Brain-derived Neutrophic Factor Research Articles

Dysbiotic microbiome induce cardiac impairment by attenuating brain-derived neurotrophic factor in inflammatory bowel diseases

Abstract Background & Aims Mounting evidence suggests that inflammatory bowel disease (IBD) is associated with increased incidences of cardiovascular diseases (CVD), including myocardial infarction and heart failure. However, the molecular mechanisms by which IBD predisposes patients to CVD are poorly understood. This study aimed to identify the role of dysbiosis in gut-heart crosstalk. Methods Chronic colitis-induced cardiac impairment was assessed in mice subjected to dextran sodium sulfate (DSS), rats treated with trinitrobenzenesulfonic acid, and IL10-/-mice which develop spontaneous colitis after weaning. Fecal microbiota of wild type or IL10-/- mice were transplanted to C57BL/6J mice treated with microbiome-depleting antibiotic cocktail and germ-free mice to determine if dysbiosis afflicts the heart. Heart function was evaluated by echocardiography. Heart transcriptomes were profiled by RNA-sequencing. Gut microbiota profiling was performed by 16S rRNA sequencing. Adverse effect of brain-derived neutrophic factor (BDNF) deficiency on the heart was evaluated in cardiac-specific BDNF knockout mice (BdnfΔheart). Results Impairment of heart function, evidenced by decreased left ventricle ejection fraction (LVEF), increased LV mass, and elevated serum B-type natriuretic peptide, was observed in all 3 models of colitis, providing direct evidence that chronic colitis deteriorates the heart (Figure 1). RNA-sequencing revealed loss of Bdnf and alterations of multiple genes critical to heart homeostasis in the myocardium. Many of the changes, including Bdnf reduction, were found in microbiota-depleted C57BL/6J mice and germ-free mice received dysbiotic fecal microbiome, compared to controls, suggesting that dysbiosis impaired the heart by suppressing Bdnf. BdnfΔheart mice had impaired heart function, including decreased contractility and EF, increased fibrosis, and impaired coronary microcirculation (lower CD31), compared to Bdnf[2lox] mice. Mechanistically, miR-155 in the heart and exosomal miR-29b in the plasma were significantly elevated by chronic colitis. miR-155 and miR-29b mimics suppressed BDNF in cardiomyocytes both in vitro and in vivo. Administration of miR-155 inhibitors or exosomes packaged with miR-29b antagonists ameliorated BDNF reduction in the heart of IL10-/- mice. BDNF supplementation markedly improved heart function in DSS mice. Conclusions Chronic colitis impairs the heart through dysbiosis/miR-29b/miR-155/BDNF signaling axis. Targeting this pathway is a promising strategy to overcome gut dysbiosis harmful for the heart in IBD.

Brain-derived neutrophic factor, glutamate and markers of apoptosis in the blood of patients with prolonged disorders of consciousness

Aim of the work was to analyze the content of factors with neuroprotective, neurotoxic and apoptotic eff ects in the blood of patients with prolonged disorders of consciousness (pDOC), depending on the level of consciousness disorder and neuroprotective therapy.Material and methods. Research included 53 patients with pDOC, who were divided into 2 groups. Group 1 included 19 vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, group 2–34 minimally conscious state (MCS “minus” and “plus”) patients. Firstly at admission and then at the end of treatment course (after 1 month on average), plasma concentrations of brain neurotrophic factor (BDNF), apoptosis antigen (APO-1), apoptosisinducing ligand (Fas-L) and glutamate were studied. Control group consisted of 16 patients without measured once.Results. Decrease of BDNF serum level was revealed in patients with pDOC,which was less pronounced those who had TBI as a etiological factor of pDOC. BDNF level signifi cantly increased after a month against the background of neuroprotective therapy. Glutamate level was higher in the fi rst group (VS/UWS). No signifi cant diff erence in the content of apoptosis factors was observed.Conclusion. In patients with pDOC, decrease serum BDNF level was observed, less pronounced in TBI as etiology of pDOC. In patients who matched MCS criteria at the admission, there was a signifi cant increase of BDNF serum level during treatment course, which could indicate that patients with a higher initial level of consciousness have better potential for realizing the eff ect of neuroprotective therapy. Levels of apoptosis factors did not correspond to the consciousness level.

