Total Brain-derived Neurotrophic Factor Research Articles

BDNF Val66Met polymorphism alters food intake and hypothalamic BDNF expression in mice.

Obesity, a rising public health burden, is a multifactorial disease with an increased risk for patients to develop several pathological conditions including type 2 diabetes mellitus, hypertension, and cardiovascular disease. Increasing evidence suggests a relationship between the human brain-derived neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism (SNP) and obesity, although the underlying mechanisms of this connection are still not completely understood. In the present study, we found that homozygous knock-in BDNFMet/Met mice were overweight and hyperphagic compared to wildtype BDNFVal/Val mice. Increased food intake was associated withreduction of total BDNF and BDNF1, BDNF4 and BDNF6 transcripts in the hypothalamus of BDNFMet/Met mice. Incontrast, in the white adipose tissue total BDNF and Glut4 expression levels were augmented, while sirtuin 1 and leptin receptor (Ob-R) expression levels were reduced in BDNFMet/Met mice. Moreover, plasmatic leptin levels were decreased in BDNFMet/Met mice. However, BDNFVal/Val and BDNFMet/Met mice showed a similar response to the insulin tolerance test and glucose tolerance test. Altogether, these results suggest that BDNF Val66Met SNP strongly contributes to adipose tissue pathophysiology, resulting in reduced circulating leptin levels and hypothalamic expression of BDNF, which, in turn, promote increased food intake and overweight in BDNFMet/Met mice.

Morphine consumption during pregnancy exacerbates neonatal hypoxia-ischemia injury in rats.

Hypoxia-Ischemia (HI) is the most common cause of death and disability in human infants. The use of opiate in pregnant women affects their children. The aim of this study was to evaluate the effect of morphine consumption during pregnancy and lactation on vulnerability to neonatal HI in rats. Female Wistar rats were randomly assigned into two groups: Group 1-Rats that did not receive any treatment during pregnancy and lactation and Group 2-Rats that received morphine during pregnancy and lactation. After delivery, male offspring were divided into four groups including: (a) SHAM, (b) SHAM/Morphine (SHAM/MO), (c) HI, (d) HI/Morphine (HI/MO). Seven days after HI induction, neurobehavioral tests were performed, and then, brain tissue was taken from the skull to measure cerebral edema, infarct volume, inflammatory factors, oxidative stress, and brain-derived neurotrophic factor (BDNF). Total antioxidant capacity (TAC) and BDNF levels in the HI/MO group were significantly lower than HI and SHAM groups. TNF-α, C-reactive protein and total oxidant capacity levels in the HI/MO group were significantly higher than HI and SHAM groups. Cerebral edema and infarct volume in the HI/MO group were significantly higher than the HI group. Based on the results, morphine consumption during pregnancy and lactation enhanced the deleterious effects of HI injury in pups.

BDNF is obverse to oxidative stress (adenosine deaminase and nitric oxide) in type II diabetes mellitus

The relational analysis of adenosine deaminase (ADA), nitric oxide (NO), BDNF (brain-derived neurotrophic factor), and TP (total protein) is accomplished by comparing these parameters with glucose levels of healthy and type II diabetes mellitus people. Type 2 diabetes (T2DM) is associated with impairment in many domains of cognitive function which may result from reduced BDNF. ADA is an important enzyme that plays a relevant role in purine and DNA metabolism, immune responses, and peptidase activity and for modulating the bioactivity of insulin. Nitric oxide is associated with loss of normal cellular function and increases the generation of nitric oxide synthetase products like nitroxyl (NO-), peroxynitrite (OONO-), and S-nitrosothiol (RSNO). In our study, a group of one hundred adult patients of either sex who had a history of not less than 6 years of diabetes mellitus and an equal number of healthy non-diabetics was selected as controls, respectively. The results of the parameters were analyzed using the SISA software and the correlation between the parameters was retrieved and represented graphically. A significant increase in adenosine deaminase activity and nitric oxide levels was observed in diabetic subjects when compared with that in controls. A significant decrease in total protein concentration and BDNF was observed in diabetic subjects when compared with that in controls. The results suggest that the increase in the glucose level has contributed to an increase in the inflammation factor ADA and oxidative stress factor NO and decrease in the total proteins especially BDNF, a neuron sentinel.

Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer's disease

Disruption of brain-derived neurotrophic factor (BDNF) biosynthesis and/or signaling has been implicated in the pathogenesis of Alzheimer's disease (AD). We used postmortem brain and fluid samples from 20 patients with variable severity of AD and 11 controls to investigate whether BDNF levels in serum and brain tissue correlated with hippocampal pathology. Total BDNF, precursor BDNF (pro-BDNF), and mature BDNF were measured in cerebrospinal fluid, serum, and 3 postmortem brain regions. Histological markers for AD pathology, the BDNF cognate receptor (TrkB), and glia were measured in the hippocampus (HIP). Lower pro-BDNF levels were observed in the entorhinal and frontal cortices in AD cases compared with controls. AD cases also exhibited significantly lower staining densities of the cognate BDNF receptor TrkB in the HIP compared with controls, and TrkB staining was inversely correlated with both Amylo-Glo and pTau staining in the same region, suggesting a relationship between the density of the cognate BDNF receptor and accumulation of AD pathology. In addition, higher serum pro-BDNF levels correlated with lower HIP pro-BDNF levels and higher pTau staining in the HIP. Total BDNF levels in cortical regions were also negatively correlated with Amylo-Glo staining in the HIP suggesting that reduced BDNF cortical levels might influence hippocampal amyloid accumulation. These results strongly suggest that altered BDNF and TrkB receptors are involved in AD pathology and therefore warrant investigations into therapies involving the BDNF pathway.

BDNF Val66Met Genetic Polymorphism Results in Poor Recovery Following Repeated Mild Traumatic Brain Injury in a Mouse Model and Treatment With AAV-BDNF Improves Outcomes.

Clinicians have long noticed that some Traumatic Brain Injury (TBI) patients have worse symptoms and take a longer time to recover than others, for reasons unexplained by known factors. Identifying what makes some individuals more susceptible is critical to understanding the underlying mechanisms through which TBI causes deleterious effects. We have sought to determine the effect of a single nucleotide polymorphism (SNP) in Brain-derived neurotrophic factor (BDNF) at amino acid 66 (rs6265) on recovery after TBI. There is controversy from human studies as to whether the BDNF Val66Val or Val66Met allele is the risk factor for worse outcomes after brain trauma. We therefore investigated cellular and behavioral outcomes in genetically engineered mice following repeated mild TBI (rmTBI) using a lateral fluid percussion (LFP) injury model. We found that relative to injured Val66Val carriers, injured Val66Met carriers had a larger inflammation volume and increased levels of neurodegeneration, apoptosis, p-tau, activated microglia, and gliosis in the cortex and/or hippocampus at 1 and/or 21 days post-injury (DPI). We therefore concluded that the Val66Met genetic polymorphism is a risk factor for poor outcomes after rmTBI. In order to determine the mechanism for these differences, we investigated levels of the apoptotic-inducing pro BDNF and survival-inducing mature BDNF isoforms and found that Met carriers had less total BDNF in the cortex and a higher pro/mature ratio of BDNF in the hippocampus. We then developed a personalized approach to treating genetically susceptible individuals by overexpressing wildtype BDNF in injured Val66Met mice using an AAV-BDNF virus. This intervention improved cellular, motor, and cognitive behavior outcomes at 21 DPI and increased levels of mature BDNF and phosphorylation of mature BDNF's receptor trkB. This study lays the groundwork for further investigation into the genetics that play a role in the extent of injury after rmTBI and highlights how personalized therapeutics may be targeted for recovery in susceptible individuals.

91 CAUSAL AND GENETIC EPIDEMIOLOGY OF URBANICITY AS A RISK FACTOR FOR PSYCHOSIS

Understanding resilience is a major challenge to improve current pharmacological therapies aimed at complementing psychological-based approaches of stress-related disorders. In particular, resilience is a multi-factorial construct where the complex network of molecular events that drive the process still needs to be resolved. Here, we exploit the acute escape deficit model, an animal model based on exposure to acute unavoidable stress followed by an escape test, to define vulnerable and resilient phenotypes in rats. Hippocampus and prefrontal cortex (PFC), two of the brain areas most involved in the stress response, were analysed for gene expression at two different time points (3 and 24 h) after the escape test. Total Brain-Derived Neurotrophic Factor (BDNF) was highly responsive in the PFC at 24-h after the escape test, while expression of BDNF transcript IV increased in the hippocampus of resistant animals 3 h post-test. Expression of memory enhancers like Neuronal PAS Domain Protein 4 (Npas4) and Activity-regulated cytoskeleton-associated protein (Arc) decreased in a time- and region-dependent fashion in both behavioural phenotypes. Also, the memory inhibitor Protein Phosphatase 1 (Ppp1ca) was increased in the hippocampus of resilient rats at 3 h post-test. Given the importance of neurotrophic factors and synaptic plasticity-related genes for the development of appropriate coping strategies, our data contribute to an additional step forward in the comprehension of the psychobiology of stress and resiliency.

