Brain-derived Neurotrophic Factor Secretion Research Articles

Effects of Training with a Brain-Computer Interface-Controlled Robot on Rehabilitation Outcome in Patients with Subacute Stroke: A Randomized Controlled Trial.

IntroductionStroke is always associated with a difficult functional recovery process. A brain–computer interface (BCI) is a technology which provides a direct connection between the human brain and external devices. The primary aim of this study was to determine whether training with a BCI-controlled robot can improve functions in patients with subacute stroke.MethodsSubacute stroke patients aged 32–68 years with a course of 2 weeks to 3 months were randomly assigned to the BCI group or to the sham group for a 4-week course. The primary outcome measures were Loewenstein Occupational Therapy Cognitive Assessment (LOCTA) and Fugl-Meyer Assessment for Lower Extremity (FMA-LE). Secondary outcome measures included Fugl-Meyer Assessment for Balance (FMA-B), Functional Ambulation Category (FAC), Modified Barthel Index (MBI), serum brain-derived neurotrophic factor (BDNF) levels and motor-evoked potential (MEP).ResultsA total of 28 patients completed the study. Both groups showed a significant increase in mean LOCTA (sham: P < 0.001, Cohen’s d = − 2.972; BCI: P < 0.001, Cohen’s d = − 4.266) and FMA-LE (sham: P < 0.001, Cohen’s d = − 3.178; BCI: P < 0.001, Cohen’s d = − 3.063) scores. The LOCTA scores in the BCI group were 14.89% higher than in the sham group (P = 0.049, Cohen’s d = − 0.580). There were no significant differences between the two groups in terms of FMA-B (P = 0.363, Cohen’s d = − 0.252), FAC (P = 0.363), or MBI (P = 0.493, Cohen’s d = − 0.188) scores. The serum levels of BDNF were significantly higher within the BCI group (P < 0.001, Cohen’s d = − 1.167), and the MEP latency decreased by 3.75% and 4.71% in the sham and BCI groups, respectively.ConclusionTraining with a BCI-controlled robot combined with traditional physiotherapy promotes cognitive function recovery, and enhances motor functions of the lower extremity in patients with subacute stroke. These patients also showed increased secretion of BDNF.Trial RegistrationChinese clinical trial registry: ChiCTR-INR-17012874.

Visualization of Reelin Secretion from Primary Cultured Neurons by Bioluminescence Imaging.

Reelin is a secreted glycoprotein important for brain development and synaptic plasticity in the adult brain. Some reports suggest that Reelin is secreted from the nerve terminals and functions as a neurotransmitter. However, the mechanism of Reelin secretion is unknown. In this study, we visualized Reelin secretion by bioluminescence imaging using a fusion protein of Reelin and Gaussia luciferase (GLase-Reelin). GLase-Reelin expressed in HEK293T cells was correctly processed and secreted. Luminescence signals from the secreted GLase-Reelin of primary cultured neurons were visualized by bioluminescence microscopy. Reelin secretory events were observed at neurites and cell bodies. Bioluminescence imaging was also performed before and after KCl depolarization to compare the secretory events of Reelin and brain-derived neurotrophic factor (BDNF). The secretion of BDNF increased markedly shortly after depolarization. In contrast, the frequency of Reelin secretion did not change significantly by depolarization. Thus, Reelin secretion from neurites might not be regulated in a neuronal activity-dependent manner.