The Key Role of Initiation Timing on Stroke Rehabilitation by Remote Ischemic Conditioning with Exercise (RICE)

ABSTRACT Objective Physical therapy is an integral part of post-stroke rehabilitation. Remote ischemic conditioning (RIC) induces neuroprotection within 24 hours after stroke, during which exercise is unsafe and ineffective. We combined RIC with exercise to establish a novel rehabilitation strategy, RICE (RIC+Exercise). The aim of this study was to optimize the RICE protocol in neurorehabilitation. Methods Thirty-two adult male Sprague-Dawley rats were placed in one of four groups: stroke with no rehabilitation or stroke with various RICE protocols. To further understand the mechanisms underlying neurorehabilitation, sixteen adult male Sprague-Dawley were added, each placed in one of two groups: stroke with exerciseor RIC . Long-term functional outcomes were determined by beam balance, rota-rod, grid walk, forelimb placing, and Morris water maze tests up to 28 days after stroke (p < 0.05). Changes in neuroplasticity including synaptogenesis (assessed by measuring synaptophysin, post-synaptic density protein-95, and brain-derived neutrophic factor), angiogenesis (via vascular endothelial growth factor, Angiopoietin-1, and Angiopoietin-2), and regulatory molecules (including hypoxia inducible factor-1α, phospholipase D2 and the mechanistic target of rapamycin pathway), were all measured at both mRNA and protein levels (p < 0.05). Results All rehabilitation groups showed significant improvement in functional outcomes and levels of synaptogenesis and angiogenesis. 5 day RICE groups, in which RIC was started five days prior to exercise, demonstrated the greatest improvement among these parameters. The results also suggested that the HIF-1α/PLD2/mTOR signaling pathway may be implicated in post-stroke neuroplasticity. Conclusions RICE, particularly RIC initiation at hour 6 post-reperfusion followed by exercise on day 5, enhanced post-stroke rehabilitation in rats.

Abstract TMP65: Remote Ischemic Conditioning With Exercise (RICE) Induced Better Neurorehabilitation After Ischemic Stroke

Objective: Although early performance is well recognized as an important concept in rehabilitation, the optimal models remain to be determined. Physical exercise has long been considered a promising strategy at the forefront of stroke rehabilitation. However, very early exercise has been demonstrated to exacerbate brain injury. Remote ischemic conditioning (RIC) is safe and feasible within 24 hours after stroke, while it has not been applied to post-stroke rehabilitation. The present study was to establish a novel rehabilitation strategy, the RIC followed by exercise (RICE). Methods: A total of 32 adult male Sprague-Dawley rats were used in 4 groups: 1) stroke, 2) stroke with exercise (exercise at day 5 and up to day 28), 3) stroke with RIC (RIC at 6 hours after reperfusion and up to day 28), and 4) stroke with RICE (initiated with RIC at 6 hours after reperfusion followed by exercise at day 5 and up to day 28). Long-term functional outcomes were determined by grid walk tests, rota-rod tests, beam balance tests, forelimb placing tests, and the Morris water maze. Synaptogenesis [synaptophysin (SYN), and post-synaptic density protein-95 (PSD-95)], angiogenesis [vascular endothelial growth factor (VEGF), Angiopoietin-1 (Ang-1), and Angiopoietin-2 (Ang-2)], and regulatory molecules [brain-derived neutrophic factor (BDNF), hypoxia inducible factor 1α (HIF-1α), phospholipase D2 (PLD2) and mechanistic target of rapamycin (mTOR) pathway] were all measured at the mRNA and protein levels with real-time PCR and Western blot. Results: Although all rehab procedures induced significant improvement in functional outcomes, including in sensory, motor, and cognitive functions, RICE but not RIC and exercise alone was better able to improve functions after stroke. The functional improvement was significantly associated with gene and protein expressions of molecules for neuroplasticity, synaptogenesis and angiogenesis, with additional increases being induced by RICE. A HIF-1α/PLD2/mTOR signaling pathway was underpinning this processes. Conclusions: RICE induced a better rehabilitation after ischemic stroke by promoting neuroplasticity. This study established the RICE strategy and provided novel clues to pave future endeavors in stroke rehabilitation.