BDNF prevents central oxidative damage in a chronic unpredictable mild stress model: The possible role of PRDX-1 in anhedonic behavior

Prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and sustained increase of glucocorticoids have been evidenced in major depression and are related to changes involving neurotrophins and markers of oxidative stress in response to inflammation. This study aimed to evaluate central measures of brain-derived neurotrophic factor (BDNF), oxidative damage and total antioxidant capacity in rats submitted to chronic unpredictable mild stress (CUMS), as well as to investigate the relationship between BDNF levels and differentially processes. For this purpose, male Wistar rats were submitted to CUMS for six weeks. Based on a sucrose preference test (SPT), the animals were divided into anhedonic or non-anhedonic clusters. Afterwards, forced swim test (FST) and open field test (OFT) were performed, and the animals were euthanized. Brain tissue was collected, followed by quantification of oxidative damage, total antioxidant capacity and BDNF levels. Anhedonic behavior was evidenced in stress-susceptible animals through decreased sucrose preference. No differences were found in FST or OFT results. We observed increased BDNF levels in the hippocampus (HPC) of animals exposed to the CUMS protocol, accompanied by decreased total antioxidant capacity, despite the absence of oxidative damage to lipids and proteins. Moreover, we used a bioinformatics approach to identify proteins involved in oxidative stress and inflammation pathways, which were differentially expressed in anhedonic animals from other studies with similar experimental protocol. expressed proteins (DEP) involved in oxidative stress and inflammatory biological Anhedonic behavior was associated with peroxiredoxin-1 (PRDX-1) up-regulation and down-regulation of proteins involved with apoptotic and inflammation signaling (RELA, ASK-1 and TAK-1) in the HPC. Taken together, these data suggest that BDNF and PRDX-1 might be involved in initial stress response, playing a compensatory role by preventing oxidative damage to lipids and proteins through the modulation of antioxidant defense after CUMS in anhedonic animals.

Interferon-beta, but not Glatiramer Acetate treatment induces gender-specific increase in BDNF serum levels in relapsing-remitting multiple sclerosis female patients

Neuroprotection is considered a major therapeutic target in Multiple Sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS). Accordingly, current disease modifying drugs (DMDs) for MS have been revaluated for their ability to stimulate production of neurotrophic factors that may provide support to neural cells against neurodegeneration. Brain-derived neurotrophic factor (BDNF) is considered the best candidate for such neuroprotective effects in MS. In the present study, we explored a potential effects of Glatiramer Acetate (GA), and Interferon-beta (IFN-b), the first two available treatments of MS, on circulating levels of BDNF considering the different BDNF forms. Using ELISA assays, we quantified mature and total BDNF in the serum of 20 relapsing-remitting MS (RR-MS) patients treated with GA and 31 with INF-beta compared with 20 age-matched RR-MS patients without any DMD. Mature BDNF but not total BDNF was significantly increased by treatment with IFN-b in female patients only, while GA had no effect. These results support a gender-specific role of BDNF in the treatment of RR-MS with INF-b. Of note, the present study was carried out with standardized ELISA assays which are commercially available and, prospectively, might be routinely used in the common clinical practice to monitor the individual response to the therapy with IFN-b.