Effect and Mechanism of Catalpol on Behavior in Rats with Post-stroke Depression

<sec><title>Objective</title> To explore the effect of catalpol on the behavior of post-stroke depression rats, and to explore its mechanism from the aspects of behavior, the expression of 5-hydroxytryptamine (5-HT), norepinephrine (NE) and brain-derived neurotrophic factor (BDNF) in peripheral serum and brain tissue. </sec><sec><title>Methods</title> A total of twenty-four SD rats were randomly divided into model group, catalpol intervention group and sham operation group, with 8 rats in each group. The rats model of post-stroke depression were established by middle cerebral artery occlusion (MCAO) combined with the chronic unpredictable mild stress (CUMS) to induce depression-like behavior. The modeling time was 7 days. After the end of modeling, the open field test was used on the 1st, 4th, and 7th day. The behavior of the rats was evaluated by elevated plus maze measurement. TTC staining was used to detect cerebral infarction volume. The serum and hippocampus levels of 5-HT, NE, and BDNF were measured by enzyme-linked immunosorbent assay. </sec><sec><title>Results</title> Compared with the model group, the number of crossing grid, the number of standing and the total distance moved were significantly increased on the 4th and 7th day after intervention in the open field test, and the differences were significant (<italic>P</italic><0.05). In the elevated plus maze measurement, the OE% and OT% were significantly increased in the catalpol intervention group on the 4th and 7th day after intervention, and the differences were significant (<italic>P</italic><0.05), indicating that the catalpol could significantly increase the spontaneous activity of rats and relieve depression-like behavior. TTC staining showed that the volume of cerebral infarction in the catalpol intervention group was significantly reduced compared with model group (<italic>P</italic><0.05). In the ELISA experiment, compared with the model group, 5-HT and BDNF in the catalpol intervention group were significantly increased on the 4th and 7th day after intervention, and the difference was significant (<italic>P</italic><0.05); there was no significant difference in NE content in the catalpol intervention group on the 4th and 7th day after intervention (<italic>P</italic>>0.05); compared with the model group, the hippocampal 5-HT and BDNF in the catalpol intervention group increased significantly (<italic>P</italic><0.05); there was no significant difference in the content of NE in hippocampus between the catalpol intervention group and the model group (<italic>P</italic>>0.05), indicating that catalpol could increase 5-HT and BDNF levels in rats with post-stroke depression, but did not significantly improve NE. </sec><sec><title>Conclusion</title> Catalpol can improve post-stroke depression, promote the recovery of neurological function, regulate the function of central serotonin system and promote the secretion of BDNF. </sec>

Jujuboside a promotes proliferation and neuronal differentiation of APPswe-overexpressing neural stem cells by activating Wnt/β-catenin signaling pathway

Mobilization of hippocampal neurogenesis has been considered as a potential strategy for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). In present study, we evaluated both the neuroprotective effects and the effects on the proliferation and differentiation of APP-overexpressing neural stem cells (APP-NSCs) by Jujuboside A (JuA) in vitro. Our results demonstrated that JuA (50 μM) decreased apoptosis and suppressed oxidative stress damage of APP-NSCs. JuA (50 μM) upregulated the secretion of brain-derived neurotrophic factor and promoted the proliferation and neuronal differentiation of APP-NSCs. Moreover, JuA (50 μM) upregulated Wnt-3a and β-catenin protein expression, and enhanced the expression of downstream genes Ccnd1, Neurod1 and Prox1. However, XAV-939, an inhibitor of the Wnt/β-catenin signaling pathway, inhibited these positive effects of JuA. Taken together, these findings suggest that JuA promote proliferation and neuronal differentiation of APP-NSCs partly by activating the Wnt/β-catenin signaling pathway. We hope that this study will provide a viable strategy for the treatment of AD.

HUC-MSC-mediated recovery of subacute spinal cord injury through enhancing the pivotal subunits β3 and γ2 of the GABAA receptor.