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer’s disease patients

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition.This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25–59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively.The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).

Effect of erythropoietin administration on expression of mRNA brain-derived Neutrophic factor, levels of stromal cell-derived Factor-1, and neuron specific enolase in brain injury model SpragueDawley

BackgroundTraumatic brain injury (TBI) is a complicated condition that is the primary cause of death and disability in children and young adults in developed countries. Various kinds of therapy have been carried out in the management of brain injury, one of which is the administration of erythropoietin (EPO). There are not many studies in Indonesia have proven that EPO administration is effective on parameters such as stromal cell-derived factor 1 (SDF-1), brain-derived neurotrophic factor (BDNF mRNA), and neuron-specific enolase (NSE) in brain injury patients. The purpose of this study was to see how EPO affected BDNF mRNA expression, SDF-1 serum levels, and NSE levels in experimental rats with TBI. MethodsThis study was conducted using a rat head injury model. Fifteen rats were randomly assigned to one of three groups: A, B, or C. EPO was administered subcutis with a dose of 30.000 U/kg. Blood samples were taken after brain injury (H0), 12 h (H12), and 24 h (H24) after brain injury. Serum level of SDF-1 and NSE were measured using mRNA BDNF gene expression was measured with Real-Time-PCR, and ELISA. ResultsThis study found EPO increase BDNF mRNA expression in group C at H-12 (7,92 ± 0.51 vs 6.45 ± 0.33) compared to group B, and at H-24 (9.20 ± 0.56 vs 7.22 ± 0.19); increase SDF-1 levels in group C at H-12 (7,56 ± 0,54) vs 4,62 ± 0,58) compared to group B, and at H-24 (11,32 ± 4,55 vs 2,55 ± 0,70); decrease serum NSE levels in group C at H-12 (17,25 ± 2,02 vs 29,65 ± 2,33) compare to group B and at H-24 (12,14 ± 2,61 vs 37,31 ± 2,76); the values are significantly different with p < 0,05. ConclusionEPO may have neuroprotective and anti-inflammatory properties in TBI by increasing mRNA BDNF expression and serum SDF-1 levels, and decrease serum NSE levels.

Down regulation of DNA topoisomerase IIβ exerts neurodegeneration like effect through Rho GTPases in cellular model of Parkinson’s disease by Down regulating tyrosine hydroxylase

ABSTRACT Initiating the transcriptional activation of neuronal genes, DNA topoisomerase IIβ (topo IIβ) has a crucial role in neural differentiation and brain development. Inhibition of topo IIβ activity causes shorter axons and deteriorated neuronal connections common in neurodegenerative diseases. We previously reported that topo IIβ silencing could give rise to neurodegeneration through dysregulation of Rho GTPases and may contribute to pathogenesis of neurodegenerative diseases. Although there are several studies available proposing a link between Parkinson’s Disease (PD) and Rho GTPases, there have been no reports analyzing the topo IIβ-dependent association of PD and Rho GTPases. Here, for the first time, we identified that topo IIβ has a regulatory role on Rho GTPases contributing to PD-like pathology. We analyzed the association between topo IIβ and PD by comparing topo IIβ expression levels of Retinoic Acid (RA) and Brain-derived neutrophic factor (BDNF) induced and MPP+-intoxicated SH-SY5Y cells used as an in vitro PD model. While both mRNA and protein levels of topo IIβ increase in neural differentiated cells, a significant decrease is detected in the PD model. Additionally, silencing of topo IIβ by specific siRNAs caused phenotypic alterations like deteriorated neural connections and transcriptional regulations such as upregulation of RhoA and downregulation of Cdc42, Rac1, and tyrosine hydroxylase gene expressions. Our results suggest that topo IIβ downregulation may cause neurodegeneration through dysregulation of Rho-GTPases leading to PD-like pathology.