Abstract 193: Antiangiogenic effect of conditioned media derived from triple negative breast cancer cells in brain microvascular endothelial cells in vitro

Abstract Breast cancer is the most common malignancy among females and is a leading cause of cancer mortality. Brain metastasis is associated with poor prognosis and reduced survival among breast cancer patients. For brain metastasis to occur, cancer cells are required to remain in direct contact with endothelial cells that line brain blood vessels. Data regarding the interaction between brain endothelial cells and breast cancer is limited. The aim of this work was to understand the interaction between breast cancer cells and brain endothelial cells. Human brain microvascular endothelial cells (hBMECs) were treated with conditioned media from MDA-MB-231 cell line and their angiogenic characteristics were evaluated. The involvement of the glycogen synthase kinase-3β (GSK-3β), vascular endothelial growth factor (VEGF), brain derived neurotrophic factor (BDNF), and thrombospondin-1 (TSP-1) was evaluated using release levels and inhibitor-based approaches. Levels of secreted proteins were assayed using ELISA. Results of the study showed that conditioned media from MDA-MB-231 breast cancer cells reduced angiogenic potential of hBMECs. Conditioned media significantly suppressed migration and tube formation of hBMECs compared to control group. In these experiments, control group represents hBMECs which were incubated with regular serum-free RPMI-1640 culture media. Inhibiting GSK-3β in conditioned media-treated hBMECs by its selective inhibitor (SB 216763; 10nM), restored the migratory potential of endothelial cells. In addition, MDA-MB-231 cells released VEGF at a rate that exceeded VEGF release from endothelial cells (6342 vs. 67.6 pg/ml). The release of VEGF from conditioned media-treated hBMECs was not altered by the high levels of VEGF presented in MDA-MB-231 cells conditioned media. GSK-3β inhibition in hBMECs significantly increased VEGF release from endothelial cells by about 1000 pg/ml compared to conditioned media-treated endothelial cells. MDA-MB-231 cells also released high levels of BDNF into the media and treating hBMECs with conditioned media from MDA-MB-231 cells did not alter the endogenous release of total BDNF from endothelial cells. GSK-3β inhibition did not alter BDNF release from endothelial cells. BDNF inhibition using TrkB-Fc (4µg/ml) did not restore the migratory potential of endothelial cells and the anti-angiogenic effect of conditioned media was maintained despite the inhibition of BDNF. Breast cancer cells released high levels of TSP-1 into the media. hBMECs treated with TSP-1 (5µg/ml) reduced wound healing by 40%, an effect that was restored by GSK-3β inhibitor. In conclusion, conditioned media from breast cancer cells induced anti-angiogenic effects in hBMECs which was found to be GSK-3β-dependent. The anti-angiogenic effect was further illustrated in terms of increased TPS-1 levels released by breast cancer cells. Citation Format: Nehad M. Ayoub, Ahmed Alhusban, Laila Alhusban. Antiangiogenic effect of conditioned media derived from triple negative breast cancer cells in brain microvascular endothelial cells in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 193.

Treating ultra-low rectal cancer by acupuncture combined with chemotherapy: a case report and literature review

Sepsis-associated encephalopathy (SAE) can cause acute and long-term cognitive impairment and increase the mortality rate in sepsis patients, and we previously reported that 2% hydrogen gas (H2) inhalation has a therapeutic effect on SAE, but the underlying mechanism remains unclear. Dynamic DNA methylation, which catalyzed by DNA methyltransferases (DNMTs), is involved in the formation of synaptic plasticity and cognitive memory in the central nervous system. And brain-derived neurotrophic factor (BDNF), to be a key signaling component in activity-dependent synaptic plasticity, can be induced by neuronal activity accompanied by hypomethylation of its promoter IV. This study was designed to illustrate whether H2 can mediate SAE by alter the BDNF promoter IV methylation mediated by DNMTs. We established an SAE model by cecal ligation and perforation (CLP) in C57BL/6 mice. The Morris water maze test from the 4th to the 10th day after sham or CLP operations were used to evaluate mouse cognitive function. Hippocampal tissues were isolated at the 24 after sham or CLP surgery. Pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and High Mobility Group Box 1 (HMGB1) were measured by enzyme-linked immunosorbent assay (ELISA). mRNA or protein levels of DNMTs (DNMT1, DNMT3a and DNMT3b), BDNF promoter IV and total BDNF were detected by RT-PCR and Western blot tests. Immunofluorescence staining were used to determine the expressions of DNMT1 and DNMT3a. The quantitative methylation analysis of the 11 CpG island of the promoter region of BDNF exon IV was determined using the Agena’s MassARRAY EpiTYPER system. We found that 2% H2 inhalation can reduce pro-inflammatory factors, alleviate DNMT1, DNMT3a but not DNMT3b expression, make hypomethylation of BDNF promoter IV at 5 CpG sites, enhance the BDNF levels and then decrease escape latency but increase platform crossing times in septic mice. Our results suggest that 2% H2 inhalation may alleviate SAE through altering the regulation of BDNF promoter IV methylation which mediated by DNMT1 and DNMT3a in the hippocampus of septic mice.