Rationale: Spinal cord injury (SCI) remains an incurable neurological disorder leading to permanent and profound neurologic deficits and disabilities. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are particularly appealing in SCI treatment to curtail damage, restore homeostasis and possible neural relay. However, the detailed mechanisms underlying hUC-MSC-mediated functional recovery of SCI have not been fully elucidated. The purpose of our current study is to identify novel therapeutic targets and depict the molecular mechanisms underlying the hUC-MSC-mediated recovery of subacute SCI.Methods: Adult female rats suffering from subacute incomplete thoracic SCI were treated with intrathecal transplantation of hUC-MSCs. The beneficial effects of hUC-MSCs on SCI repair were evaluated by a series of behavioral analyses, motor evoked potentials (MEPs) recording of hindlimb and immunohistochemistry. We carried out extensive transcriptome comparative analyses of spinal cord tissues at the lesion site from the subacute phase of SCI (sub-SCI) either treated without (+PBS) or with hUC-MSCs (+MSC) at 0 (sub-SCI), 1, 2, and 4 weeks post-transplantation (wpt), as well as normal spinal cord segments of intact/sham rats (Intact). Adeno-associated virus (AAV)-mediated neuron-specific expression system was employed to functionally screen specific γ-aminobutyric acid type A receptor (GABAAR) subunits promoting the functional recovery of SCI in vivo. The mature cortical axon scrape assay and transplantation of genetically modified MSCs with either overexpression or knockdown of brain-derived neurotrophic factor (BDNF) were employed to demonstrate that hUC-MSCs ameliorated the reduction of GABAAR subunits in the injured spinal cord via BDNF secretion in vitro and in vivo, respectively.Results: Comparative transcriptome analysis revealed the GABAergic synapse pathway is significantly enriched as a main target of hUC-MSC-activated genes in the injured spinal cord. Functional screening of the primary GABAAR subunits uncovered that Gabrb3 and Garbg2 harbored the motor and electrophysiological recovery-promoting competence. Moreover, targeting either of the two pivotal subunits β3 or γ2 in combination with/without the K+/Cl- cotransporter 2 (KCC2) reinforced the therapeutic effects. Mechanistically, BDNF secreted by hUC-MSCs contributed to the upregulation of GABAAR subunits (β3 & γ2) and KCC2 in the injured neurons.Conclusions: Our study identifies a novel mode for hUC-MSC-mediated locomotor recovery of SCI through synergistic upregulation of GABAAR β3 and γ2 along with KCC2 by BDNF secretion, indicating the significance of restoring the excitation/inhibition balance in the injured neurons for the reestablishment of neuronal circuits. This study also provides a potential combinatorial approach by targeting the pivotal subunit β3 or γ2 and KCC2, opening up possibilities for efficacious drug design.

Inflammatory Mastitis in Implant Breast Carriers-A New Form of Presentation of Covid-19: Case Report

Introduction: Today with more than 190 million confirmed cases and more than 4 million deaths worldwide, SARS-COVID-19 has become an unprecedented challenge. Its molecular structure, spread-forms, and clinical presentation are areas of continuous study due to its constant change and new forms of presentation and dicipation. A clinical case with COVID-19 disease with bilateral non-lactating inflammatory mastitis in a patient with breast implants is presented. Discussion: Depending on its etiology, mastitis can be classified as infectious (septic or bacterial) and non-infectious (aseptic or inflammatory). Non-infectious or inflammatory mastitis is not related to the infection of a pathogen. This group can be related to mammary duct ectasia, inflammatory cross-reaction and foreign bodies. A new etiology has been reported as postCOVID-19 vaccination mastitis; however, mastitis has not been documented during coviD-19 infection. We can hypothesize that the pathophysiology of our case can involve a cross-reaction to the viral peak protein of 1273 amino acids with antigens found on the surface of microtextured implants or related in a loss on the homeostasis in the production and secretion of Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) during COVID-19 infection. Conclusion: Mastitis represents a common pathology before and during the COVID-19 pandemic. Although they are considered different entities, mastitis could be considered a rare manifestation fo COVID- 19 disease. Its approach, diagnosis and treatment must be timely and protocolized through a multidisciplinary group.