The importance of brain-derived neutrophic factor for lipid profile among Parkinson's patients

Background: Parkinson's disease (PD) is a neurodegenerative disorder that affects many body systems, including cardiometabolic function. Brain-derived neutrophic factor (BDNF) is altered in PD and has also been implicated in cardiometabolic function. However, few studies examined the effect altered BDNF on lipid profile among PD.

One-Week High-Intensity Interval Training Increases Hippocampal Plasticity and Mitochondrial Content without Changes in Redox State.

Evidence suggests that physical exercise has effects on neuronal plasticity as well as overall brain health. This effect has been linked to exercise capacity in modulating the antioxidant status, when the oxidative stress is usually linked to the neuronal damage. Although high-intensity interval training (HIIT) is the training-trend worldwide, its effect on brain function is still unclear. Thus, we aimed to assess the neuroplasticity, mitochondrial, and redox status after one-week HIIT training. Male (C57Bl/6) mice were assigned to non-trained or HIIT groups. The HIIT protocol consisted of three days with short bouts at 130% of maximum speed (Vmax), intercalated with moderate-intensity continuous exercise sessions of 30 min at 60% Vmax. The mass spectrometry analyses showed that one-week of HIIT increased minichromosome maintenance complex component 2 (MCM2), brain derived neutrophic factor (BDNF), doublecortin (DCX) and voltage-dependent anion-selective channel protein 2 (VDAC), and decreased mitochondrial superoxide dismutase 2 (SOD 2) in the hippocampus. In addition, one-week of HIIT promoted no changes in H2O2 production and carbonylated protein concentration in the hippocampus as well as in superoxide anion production in the dentate gyrus. In conclusion, our one-week HIIT protocol increased neuroplasticity and mitochondrial content regardless of changes in redox status, adding new insights into the neuronal modulation induced by new training models.

Effects of PACAP-38 and an analog, acetyl-[Ala15, Ala20] PACAP-38-propylamide, on memory consolidation in the detection of spatial novelty task in rats

PACAP-38 (P38) is a pleiotropic peptide that exerts multiple peripheral and central actions, including neurotrophic, neuroprotective and anti-inflammatory actions. Previous studies have suggested an improvement of memory in rats that have received a single systemic injection of P38. In a therapeutic perspective, we used an analog, acetyl-[Ala15, Ala20]PACAP-38-propylamide (ALG), to improve both stability and affinity for PAC1 receptors vs. endogen PACAP. We investigated the effect of P38 and ALG on memory consolidation using a spatial novelty detection (SND) task in which rats had to memorize a configuration of objects to identify that, during a test session, a familiar object has been moved to a new location. Rats received an intravenous injection of P38 or ALG after the last training session. In Experiment 1, P38 (30 µg/kg) improved spatial memory consolidation allowing detection of novelty vs. saline injection. In Experiment 2, we confirmed this effect and showed that P38 restored the performance similar to what was found using non-injected rats. This suggests that, contrary to ALG, P38 exerted a promesiant rather than an anxiety-related effect whereas ALG did not show similar action. We also examined whether P38 effect involved an interaction with NR2B-containing NMDA receptors (NMDARs) by administrating ifenprodil (IFE; a selective NR2B-containing NMDAR antagonist) alone or in combination with P38 or ALG. The results suggested that P38 action on memory involved NR2B-containing NMDARs. Lastly, brain-derived neutrophic factor (BDNF) modulation appeared to be not related to the behavioral performance in the SND task. Overall, the results indicate that P38 exerted a beneficial effect on memory consolidation in a non-associative task, whereas ALG did not have this action.