Modulatory effects of swimming exercise against malathion induced neurotoxicity in male and female rats

Malathion is one of the most commonly used organophosphorus (OP) pesticides. It is important to regard that exposure to OP poisoning may cause anxiety and depression. Malathion toxicity induces cholinergic symptoms. Brain-derived neurotrophic factor (BDNF) is the most profusely expressed neurotrophin in the central nervous system; it promotes the survival of neurons. Regular exercise improves brain well-being and enhances recovery from brain Injuries. It is suggested that BDNF may mediate these effects. Therefore, this study was planned to assess the modulatory effects of regular exercise performance on brain BDNF level, cholinergic activity, oxidative stress and apoptosis in male and female rats subjected to neurotoxicity induced by malathion administration. Materials and methodsThirty-two adult male and thirty-two adult female albino rats were included in this study. The rats were divided into four equal groups (8rats). Control group, malathion treated group, exercised group, malathion exercised group. Acetylcholinesterase (AchE) activity, total antioxidant capacity (TAC), BDNF level and Caspase 3 activity were assessed. ResultsFemale rats had higher baseline content of BDNF in brain homogenate than male rats. Malathion administration induced a significant decrease in BDNF level in female rats and in the total antioxidant capacity in both male and female rats. A significant elevation in caspase 3 activity was detected in the malathion treated groups, with more elevation in female rats. Swimming exercise improved BDNF level, AchE activity, and apoptosis in both male and female rats in all groups. In addition, male rats were more cholinergic system responders to regular exercise than female rats. ConclusionIt could be concluded that malathion induced elevation in oxidative stress and apoptosis in all rats, with reduction in BDNF level in female rats. Meanwhile, regular swimming exercise was found to improve brain health through modulation of BDNF level and cholinergic activity. It is recommended to practice regular exercise to maintain brain health. Further studies are required to clarify the involvement of sex hormones in BDNF regulation.

Modulation of neuroplasticity-related targets following stress-induced acute escape deficit.

Understanding resilience is a major challenge to improve current pharmacological therapies aimed at complementing psychological-based approaches of stress-related disorders. In particular, resilience is a multi-factorial construct where the complex network of molecular events that drive the process still needs to be resolved. Here, we exploit the acute escape deficit model, an animal model based on exposure to acute unavoidable stress followed by an escape test, to define vulnerable and resilient phenotypes in rats. Hippocampus and prefrontal cortex (PFC), two of the brain areas most involved in the stress response, were analysed for gene expression at two different time points (3 and 24 h) after the escape test. Total Brain-Derived Neurotrophic Factor (BDNF) was highly responsive in the PFC at 24-h after the escape test, while expression of BDNF transcript IV increased in the hippocampus of resistant animals 3 h post-test. Expression of memory enhancers like Neuronal PAS Domain Protein 4 (Npas4) and Activity-regulated cytoskeleton-associated protein (Arc) decreased in a time- and region-dependent fashion in both behavioural phenotypes. Also, the memory inhibitor Protein Phosphatase 1 (Ppp1ca) was increased in the hippocampus of resilient rats at 3 h post-test. Given the importance of neurotrophic factors and synaptic plasticity-related genes for the development of appropriate coping strategies, our data contribute to an additional step forward in the comprehension of the psychobiology of stress and resiliency.