Exploring lipophilic compounds that induce BDNF secretion in astrocytes beyond the BBB using a new multi-cultured human in vitro BBB model

Brain-derived neurotrophic factor (BDNF) cannot cross the blood-brain barrier (BBB) when administered peripherally, which hinders its therapeutic potential. We utilized an in vitro BBB model—a tri-culture of a human endothelial cell line, a pericyte cell line, and an astrocyte cell line—to study the effect of twenty candidate lipophilic compounds on stimulating BDNF secretion in pericytes and astrocytes. The prostaglandin E2 receptor 4 agonist and sphingosine-1-phosphate receptor 5 agonist facilitated secretion of BDNF in the astrocyte, but did not decrease the transendothelial electrical resistance. These compounds may be promising agents for neurodegenerative and neuroinflammatory diseases.

Neuroplasticity Mechanisms and Prospects for Personalized Rehabilitation Strategies in Patients with Motor and Cognitive Impairments

Aim. To highlight the most important areas of research on the problems of rehabilitation after stroke and the prospects for the development of new rehabilitation strategies, taking into account individual characteristics. Neuroplastic outcomes of anemic infarctions are presented by multi-pattern positive processes of synaptogenesis, sprouting, synthesis of neuroprotective proteins, and destructive effects of stress plasticity inducing dystonic disturbances, deterioration of stabilometric parameters and locomotor gait mechanisms with support deterioration [1]. Thus, specialists in neurorehabilitation should know the basics of fundamental neurophysiological processes in the central nervous system, interhemispheric networks of the brain, and optimize rehabilitation programs, taking into account individualized recovery profiles [2]. One of the factors influencing recovery after a stroke is nervous reorganization, which is proportional to the amount of damage [3]. The processes of neuroplasticity are studied from the standpoint of returning to the pre-stroke recovery model (with minor injuries) – forming “optimal” plasticity and compensatory strategies of “destructive” plasticity (with extensive hemispheric injuries). Micro-RNA (miRNA) are understudied in the neuroprotective reaction to cerebral ischemia. Another important modulator of stroke outcomes is the brain-derived neurotrophic factor (BDNF). Processing of the defective BDNF synthesis when the amino acid valine is replaced by methionine (val-met) that occurs during allelic disorders is of outstanding interest. Conclusion. Promising research areas for strategic approaches to rehabilitation after a stroke are the study of hemispheric introduction, miRNA and neuroprotection cascades; BDNF as an inducer of neuronal differentiation. Allelic BDNF polymorphisms induce lower recovery potential after stroke. Under certain environmental conditions motor learning can overcome the neuroplasticity deficit in the BDNF gene polymorphism. The studies have shown general patterns of positive effects of aerobic stimuli with enhanced BDNF secretion in the recovery of patients with cognitive and motor impairments; nevertheless, the onset period, intensity, duration and exercises rhythmicity have not been established in cerebral stroke. Future studies are likely to optimize rehabilitation profiles based on genetic characteristics.

Endocytic BDNF secretion regulated by Vamp3 in astrocytes

Brain-derived neurotrophic factor (BDNF) regulates diverse brain functions via TrkB receptor signaling. Due to the expression of TrkB receptors, astrocytes can internalize extracellular BDNF proteins via receptor-mediated endocytosis. Endocytosed BDNF can be re-secreted upon stimulation, but the molecular mechanism underlying this phenomenon remains unrecognized. Our study reveals that vesicle-associated membrane protein 3 (Vamp3) selectively regulates the release of endocytic BDNF from astrocytes. By using quantum dot (QD)-conjugated mature BDNF (QD-BDNF) as a proxy for the extracellular BDNF protein, we monitored the uptake, transport, and secretion of BDNF from cultured cortical astrocytes. Our data showed that endocytic QD-BDNF particles were enriched in Vamp3-containing vesicles in astrocytes and that ATP treatment sufficiently triggered either the antero- or retrograde transport and exocytosis of QD-BDNF-containing vesicles. Downregulation of Vamp3 expression disrupted endocytic BDNF secretion from astrocytes but did not affect uptake or transport. Collectively, these results provide evidence of the selective ability of astrocytic Vamp3 to control endocytic BDNF secretion during BDNF recycling.

