorders and adolescents from the same community without internalizing disorders. A total of 134 non-medicated subjects (n=76 with internalizing disorders) were recruited from a larger sample of 2457 individuals. Serum levels of IL-6 and IL-10 were quantified and psychiatric diagnosis was evaluated using structured clinical interviews. Adolescents with internalizing disorders presented significantly higher levels of IL-6 as compared to youngsters without internalizing disorders. Differences between groups in IL-10 levels were not statistically significant. This study points out that IL-6 levels may be associated with internalizing disorders in youths and suggests that inflammation might be an early biomarker of emotional distress. High levels of cytokines may adversely affect general health in the long-term, which raise broader issues in terms of public health if results are replicated.

Differences in biomarkers of crack-cocaine adolescent users before/after abstinence.

AIMS: To measure the variation in Brain-Derived Neurotrophic Factor (BDNF), Thiobarbituric Acid Reactive Substances (TBARS) and interleukin (IL) levels in crack-cocaine dependent adolescents after 21days of abstinence, comparing to levels found in a group of healthy controls. DESIGN: Cross-sectional nested on a short follow-up study. SETTING: Two inpatient treatment units for adolescents, and a low-income neighborhood. PARTICIPANTS: 90 adolescents, of both genders, with diagnosis of crack cocaine dependence, and 81 healthy adolescents. MEASUREMENTS: Serum levels of IL-6, IL-10, TBARS and BDNF were assessed on admission and discharge. Drug addiction severity was assessed by the Addiction Severity Index - Teen Version (T-ASI) and Cocaine Craving Questionnaire - Brief version (CCQ-b). Psychiatric comorbidities were assessed by the Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version (K-SADS-PL). Generalized Estimating Equations (GEE) were used to estimate the IL-6, IL-10, TBARS and BDNF levels, adjusted for confounders. Hedges' g was used to estimate effect size. FINDINGS: TBARS (p=0.005, d=0.04), IL-6 (p=0.027, d=0.40) and IL-10 (p=0.025, d=0.41) were elevated and BDNF (p<0.001, d=0.62) was reduced (p<0.001), in patients, in comparison to controls, at admission time. Variation in those levels between admission and discharge were not significant. CONCLUSIONS: Crack-cocaine use seems to be associated with inflammatory and oxidative imbalances in adolescents.

Oxidative stress and BDNF as possible markers for the severity of crack cocaine use in early withdrawal.

RATIONALE: An important goal of addiction research is to discover neurobiological markers that could predict the severity of addiction and help to determine appropriate treatment. Brain-derived neurotrophic factor (BDNF) and thiobarbituric acid reactive substances (TBARS) are being related to cerebral plasticity and impairment caused by substance abuse. OBJECTIVES: This study aims to evaluate alteration of TBARS and BDNF levels among crack cocaine users during early drug withdrawal and its relationship to severity of drug use. METHODS: Forty-nine adults crack cocaine users were recruited at a public psychiatric hospital with a specialized addiction treatment unit. Blood sample was collected at intake and discharge for the analysis of TBARS and BDNF measures. Information about drug use was assessed by the Addiction Severity Index 6th Version (ASI-6). Detailed information about crack cocaine use was obtained through the "Profile of the crack cocaine user." Severity of crack use was estimated using information from age of first crack use, years of crack use, and crack rocks used in the previous 30 days. RESULTS: There is a positive correlation between TBARS levels and severity of crack cocaine use (R = 0.304, p = 0.04) and a negative correlation between BDNF and severity of crack cocaine use (R = -0.359, p = 0.01) at discharge. Also, we found an inverse correlation between TBARS and BDNF levels (R = -0.294, p = 0.004) at discharge. CONCLUSIONS: Our findings suggest that BDNF and TBARS could be possible markers for the severity of drug use. Further studies may show how those markers could be related to staging, prognosis, and treatment in crack cocaine dependence.

Mineralocorticoid receptor genotype moderates the association between physical neglect and serum BDNF.

The objective of this study is to investigate if a polymorphism in the NR3C2 gene moderates the association between childhood trauma on serum levels of brain derived neurothrophic factor (sBDNF). sBDNF was used here as a general marker of alteration in brain function. This is a community cross sectional study comprising 90 adolescents (54 with anxiety disorders). DNA was extracted from saliva in order to genotype the MR-2G/C (rs2070951) polymorphism using real time PCR. Blood was collected for sBDNF Elisa immunoassay. The Childhood Trauma Questionnaire (CTQ) was used to evaluate childhood abuse and neglect. Main effects and gene environment interactions were tested using linear regression models. Anxiety disorders were not associated with the MR-2G/C polymorphism or with sBDNF levels, but the number of C alleles of the MR-2G/C polymorphism was significantly associated with higher sBDNF levels (b = 8.008; p-value = 0.001). Subjects with intermediate and high exposure to physical neglect showed higher sBDNF levels if compared to subjects non-exposed (b = 11.955; p = 0.004 and b = 16.186; p = 0.009, respectively). In addition, we detected a significant physical neglect by MR-2G/C C allele interaction on sBDNF levels (p = 0.005), meaning that intermediate and high exposure to childhood neglect were only associated with increased sBDNF levels in subjects with the CC genotype, but not in subjects with other genotypes. Our findings suggest that genetic variants in NR3C2 gene may partially explain plastic brain vulnerability to traumatic events. Further studies are needed to investigate the moderating effects of NR3C2 gene in more specific markers of alteration in brain function.

Vulnerability to dietary n-3 polyunsaturated fatty acid deficiency after exposure to early stress in rats.

The exposure to adverse events early in life may affect brain development. Omega-3 polyunsaturated fatty acid (n-3 PUFA) deficiency has been linked to the development of mood and anxiety disorders. The aim of this study was to examine the interaction between variations in the early environment (handling or maternal separation) and the chronic exposure to a nutritional n-3 PUFA deficiency on locomotor activity, sucrose preference, forced swimming test and on serum and hippocampal brain-derived neurotrophic factor (BDNF) levels. Rats were randomized into Non-handled (NH), Neonatal Handled (H) and Maternal Separated (MS) groups. Pups were removed from their dams (incubator at 32°C on postnatal days (PND) 1-10) during 10 min/day (H) or 3h/day (MS). On PND 35, males were subdivided into diets adequate or deficient in n-3 PUFA for 15 weeks. H and MS gained weight differently, and animals receiving the n-3 PUFA deficient diet gained less weight. MS displayed a higher food consumption and higher consumption of sucrose solution during the second hour of exposure to the sucrose preference test. No differences were observed in the swimming test. H group had increased locomotion and showed a higher response to amfepramone. No significant effect was observed on serum BDNF levels. BDNF protein levels were decreased in animals receiving the n-3 PUFA deficient diet. We observed that early life environment and a mild n-3 PUFA deficiency are able to affect several behavioral aspects (food and sucrose consumption and locomotor response), and lead to a differential hippocampal BDNF metabolism in adult life.