Downregulated hippocampal expression of brain derived neurotrophic factor and tyrosine kinase B in a rat model of comorbid epilepsy and depression

ABSTRACTObjective: To investigate the expression of brain-derived neurotrophic factor(BDNF) and tyrosine kinase B (TrkB) protein in the hippocampus of model rats of comorbid epilepsy and depression.Methods: A rat model of epilepsy was established using lithium chloride.pilocarpine. Among these epileptic rats, those with comorbid depression were selected by a battery of behavioral tests starting on the 14th day after establishing the epilepsy model. A depression group was established by unpredicted chronic mild stress (UCMS) and separate housing. These treatment groups were compared to an untreated control group. Thirteen rats per group were examined by immunofluorescence staining with optical density quantitation to determine the distribution of BDNF- and TrkB-positive cells in the hippocampus and by western blotting to estimate total protein expression levels during the 4th week after establishing the models. Immunofluorescence staining for NeuN was also conducted in hippocampus to evaluate neuronal survival. Depression-like behaviors were also assessed.Results: Compared to the untreated control group and the epilepsy alone group, the comorbid group exhibited lower average optical densities of BDNF- and TrkB-immunopositive cells as well as lower total BDNF and TrkB protein expression levels (all P = 0.000). The comorbid group exhibited lower behavioral scores compared to all other groups (all P=0.000). Numbers of NeuN–positive cells were lower in the hippocampus of all three experimental groups compared to the untreated control group (all P = 0.000).Conclusions: These results suggest that hypofunctional BDNF-TrkB signaling may contribute to depression in epilepsy.Abbreviations: BDNF: Brain-derived neurotrophic factor; TrkB: tyrosine kinase B; UCMS: unpredicted chronic mild stress; PBS: phosphate-buffered saline; HS: Hippocampal sclerosis

Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein.

SummaryThe absence of FMR1 protein (FMRP) causes fragile X syndrome (FXS) and disturbed FMRP function is implicated in several forms of human psychopathology. We show that intracellular calcium responses to depolarization are augmented in neural progenitors derived from human induced pluripotent stem cells and mouse brain with FXS. Increased calcium influx via nifedipine-sensitive voltage-gated calcium (Cav) channels contributes to the exaggerated responses to depolarization and type 1 metabotropic glutamate receptor activation. The ratio of L-type/T-type Cav channel expression is increased in FXS progenitors and correlates with enhanced progenitor differentiation to glutamate-responsive cells. Genetic reduction of brain-derived neurotrophic factor in FXS mouse progenitors diminishes the expression of Cav channels and activity-dependent responses, which are associated with increased phosphorylation of the phospholipase C-γ1 site within TrkB receptors and changes of differentiating progenitor subpopulations. Our results show developmental effects of increased calcium influx via L-type Cav channels in FXS neural progenitors.

Serum hs-CRP, YKL-40 and brain-derived neurotrophic factor (BDNF) associated biomarkers in non-dipper hypertension profile?

Abstract Background: Twenty-four hours dynamic blood pressure (BP) behaviour displays dipper profile defined as nocturnal systolic BP (SBP) reduction>10% compared to daytime. Non-dipper profile, nocturnal absence of SBP fall, associates an increased cardiovascular risk. We investigated the concomitant association of inflammatory bio-markers - high-sensitivity- C-reactive protein (hs-CRP), Human Chitinase3-like1 (YKL-40) and autonomic nervous system (total brain-derived neurotrophic factor, BDNF) with respect to non-dipping blood pressure status. Material and method: Using 24h automatic BP measurements, 80 known hypertensive patients were divided into two groups: dipper group included fifty-one dipper patients (age 55.6 ±13.5 years) and non-dipper group consisted of 29 non-dipper subjects (62.07±12.03 years). Serum levels of hs-CRP were evaluated with enhanced immunoturbidimetric assay. Plasma levels of YKL-40 were measured by commercial sandwich ELISA using microplate coated with a monoclonal antibody for CHI3L1. Plasma levels of total BDNF were determined using quantitative sandwich enzyme-linked immunoassay. Statistical analysis of obtained data was performed. Results: In the non-dipper group, a significant positive association with age over 60 years, hs-CRP values above 1.90 mg/dl was observed along with increased mean values of YKL-40. Non-dipper status is independently and statistically significantly associated with elevated levels of hs-CRP (OR: 3.248, 95% CI: 1.022-10.317, p=0.046) in multivariate odds ratio analysis. No statistically significant positive association between a median total BDNF plasma level of 1430 pg/ml and the non-dipper hypertension profile was identified. Conclusion: Our study demonstrated that patients over 60 years, in particular, have a higher probability to present a non-dipping pattern of hypertension. hs-CRP and YKL-40 values are more likely to increase in the non-dipping hypertensive patients, and hs-CRP values above 1.9 mg/dl can identify the presence of a non-dipper blood pressure profile.