Distinct roles of astroglia and neurons in synaptic plasticity and memory.

Long-term potentiation (LTP) in the hippocampus is the most studied form of synaptic plasticity. Temporal integration of synaptic inputs is essential in synaptic plasticity and is assumed to be achieved through Ca2+ signaling in neurons and astroglia. However, whether these two cell types play different roles in LTP remain unknown. Here, we found that through the integration of synaptic inputs, astrocyte inositol triphosphate (IP3) receptor type 2 (IP3R2)-dependent Ca2+ signaling was critical for late-phase LTP (L-LTP) but not early-phase LTP (E-LTP). Moreover, this process was mediated by astrocyte-derived brain-derived neurotrophic factor (BDNF). In contrast, neuron-derived BDNF was critical for both E-LTP and L-LTP. Importantly, the dynamic differences in BDNF secretion play a role in modulating distinct forms of LTP. Moreover, astrocyte- and neuron-derived BDNF exhibited different roles in memory. These observations enriched our knowledge of LTP and memory at the cellular level and implied distinct roles of astrocytes and neurons in information integration.

Exercise improves health-related quality of life sleep and fatigue domains in adult high- and low-grade glioma patients.

The impact of exercise on health-related quality of life (HRQOL) in patients with glioma remains unknown. We hypothesized that glioma patients with low exercise tolerance experience more distress in HRQOL sleep and fatigue domains than patients with high tolerance to exercise. Thirty-eight male and female patients with low- or high-grade glioma treated at a single tertiary care institution participated. Patients completed a validated telephone survey to determine their exercise habits before and following diagnosis. An unpaired t-test was run to measure the interaction between exercise tolerances on HRQOL functional and impairment domains. Those with low pre-morbid physical activity levels had more distress in HRQOL sleep and fatigue domains. The effects were independent of plasma brain-derived neurotrophic factor (BDNF) levels and the degree of exercise did not appear to impact plasma BDNF in adult glioma patients. The aim of this study was to examine the significance of exercise habits on perioperative functional outcomes in patients with low-grade or high-grade glioma. We found that glioma patients with low tolerance to exercise had more sleep disturbances and greater fatigue than glioma patients with high tolerance to exercise. Furthermore, exercise tolerance in the adult glioma population does not appear to impact plasma BDNF secretion.

Neuron-Glia Crosstalk Plays a Major Role in the Neurotoxic Effects of Ketamine via Extracellular Vesicles.

Background: There is a compelling evidence from animal models that early exposure to clinically relevant general anesthetics (GAs) interferes with brain development, resulting in long-lasting cognitive impairments. Human studies have been inconclusive and are challenging due to numerous confounding factors. Here, we employed primary human neural cells to analyze ketamine neurotoxic effects focusing on the role of glial cells and their activation state. We also explored the roles of astrocyte-derived extracellular vesicles (EVs) and different components of the brain-derived neurotrophic factor (BDNF) pathway.Methods: Ketamine effects on cell death were analyzed using live/dead assay, caspase 3 activity and PARP-1 cleavage. Astrocytic and microglial cell differentiation was determined using RT-PCR, ELISA and phagocytosis assay. The impact of the neuron-glial cell interactions in the neurotoxic effects of ketamine was analyzed using transwell cultures. In addition, the role of isolated and secreted EVs in this cross-talk were studied. The expression and function of different components of the BDNF pathway were analyzed using ELISA, RT-PCR and gene silencing.Results: Ketamine induced neuronal and oligodendrocytic cell apoptosis and promoted pro-inflammatory astrocyte (A1) and microglia (M1) phenotypes. Astrocytes and microglia enhanced the neurotoxic effects of ketamine on neuronal cells, whereas neurons increased oligodendrocyte cell death. Ketamine modulated different components in the BDNF pathway: decreasing BDNF secretion in neurons and astrocytes while increasing the expression of p75 in neurons and that of BDNF-AS and pro-BDNF secretion in both neurons and astrocytes. We demonstrated an important role of EVs secreted by ketamine-treated astrocytes in neuronal cell death and a role for EV-associated BDNF-AS in this effect.Conclusions: Ketamine exerted a neurotoxic effect on neural cells by impacting both neuronal and non-neuronal cells. The BDNF pathway and astrocyte-derived EVs represent important mediators of ketamine effects. These results contribute to a better understanding of ketamine neurotoxic effects in humans and to the development of potential approaches to decrease its neurodevelopmental impact.

