Developmental changes in the hypothalamic mRNA expression levels of brain-derived neurotrophic factor and serum leptin levels: Their responses to fasting in male and female rats

The actions and responses of hypothalamic appetite regulatory factors change markedly during the neonatal to pre-pubertal period in order to maintain appropriate metabolic and nutritional conditions. In this study, we examined the developmental changes in the hypothalamic mRNA levels of brain-derived neurotrophic factor (BDNF), which is a potent anorectic factor and the changes in the sensitivity of the hypothalamic expression of this factor to fasting during the neonatal to pre-pubertal period. Under fed conditions, hypothalamic BDNF mRNA expression decreased during development in both male and female rats. Similarly, the serum levels of leptin, which is a positive regulator of hypothalamic BDNF expression, also tended to fall during the developmental period. The serum leptin level and the hypothalamic BDNF mRNA level were found to be positively correlated in both sexes under the fed conditions. Hypothalamic BDNF mRNA expression was decreased by 24 h fasting (separating the rats from their mothers) in the early neonatal period (postnatal day 10) in both males and females, but no such changes were seen at postnatal day 20. Twenty-four hours’ fasting (food deprivation) did not affect hypothalamic BDNF mRNA expression in the pre-pubertal period (postnatal day 30). On the other hand, the rats’ serum leptin levels were decreased by 24 h fasting (separating the rats from their mothers at postnatal day 10 and 20, and food deprivation at postnatal day 30) throughout the early neonatal to pre-pubertal period. The correlation between serum leptin and hypothalamic BDNF mRNA levels was not significant under the fasted conditions. It can be speculated that leptin partially regulates hypothalamic BDNF mRNA levels, but only in fed conditions. Such changes in hypothalamic BDNF expression might play a role in maintaining appropriate metabolic and nutritional conditions and promoting normal physical development. In addition, because maternal separation induces a negative energy balance and short- and long-term stress responses, it is also possible that reductions in hypothalamic BDNF mRNA levels in the early neonatal period (postnatal day 10) may be partially induced by stress responses of the maternal deprivation.     

Oral administration of BDNF and/or GDNF normalizes serum BDNF level in the olfactory bulbectomized rats: A proof of concept study

BackgroundNeurotrophins, especially brain-derived neurotrophic factor (BDNF) have gained significant therapeutic interest particularly in neurologic and psychiatric disorders and they have been found in human breast milk of mothers who suffered from adverse outcomes in pregnancy. This study tested the hypothesis that oral administration of BDNF/GDNF (glial cell line-derived neurotrophic factor) can exert a biological effect in a rat model of severe neuropathology induced by olfactory bulbectomy (OBX), which exhibits dysregulation of BDNF signaling and impaired blood-brain barrier.MethodsAdult male albino Sprague-Dawley rats underwent the OBX surgery and separate groups of OBX and sham-operated controls received one oral dose of vehicle, BDNF (0.005 mg/kg), GDNF (0.03 mg/kg) or their combination. One week after neurotrophin dosing the rats were sacrificed and BDNF level was assessed by ELISA in the blood serum and cerebrospinal fluid.ResultsA significant decrease of serum BDNF level was found in the OBX model. This alteration was normalized by all types of treatment BDNF, GDNF, or their combination. No influence of sham surgery or treatment was observed in the control rats. BDNF levels in cerebrospinal fluid were below detection limit.ConclusionThis study indicates that oral administration of neurotrophins is able to exert a biological effect in the OBX model. There is a number of potential mechanisms, which remain to be elucidated.     

Genetic polymorphisms for BDNF,COMT, and APOE do not affect gait or ankle motor control in chronic stroke: A preliminary cross-sectional study

ABSTRACT

Background: Motor deficits after stroke are a primary cause of long-term disability. The extent of functional recovery may be influenced by genetic polymorphisms.

Objectives: Determine the effect of genetic polymorphisms for brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), and apolipoprotein E (APOE) on walking speed, walking symmetry, and ankle motor control in individuals with chronic stroke.

Methods: 38 participants with chronic stroke were compared based upon genetic polymorphisms for BDNF (presence [MET group] or absence [VAL group] of a Met allele), COMT (presence [MET group] or absence [VAL group] of a Met allele), and APOE (presence [ε4+ group] of absence [ε4- group] of ε4 allele). Comfortable and maximal walking speed were measured with the 10-m walk test. Gait spatiotemporal symmetry was measured with the GAITRite electronic mat; symmetry ratios were calculated for step length, step time, swing time, and stance time. Ankle motor control was measured as the accuracy of performing an ankle tracking task.

Results: No significant differences were detected (p ≥ 0.11) between the BDNF, COMT, or APOE groups for any variables.

Conclusions: In these preliminary findings, genetic polymorphisms for BDNF, COMT, and APOE do not appear to affect walking speed, walking symmetry, or ankle motor performance in chronic stroke.     