Haplo-Insufficiency or Knockout of the Serotonin Transporter Does not Affect Heroin Self-Administration but Decreases BDNF in the Frontal Cortex

(1) Background: Drug addiction places a heavy burden on those affected by it but only a small percentage of individuals (~20%), regardless of their drug of abuse, go on to develop the compulsive behaviours that define drug addiction. Clinical studies have shown that genetic variations that reduce serotonin transporter (SERT) activity increase the vulnerability to developing a variety of psychiatric disorders such as depression, anxiety and drug addiction. (2) Methods: To investigate the influence of reduced SERT function in the laboratory, we studied the effects of heroin self-administration in a SERT knockout rat model. Groups of homozygous knockout (HOM), heterozygous (HET) or wild type (WT) animals completed a series of heroin self-administration experiments. In addition, quantitative reverse transcription polymerase chain reaction was used to measure relative abundance of brain derived neurotrophic factor (BDNF) transcripts of in the frontal cortex and striatum in animals that had previously self-administered heroin. (3) Results: There were no differences between the genotypes for acquisition, maintenance and progressive ratio responding for heroin self-administration. However, relative expression of total BDNF and the BDNF III and BDNF VI isoforms were significantly decreased in the frontal cortex of animals that had self-administered heroin for all genotypes, however, no differences in BDNF expression were found in RNA isolated from the striatum relative to untreated control animals. (4) Conclusions: These data suggest that reduced SERT function does not augment the addictive properties of heroin and support the hypothesis that different classes of addictive substances act through different neurobiological pathways.

Cognitive and hippocampus biochemical changes following sleep deprivation in the adult male rat

Sleep deprivation (SD) influences physiological processes such as cognitive function. The balance of oxidant and antioxidant markers, neurotrophic factors and magnesium are affected by sleep deprivation but there is no difference between pre and post training sleep deprivation. This study was designed to investigate memory retrieval and biochemical factors such as oxidant and antioxidant enzyme, brain-derived neurotrophic factor (BDNF) and magnesium levels in the hippocampus following pre and post-training sleep deprivation.Male Wistar rats (weighing 200 ± 20 g) in below groups were used: control 1, 24, 48 and 72 h SD before training groups, control2, 24 h SD1 after training (being evaluated 24 h after training) and SD2 24 after training (being evaluated 48 h after training). Memory was evaluated 90 min, 24 h or 48 h after training by step-through passive avoidance apparatus. Multiple platforms method was used to induce SD. Oxidant and antioxidant markers including glutathione (GSH), glutathione reductase (GPx), malonedialdehyde (MDA), Total antioxidant concentration, catalase, superoxide dismutase (SOD), magnesium and BDNF were assessed in the hippocampus or/and brain.72 h pre-training SD impaired short and long-term memory significantly. There was no significant difference in hippocampus oxidant and antioxidant markers compared to control. Hippocampal BDNF and magnesium did not show any changes in all SD groups.Lack of correlation between memory impairment and levels of BDNF, magnesium and/or oxidant and antioxidant balance in the hippocampus is likely to be related to animal locomotor activity in the multiple platforms method. More research is needed to clarify the role of neurochemical systems.

NR2B-containing NMDA receptors contribute to diarrhea-predominant irritable bowel syndrome

// Wenxue Zhang 1, 2, 3, 4 , Dongyan Zhao 5 , Qingqing Qi 1, 2 , Xin Long 1, 2 , Yueyue Li 1, 2 , Peng Wang 1, 2 , Yanbo Yu 1, 2 , Lixiang Li 1, 2 , Yiyuan Sun 1, 2 , Zhen Li 1, 2 , Yanqing Li 1, 2 and Xiuli Zuo 1, 2 1 Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China 2 Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China 3 Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China 4 Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China 5 Department of Gastroenterology, General Hospital of Puyang Oilfield, Puyang 457000, China Correspondence to: Xiuli Zuo, email: zuoxiuli@sina.com Keywords: NMDARs; NR2B; proBDNF; visceral hypersensitivity; diarrhea-predominant irritable bowel syndrome Received: December 01, 2016 Accepted: January 02, 2018 Published: January 02, 2018 ABSTRACT Colonic mucosal N-methyl-D-aspartate receptors (NMDARs) contribute to visceral hypersensitivity in diarrhea-predominant irritable bowel syndrome (IBS-D) by increasing the production of brain-derived neurotrophic factor (BDNF). We investigated which of the multiple NMDAR subtypes and BDNF isoforms are responsible for this effect. Immunohistochemistry and Western blotting were used to detect levels of colonic mucosal NR2A-D subunits and the precursor (proBDNF) and mature (mBDNF) forms of BDNF in 67 participants. Only NR2B subunit expression was elevated in the colonic mucosa of IBS-D patients, in parallel with increased total BDNF and proBDNF expression. Expression of 15 kDa mBDNF was not detected in the colonic mucosa. NR2B, total BDNF and proBDNF levels correlated with abdominal pain scores. Quantitative real-time PCR and Western blotting showed that NMDAR activation substantially induced total BDNF/proBDNF expression in HT-29 cells, while the NMDAR inhibitor MK-801 and the NR2B subunit antagonist Ro25-6981 each completely blocked these effects. Thus, colonic mucosal NR2B-containing NMDARs may contribute to visceral hypersensitivity in IBS-D patients by upregulating BDNF, especially proBDNF.