The BDNF val66met polymorphism is associated with decreased use of landmarks and decreased fMRI activity in the hippocampus during virtual navigation.

People can navigate in a new environment using multiple strategies dependent on different memory systems. A series of studies have dissociated between hippocampus-dependent 'spatial' navigation and habit-based 'response' learning mediated by the caudate nucleus. The val66met polymorphism of the brain-derived neurotrophic factor (BDNF) gene leads to decreased secretion of BDNF in the brain, including the hippocampus. Here, we aim to investigate the role of the BDNF val66met polymorphism on virtual navigation behaviour and brain activity in healthy older adults. A total of 139 healthy older adult participants (mean age = 65.8 ± 4.4 years) were tested in this study. Blood samples were collected, and BDNF val66met genotyping was performed. Participants were divided into two genotype groups: val homozygotes and met carriers. Participants were tested on virtual dual-solution navigation tasks in which they could use either a hippocampus-dependent spatial strategy or a caudate nucleus-dependent response strategy to solve the task. A subset of the participants (n = 66) were then scanned in a 3T functional magnetic resonance imaging (fMRI) scanner while engaging in another dual-solution navigation task. BDNF val/val individuals and met carriers did not differ in learning performance. However, the two BDNF groups differed in learning strategy. BDNF val/val individuals relied more on landmarks to remember target locations (i.e., increased use of flexible spatial learning), while met carriers relied more on sequences and patterns to remember target locations (i.e., increased use of inflexible response learning). Additionally, BDNF val/val individuals had more fMRI activity in the hippocampus compared with BDNF met carriers during performance on the navigation task. This is the first study to show in older adults that BDNF met carriers use alternate learning strategies from val/val individuals and to identify differential brain activation of this behavioural difference between the two groups.

Role of brain-derived neurotrophic factor in shaping the behavioural response to environmental stressors.

Brain-derived neurotrophic factor (BDNF) is an important neurotrophin involved in an integration of the brain activity in physiological and pathological conditions, with formation of a short- and long-term functional and structural neuroplasticity. This process proceeds, with a changeable dynamics, in the subsequent stages of ontogenesis. In addition to many other functions in the central nervous system, BDNF is also involved in shaping a response to stress stimuli in the form of precisely adjusted behavioural reactions involving the limbic system, and the endocrine system with stimulation of the hypothalamic-pituitary-adrenal axis (HPA). Although almost every stressor increases the activity of the HPA, the neuronal response to it can vary substantially. This may be due to involvement of different neurotransmitter pathways, neuromodulators and neurohormones, as well as changes in gene expression. It is widely accepted that BDNF synthesis and secretion are modulated by stress. Furthermore, age is an important factor influencing the BDNF expression in response to different stressors. In this work, we focused on the analysis of the role of mild stressful stimuli, which commonly occur in the natural environment, on changes in BDNF expression at various stages of ontogenetic development. Although, the presented data comes from animal studies, probably similar mechanisms of stress regulation are also present in humans. This comprehensive review shows that the influence of stressors on the BDNF expression depends on many factors, including a type and duration of a stressor, time of neurotrophin detection, animal's resistance to stress, brain area, and genotypic characteristics of an individual. A more detailed understanding of the mechanisms shaping stress reactions, including the role of BDNF, may be of both theoretical and practical importance, allowing designing more effective strategies for preventing and treating stress itself and the stress-related disorders.