Molecular Markers of Ischemic Stroke

The purpose of the study was to evaluate the clinical significance of CNS biological markers in an ischemic stroke.Materials and methods. Blood serum biomarkers of CNS were assayed by ELISA in patients suffering from cerebrovascular disorders of ischemic origin. Neuron-specific enolase, brain-derived neutrophic factor (BDNF), glial-derived neutrophic factor (GDNF), protein S-100 total (ɑβ–ββ), sialyl carbohydrate antigen (KL-6), vascular endothelial growth factor, and superoxide dismutase were analyzed. All tests were carried out using automatic microplate immunoassay analyzer Immunomat TM. The study included 43 patients of 50 to 80 years of age, suffering from cerebrovascular disorders; among them there were 24 women and 19 men. Blood serum biomarkers of CNS were assayed within the first 3–6 hours, and on week 2, 3, and 4 from onset of the disease. The control group consisted of 20 volunteers (apparently healthy donors). Statistical analysis was carried out using non-parametrical Mann–Whitney test. Results were considered as significant at P 0.05.Results. During the pre-necrotic and early necrotic period, higher neuron-specific enolase, protein S-100, superoxide dismutase, and lower brain-derived neutrophic factor and glial-derived neutrophic factor were observed, reflecting structural brain alterations due to disturbed circulation. At later follow-up time-points, BDNF, GDNF, VEGF, and KL-6 increased evidencing activated CNS regeneration processes.Conclusion. The content of biological markers in blood serum of ischemic stroke patients reflects the disease stages, which helps managing the CNS regeneration processes.

Brain-derived neutrophic factor in adolescents smoking waterpipe: The Irbid TRY

BackgroundBrain-derived neutrophic factor (BDNF) and tobacco consumption can affect many body functions and health. However, the relationship of BDNF with waterpipe (Wp) smoking is unknown. Therefore, the current study examined the relationship between Wp smoking and BDNF in adolescents. MethodsSelf-reported tobacco consumption and serum BDNF were determined in 195 waterpipe and 288 nonsmokers in 7th–10th grade students. ResultsStepwise regression that included Wp smoking, gender, BMI, and location, showed that only Wp smoking (p < 0.0001) and gender (p < 0.0001) were related to serum BDNF. In addition, the ANCOVA found a main effect for Wp smoking (p < 0.0001) and gender (p < 0.0001) with lower BDNF in males smoking waterpipe. DiscussionBDNF was diminished in adolescent Wp smokers, which might predispose adolescents for systematic adverse health and behavioral alterations. These results extend the negative health risks associated with cigarette smoking to that of water-pipe tobacco smoking.

MiR-613 inhibits gastric cancer progression through repressing brain derived neurotrophic factor.

MicroRNA (miR)-613 has been reported to function as a tumor suppressor in several types of cancer. However, the biological function and underlying mechanism in gastric cancer (GC) has remained elusive. Therefore, the aim of the present study was to assess the expression and biological role of miR-613 in GC tissues and cell lines. miR-613 expression was found to be downregulated in 38 GC tissue samples compared to that in their adjacent non-cancerous tissues, and low expression of miR-613 was associated with lymph node metastasis and advanced tumor-nodes-metastasis stage. A gain-of-function assay demonstrated that miR-613 overexpression reduced tumor cell proliferation, migration and invasion of SGC-7901 cells, as determined by MTT and Transwell assays. Furthermore, brain-derived neutrophic factor (BDNF) was identified as a direct target of miR-613 in GC cells by a luciferase reporter assay. BDNF expression was upregulated and inversely correlated with miR-613 levels in GC tissues. In addition, knockdown of BDNF expression mimicked the tumor suppressive effect of miR-613 in GC cells. In conclusion, these findings demonstrated that miR-613 functions as a tumor suppressor in GC by targeting BDNF. Thus, miR-613 is a potential therapeutic target for GC.