Glucocorticoid receptor represses brain-derived neurotrophic factor expression in neuron-like cells

Brain-derived neurotrophic factor (BDNF) is involved in many functions such as neuronal growth, survival, synaptic plasticity and memorization. Altered expression levels are associated with many pathological situations such as depression, epilepsy, Alzheimer’s, Huntington’s and Parkinson’s diseases. Glucocorticoid receptor (GR) is also crucial for neuron functions, via binding of glucocorticoid hormones (GCs). GR actions largely overlap those of BDNF. It has been proposed that GR could be a regulator of BDNF expression, however the molecular mechanisms involved have not been clearly defined yet. Herein, we analyzed the effect of a GC agonist dexamethasone (DEX) on BDNF expression in mouse neuronal primary cultures and in the newly characterized, mouse hippocampal BZ cell line established by targeted oncogenesis. Mouse Bdnf gene exhibits a complex genomic structure with 8 untranslated exons (I to VIII) splicing onto one common and unique coding exon IX. We found that DEX significantly downregulated total BDNF mRNA expression by around 30%. Expression of the highly expressed exon IV and VI containing transcripts was also reduced by DEX. The GR antagonist RU486 abolished this effect, which is consistent with specific GR-mediated action. Transient transfection assays allowed us to define a short 275 bp region within exon IV promoter responsible for GR-mediated Bdnf repression. Chromatin immunoprecipitation experiments demonstrated GR recruitment onto this fragment, through unidentified transcription factor tethering. Altogether, GR downregulates Bdnf expression through direct binding to Bdnf regulatory sequences. These findings bring new insights into the crosstalk between GR and BDNF signaling pathways both playing a major role in physiology and pathology of the central nervous system.

Brain-derived neurotrophic factor (BDNF) serum basal levels is not affected by power training in mobility-limited older adults — A randomized controlled trial

Brain-derived neurotrophic factor (BDNF) is a potential important factor involved in neuroplasticity, and may be a mediator for eliciting adaptations in neuromuscular function and physical function in older individuals following physical training. As power training taxes the neural system to a very high extent, it may be particularly effective in terms of eliciting increases in systemic BDNF levels. We examined the effects of 12weeks of power training on mature BDNF (mBDNF) and total BDNF (tBDNF) in mobility-limited older adults from the Healthy Ageing Network of Competence (HANC) study. We included 47 older men and women: n=22 in the training group (TG: progressive high intensity power training, 2 sessions per week; age 82.7±5.4years, 55% women) and n=25 in the control group (CG: no interventions; age 82.2±4.5years, 76% women). Following overnight fasting, basal serum levels of mBDNF and tBDNF were assessed (human ELISA kits) at baseline and post-intervention. At baseline, mBDNF and tBDNF levels were comparable in the two groups, TG and CG. Post-intervention, no significant within-group or between-group changes were observed in mBDNF or tBDNF. Moreover, when divided into responder tertiles based upon changes in mBDNF and tBDNF (i.e. decliners, maintainers, improvers), respectively, comparable findings were observed for TG and CG. Altogether, basal systemic levels of serum mBDNF and tBDNF are not affected in mobility-limited older adults following 12-weeks of power training, and do not appear to be a major mechanistic factor mediating neuroplasticity in mobility-limited older adults.