A-5 Brain-Derived Neurotrophic Factor Val66Met and Neuropsychological Functioning Following Early Childhood Traumatic Brain Injury

Abstract Objective The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on neuropsychological functioning in children with traumatic brain injury (TBI) relative to children with orthopedic injury (OI). Method Participants were drawn from a prospective, longitudinal study of children who sustained a TBI (n = 69) or OI (n = 72) between 3 and 7 years of age. Children completed a battery of neuropsychological measures targeting attention, memory, and executive functions at four time points spanning the immediate post-acute period to 18 months post-injury. Children also completed a comparable age-appropriate battery of measures approximately 7 years post-injury. Parents rated children’s executive functioning at all time points. Results Longitudinal mixed models revealed a significant allele status x injury group interaction for verbal fluency (p = 0.007) and a non-significant trend for parent-rated dysexecutive behaviors (p = 0.069), and cross-sectional models at 7 years post-injury revealed a non-significant trend for the allele status x injury group interaction for fluid reasoning skills (p = 0.074). Post hoc analyses suggested a consistent pattern of poorer neuropsychological functioning in Met carriers relative to Val/Val homozygotes in the TBI group; in contrast, the opposite trend was observed in the OI group. Conclusions The results suggest a differential effect of the BDNF Val66Met polymorphism on verbal fluency, dysexecutive behaviors, and fluid reasoning skills in children with early TBI relative to OI, and that the Met allele—associated with reduced activity-dependent secretion of BDNF—confers risk for poorer neuropsychological functioning in children with TBI.

Brain-derived neurotrophic factor in relation to central obesity in children with sleep disordered breathing.

IntroductionSleep disordered breathing (SDB) represents common comorbidities of childhood obesity leading to interrupted sleep and sleep deprivation. Sleep deprivation alters secretion of brain-derived neurotrophic factor (BDNF), which is an appetite regulator. However, little is known about the relation between BDNF and central obesity in children with SDB. The aim of the study was to evaluate BDNF level and anthropometric indices in relation to SDB in children with obesityMaterial and methodsA prospective case-control study was conducted on 30 children with obesity (BMI > 95th percentile) and 30 healthy lean children (BMI 5th-85th percentile). Polysomnographic, anthropometric data and BDNF serum level were obtained from all included children. Serum level of BDNF and anthropometric indices of obesity were assessed in relation to SDB in children with obesity. Regression analysis was done to determine predictors for SDB in children with obesity.ResultsIn comparison to healthy controls, anthropometric indices of central obesity were significantly higher while BDNF was significantly lower in obese children, especially those with SDB. Respiratory disturbance index has a significant positive correlation with anthropometric indices of central obesity and a significant negative correlation with BDNF level. Central obesity and decreased BDNF were associated with 2-fold increased risk for SDB. Waist circumference/height ratio and neck circumference/height ratio have 89.5%, 75% sensitivity and 81.23%, 84.62% specificity at a cutoff point > 0.62, > 0.24 respectively for prediction of SDB in children with obesity.ConclusionsCentral obesity and decreased BDNF represent independent predictors for SDB in children with obesity. Anthropometric indices adjusted to height are a simple screening tool for SDB in obese children.

Low Skeletal Muscle Mass Is Associated With Perioperative Neurocognitive Disorder Due To Decreased Neurogenesis in Rats.