A meta-analysis of circulating BDNF concentrations in anorexia nervosa

Abstract

Objectives. Brain derived neurotrophic factor (BDNF) is involved in neuroplasticity, and in the homeostatic regulation of food intake and energy expenditure. It also has a role in stress responsivity and reward processing. On the basis of its involvement in these various processes, BDNF can be hypothesized to be an important factor in the development and maintenance of anorexia nervosa (AN). This study meta-analytically summarizes investigations of serum BDNF concentrations in people currently ill with AN, in comparison to healthy controls. Methods. Seven studies measuring BDNF in serum of individuals with AN (n = 155) and healthy controls (n = 174) were identified and included in the meta-analysis of the mean differences between case and control groups. Results. This study confirms that AN is associated with decreased serum BDNF concentrations, in comparison to healthy controls. The combined effect size (standardized mean difference, SMD) was large (SMD = ?0.96; 95% CI –1.33 to ?0.59; P < 0.001). Significant heterogeneity of effect sizes was identified (I² = 58.3%; P < 0.001), which emerged as being primarily attributable to the first published study on the investigated association. Conclusions. The present meta-analytical summary of studies measuring circulating BDNF concentrations in women with AN and healthy controls confirms that it is significantly reduced in this patient group. Difficulties associated with the measurement of BDNF have been identified and potential confounding factors have been discussed. Current data do not allow inferences to be made about causal links between levels of circulating BDNF and AN. However, possible explanations for the relationship between BDNF and AN have been presented.     

Binge alcohol-induced alterations in BDNF and GDNF expression in central extended amygdala and pyriform cortex on infant rats

Mothers who consume alcohol during pregnancy may cause a neurotoxic syndrome termed fetal alcohol spectrum disorder (FASD) in the offspring, which includes cognitive deficits and emotional/social disturbances. These alterations are thought to be caused, at least in part, by alcohol-induced imbalance in neurotrophic factor levels, which are critically involved in normal neurodevelopment. Our goal was to study whether brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) expression were affected by alcohol in central extended amygdala (CEXA) and pyriform cortex (Pyr), structures strongly involved in emotional/social behaviors. Further, we evaluated how these changes could be related to blood and brain alcohol concentrations. Postnatal day (PND) pups at 7, 15 and 20-days old were administered alcohol (2.5 g/kg s.c. at 0 and 2 h) or saline. Immunohistochemistry was used to detect the expression of BDNF and GDNF at 2, 12 and 24 h after drug administration. Also, gas chromatography was bused to measure blood alcohol levels (BALs) and brain alcohol levels (BrALs) at each hour, from 2 to 8 h after the second alcohol administration. Results showed: (1) alcohol-induced enhancement of BDNF positive cells on PND 7 and 20, a decrease on PND 15 in the CEXA, and no changes in the Pyr on PND 7 and 20, but a diminished on PND 15; (2) GDNF positive cells rise after alcohol administration for the three ages in the CEXA and Pyr except on PND 15, where there was a decline; and (3) pharmacokinetics analysis demonstrated age-related differences showing equal BALs on PND 7 and 20 but higher BALs on PND 15. In contrast, BrALs were higher on PND 7 than 15 and 20. Hence, BALs may not be predictive of BrALs in postnatal rats. Furthermore, we did not find a relationship between age in pharmacokinetic differences and neurotrophins response. In conclusion, the CEXA and Pyr are brain structures sensitive to alcohol-induced imbalance in neurotrophic factors expression; and BALs are not a mirror of BrALs.     

Alcohol exposure during development: Impact on the epigenome

Fetal alcohol spectrum disorders represent a wide range of symptoms associated with in utero alcohol exposure. Animal models of FASD have been useful in determining the specific neurological consequences of developmental alcohol exposure, but the mechanisms of those consequences are unclear. Long-lasting changes to the epigenome are proposed as a mechanism of alcohol-induced teratogenesis in the hippocampus. The current study utilized a three-trimester rodent model of FASD to examine changes to some of the enzymatic regulators of the epigenome in adolescence. Combined pre- and post-natal alcohol exposureresulted in a significant increase in DNA methyltransferase activity (DNMT), without affecting histone deacetylase activity (HDAC). Developmental alcohol exposure also caused a change in gene expression of regulators of the epigenome, in particular, DNMT1, DNMT3a, and methyl CpG binding protein 2 (MeCP2). The modifications of the activity and expression of epigenetic regulators in the hippocampus of rodents perinatally exposed to alcohol suggest that alcohol's impact on the epigenome and its regulators may be one of the underlying mechanisms of alcohol teratogenesis.     

The effects of sEH inhibitor on depression‐like behavior and neurogenesis in male mice

Currently antidepressants take several weeks to be effective, which is one of the main reasons why patients with depression quit therapy. In the present study, we examine the acute and subacute effects of soluble epoxide hydolase (sEH) inhibitor (sEHI), a compound shown to have antidepressant effects, on mice. We found that acute administration of sEHI TPPU decreases immobility time in the forced swimming test and reduces latency to feed in the novelty suppressed‐feeding test in adult male mice. Intraperitoneal administration of TPPU for seven days also increased interaction time of socially defeated mice in the social defeat test. Hippocampal BDNF expression and cell proliferation in the dentate gyrus increased six and 24 hours after TPPU treatment, respectively. Improvement in antidepressant behavior and cell proliferation were inhibited by BDNF‐trkB antagonist K252a, which suggests that anti‐depressant effects of sEHI may be involved in BDNF signaling. Taken together, our findings suggest that sEHI may provide a rapid antidepressant effect through alterations to BDNF‐trkB signaling in the hippocampus and may provide an alternative to current slow‐acting antidepressants. © 2017 Wiley Periodicals, Inc.     

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.