Hippocampal BDNF overexpression or microR124a silencing reduces anxiety- and autism-like behaviors in rats

MicroRNA124a (miR124a) has emerged recently as a key player for multiple neuropsychiatric disorders including depression, anxiety, alcoholism, and cocaine addiction. Although we have previously reported that miR124a and its target the brain-derived neutrophic factor (BDNF) play an important role in autism-like behaviors, the molecular and behavioral dysfunctions remain unknown. The aim of this study was to understand the effects of sustained decreases in miR124a and increases of BDNF in the dentate gyrus (DG) on neonatal isolation-induced anxiety-and autism like behaviors in rats. Here we report that lentiviral-mediated silencing of miR124a in the adult DG attenuated neonatal isolation-induced anxiety-like behavior in the elevated plus maze (EPM) and open-field (OF) tests. Also, miR124a silencing decreased autism-like phenotype in the marble burying test (MBT), self-grooming (SG), and social interaction tests. Pearson’s correlations demonstrated that high levels of BDNF, a direct target of miR124a, were negatively correlated with miR124a expression. Interestingly, viral-mediated BDNF overexpression in the DG also reversed the neonatal isolation-induced anxiety-and autism like phenotypes. Collectively, these findings suggest that miR124a, through its target BDNF, may influence neonatal isolation-induced anxiety-and autism like behaviors. In conclusion, these results do support the hypothesis that miR124a in discrete hippocampal areas contributes to anxiety- and autism-like behaviors and may be involved in the neuroadaptations underlying the development of autism spectrum disorders as a persistent and lasting condition, and therefore provide a clearer mechanistic framework for understanding the physiopathology of such psychiatric illnesses.

Brain derived neutrophic factor (BDNF) coordinates lympho-vascular metastasis through a fibroblast-governed paracrine axis in the tumor microenvironment.

It has long been known that the tumor microenvironment contributes to the proliferation and survival of neoplasms through the constant interaction with the stromal and immune compartments. In this investigation, we explored the role of cancer-associated fibroblasts (CAFs) in the regulation of the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC) though a complex intercellular BDNF-TrkB signaling system. Our studies show that conditioned media derived from patient-derived CAFs promoted HNSCC cell proliferation, in vitro cell migration, cell invasion and chemotherapy resistance, compared to normal fibroblasts. Furthermore, examination of the in vivo impact of CAF pathophysiology in the tumor microenvironment in animal xenograft models revealed that HNSCC cell lines in combination with CAFs promoted tumor growth and increased incidence of lymphovascular metastasis as compared to injection of tumor cells or CAF cells alone. Using pharmacological and genetic alterations, we mechanistically demonstrate the critical importance of BDNF-TrkB signaling in the tumor microenvironment. These investigations further support the rationale for BDNF/TRKB targeted therapy against in the treatment of HNSCC.

Abstract PR156

Background & Objectives: Every year, millions of children receive anesthesia for surgical procedures that may affect the developing brain causing cognitive decline. While most studies have demonstrated the effects of inhalational agents on memory, a critical component in the cognitive process involving acquisition to retention, we wanted to examine the effects of remifentanil on short-term memory loss and levels of brain-derived neutrophic factor (BDNF) in young adult rats. Materials & Methods: To establish aversive memory, 12 young female Sprague-Dawley rats, weighing 247.92 ± 16.56g were trained in a step-down inhibitory avoidance apparatus in 3 successive sessions 8 hours apart until they remained on the platform without descent for ≥ 300s. They were then randomized to either saline group (S) or remifentanil (R). One hour after the last training, they were induced with 2% isoflurane in 50% oxygen at 2L/min in a temperature-controlled chamber for venous cannulation followed by maintenance with 0.5% isoflurane under spontaneous ventilation. Group S had saline at 4ml/kg/hr and Group R had remifentanil (Ultiva®), 4–8 ug/kg/min both over 1 hour. Once the rats were fully recovered, we tested the number of rats and their timing to step-down latency (SDL) in the same apparatus without cues or foot-shocks. The test was considered negative for loss of acquired short-term memory if the animal remained on the platform ≥ 300s. Their brain BDNF levels were determined using an ELISA kit. To find the difference between the two groups, Mann Whitney U test was used. Results:Table:a): Physiological findings during the infusion b) Results of memory testing after the infusionNo statistical difference was found in the memory retained from the training sessions in both groups (p=0.873). Conclusion: The authors conclude that a single high dose of remifentanil infusion does not produce loss of acquired short term memory in young adult rats. These findings suggest that remifentanil being a short-acting, rapidly metabolised opioid with a predictable phamacological profile has no effects on cognitive function in the developing brain of the young.

Brain Derived Neutrophic Factor, Cerebral Activation and Memory Responses to Five Weeks of Aerobic Exercise Training

Studies have shown that the production of brain derived neutrophic factor (BDNF) in the hippocampus increases following exercise which may be the molecular link between physical activity and the improvements reported in memory and learning. PURPOSE: To determine if moderate intensity exercise training leads to an increase in plasma [BDNF] which may be associated with improvements in cognitive function, increased brain activity and/or structure. METHODS: 11 healthy males (23 ± 7 yrs (±SD)) completed a 5 week aerobic training program (92 ± 5% compliance) at an intensity of 65% maximal heart rate, 5 days/wk on a cycle ergometer. Prior to, and following training, each subject performed a ramp exercise test to fatigue for the determination of peak VO2 (VO2pk), work rate (WRpk), and estimated lactate threshold (LT). Arterialized-venous blood samples were obtained from a dorsal hand vein at rest, exhaustion and during recovery for the determination of plasma [BDNF]. Subjects underwent magnetic resonance imaging (fMRI) and a memory task before and after the training program. All exercise was performed on a cyle ergometer; pulmonary gas exchange was measured using standard techniques. RESULTS: While there was no difference in VO2pk between pre- and post-training (pre, 43.9 ± 9.2; post, 45.4 ± 8.5 ml/kg/min), the VO2 at LT was higher (p<0.05) following training (pre, 1773 ± 262; post, 2047 ± 289 ml/kg/min). Similarly, WRpk was higher (p<0.05) following training (pre, 288 ± 50; post, 313 ±56 W). Brain volume in right hippocampus and left cerebral cortex was significantly decreased following training. Compared to pre-training, fMRI showed an increase in the activation of the left hippocampus after training. There was no difference in plasma [BDNF] at rest between pre- and post-training; plasma [BDNF] increased (p<0.05) at exhaustion and was higher following training (pre, 15.4 ± 3.7; post, 17.5 ± 4.4 ng/ml: p<0.05). CONCLUSION: A moderate intensity training program resulted in small, but significant increases in exercise tolerance, brain structural and functional activation, particularly in the hippocampal region. However, there was little evidence for a relationship between changes in plasma [BDNF], brain structure and memory function.

Influence of brain-derived neutrophic factor on tissue of oxidative stress and cell apoptosis of secondary brain injury after traumatic brain injury in rats

Objective To investigate the changes of the level of oxidative stress and cell apoptosis of secondary brain injury after traumatic brain injury, and the influence of brain-derived neutrophic factor on these parameters in rats, as well as its potential mechanisms. Methods A total 84 adult and healthy male rats was divided randomly into 2 groups: control (n=42) and traumatic brain injury (TBI) groups (n=42). The brain-derived neurotrophic factor (BDNF) group was induced using improved Feeney method and was received abdominal injections of BDNF (0.5 μg/μl) immediately after injury, the control group were received abdominal injections with the same dose sodium chloride injection immediately after injury and repeat one time everyday until the rats was killed. Each group was divided into seven subgroups by sacrificed time after injury, those are 1 h, 3 h, 6 h, 12 h, 24 h, 3 d, and 7 d, each subgroup got 6 rats. Each subgroup was randomly selected three rats after being killed. The water content, superoxide dismutase (SOD), malonic aldehyde (MDA), and glutathione (GSH) of rats were measured contusion peri tissues brain tissue. Specimens were taken from left three rats of subgroup, which was part of the brain tissue. The expression of NF-κB p65, around the brain tissue with immunohistochemical methods were detected. TdT-mediated dUTP nick-end labeling (TUNEL) method was used to observe the peri cell apoptosis after brain contusion. Results NF-κB p65 was expressed obviously around the lesion in 1h group, and strongly expressed in TBI-3 h-12 h, and reached a peak in 24 h after the injury, while NF-κB p65 expression reduced in TBI-3 d-7 d, and still in high expression. NF-κB p65 expression strongly correlated with the degree of cerebral edema (r=0.651, P<0.05). For two groups, NF-κB p65 expression strongly correlated with the level of MDA (r1=0.947, P<0.01; r2=0.961, P<0.01). Conclusions Changes of NF-κB protein expression after brain injury were involved in a series of pathological processes of secondary brain injury, such as oxidative stress, and apoptosis, brain-derived neutrophic factor is probably through inhibit oxidative stress levels, control apoptosis, prevent the development of vasogenic cerebral edema, and reduce or mitigate secondary brain injury. Key words: Brain-derived neurotrophic factor/ME/PD; Craniocerebral trauma/ME/DT; Oxidative stress/DE; Apoptosis/DE

Disruption of the brain-derived neurotrophic factor (BDNF) immunoreactivity in the human Kölliker-Fuse nucleus in victims of unexplained fetal and infant death.

Experimental studies have demonstrated that the neurotrophin brain-derived neutrophic factor (BDNF) is required for the appropriate development of the central respiratory network, a neuronal complex in the brainstem of vital importance to sustaining life. The pontine Kölliker-Fuse nucleus (KFN) is a fundamental component of this circuitry with strong implications in the pre- and postnatal breathing control. This study provides detailed account for the cytoarchitecture, the physiology and the BDNF behavior of the human KFN in perinatal age. We applied immunohistochemistry in formalin-fixed and paraffin-embedded brainstem samples (from 45 fetuses and newborns died of both known and unknown causes), to analyze BDNF, gliosis and apoptosis patterns of manifestation. The KFN showed clear signs of developmental immaturity, prevalently associated to BDNF altered expression, in high percentages of sudden intrauterine unexplained death syndrome (SIUDS) and sudden infant death syndrome (SIDS) victims. Our results indicate that BDNF pathway dysfunctions can derange the normal KFN development so preventing the breathing control in the sudden perinatal death. The data presented here are also relevant to a better understanding of how the BDNF expression in the KFN can be involved in several human respiratory pathologies such as the Rett's and the congenital central hypoventilation syndromes.

Baclofen prevented the changes in c-Fos and brain-derived neutrophic factor expressions during mecamylamine-precipitated nicotine withdrawal in mice.

Previous studies from our laboratory showed that baclofen (BAC, GABAB receptor agonist) prevented the behavioral and neurochemical alterations of nicotine (NIC) withdrawal syndrome. To further investigate the mechanisms underlying these effects, we analyzed the c-Fos and brain-derived neutrophic factor (BDNF) expression during NIC withdrawal and its prevention with BAC. Swiss-Webster mice received NIC (2.5 mg/kg, sc) four times daily, for 7 days. On the 8th day, NIC-treated mice received the nicotinic antagonist mecamylamine (MEC; 2 mg/kg, i.p.) 1 h after the last dose of NIC. A second group of NIC-treated mice received BAC (2 mg/kg, i.p.) prior to MEC administration. Thirty minutes after MEC, mice were sacrificed and the immunohistochemistry assays (c-Fos and BDNF) were performed at different anatomical levels. c-Fos expression decreased in the dentate gyrus of the hippocampus (DG) and the bed nucleus of the stria terminalis (BST), and increased in the habenular (Hb), accumbens shell (AcbSh) nuclei during NIC withdrawal. BAC re-established the modified c-Fos expression only in the DG, BST and AcbSh during NIC withdrawal. Conversely, BDNF expression decreased in the CA1 and CA3 area of the hippocampus, the Hb, and caudate putamen (CPu) during NIC withdrawal. Finally, BAC restored the decreased BDNF expression during NIC withdrawal in the CA1, CA3, Hb, and CPu. The results suggest a relationship between BAC's preventive effect of the expression of NIC withdrawal signs, and its ability to restore the changes in c-Fos and BDNF expression, observed in specific brain areas of NIC-withdrawn mice.