Perioperative neurocognitive disorder (PND) is a postsurgical complication associated with neuroinflammation and impaired hippocampal neurogenesis, in which brain-derived neurotrophic factor (BDNF) plays a key role. Sarcopenia refers to age-related muscle loss that causes cognitive decline, muscle atrophy, and postoperative delirium. Rats with tail suspension (TS) were used to represent a low-activity model, which involves decreased hind limb function by TS. This hind limb unloading by TS can induce sarcopenia in 2 weeks. However, the relationship between PND and muscle atrophy is unclear. In this experiment, we investigated whether preoperative muscle atrophy induced by TS would affect neurogenesis and accelerate PND in rats. Sixty 21-week-old rats were assigned to 4 groups: the TS group, the TS with surgery (TS + S) group, the control group, and the control with surgery (control + S) group. After the abdominal manipulation under 3% sevoflurane anesthesia, cognitive function was assessed using the Morris water maze test and a fear-conditioning test. Neurogenesis was evaluated by checking BDNF secretion and immunohistochemical staining in the hippocampus. The TS + S group showed impaired swimming latency (difference of means = 12.4 versus control + S; 95% confidence interval [CI], 2.0-22.7; P = .016) (difference of means = 15.2 versus TS; 95% CI, 0.4-30.1; P = .043) and path length (difference of means = 147.8 versus control + S; 95% CI, 20.7-274.9; P = .020) in the maze test and cued fear memory (difference of means = -26.0 versus TS; 95% CI, -46.4 to -5.6; P = .006) (difference of means = -22.3 versus control + S; 95% CI, -42.7 to -1.9; P = .026) in the fear-conditioning test. The postoperative levels of BDNF in the TS + S and TS groups were reduced compared with the other groups (P = .002). The number of neural precursors in the dentate gyrus was significantly lower in the TS + S group (P < .001). We observed that preoperative hind limb muscle atrophy, indicated by TS, was associated with an increased occurrence of PND through the reduction in BDNF and neurogenesis after abdominal surgery in young adult rats. Therefore, we concluded that preoperative low skeletal muscle mass can induce PND due to impaired postoperative neurogenesis. Our findings might indicate that low-cost perioperative interventions, such as preoperative exercise, is beneficial to preventing PND.

Music Therapy Alleviates Motor Dysfunction in Rats With Focal Cerebral Ischemia-Reperfusion Injury by Regulating BDNF Expression.

Background/Aim: Music-based therapy plays a role in central nervous system diseases. We aimed to explore the effect of different doses and durations of music therapy on motor function recovery after stroke and the underlying molecular mechanisms.Methods: Adult male Sprague–Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h, which was followed by reperfusion. In experiment 1, the rats that survived 1 week after MCAO surgery were randomly allocated into four groups (n = 10 per group): MCAO group, 1 h music group (Mozart K.448 music therapy 1 h per day for 2 weeks), 12 h music group (Mozart K.448 music therapy 12 h/day for 2 weeks), and accelerated music group (reversely accelerated music therapy 12 h for 2 weeks, AM group). In experiment 2, the survived rats were randomly divied into three groups: MCAO group, 12 h music group (music therapy 12 h/day for 3 weeks), and 12 h music-R group (music therapy 12 h/day for 2 weeks and rest for 1 week). Three neuroscores were evaluated daily, starting on the first day after surgery until the end of the experiment. The rats were killed 3 weeks after MCAO surgery in experiment 1 or 4 weeks after surgery in experiment 2. Nissl staining of infart core, peri-infarct zone, and motor cortex was performed to assess neuronal survival and regeneration. Western blot and immunofluorescence were used to detect the expression and distribution of brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) in ipsilateral hemispheres.Results: In the experiment of different music therapy doses, the motor function in the 12-h music group but not in the 1-h music group and AM group was significantly improved compared with that of the MCAO group. The BDNF protein level of the ipsilateral hemisphere motor cortex in the 12-h music group and the 1-h music group was higher than that of the MCAO group. The neurons and Nissl bodies were more in the 12-h music group than in the MCAO group. Immunofluorescence assay showed that a 12 h music therapy induces BDNF and GFAP accumulation at the damage boundary. In the experiment of different music therapy durations, 3 weeks music therapy (12 h music group) induced more longer cell synapses and more clearer cell-to-cell connections than 2 weeks music intervention (12 h music-R group). Moreover, the GFAP morphology in the 12-h music group was more similar to mature activated astrocytes than that in the 12-h music-R group.Conclusions: Music therapy may improve poststroke motor function and promote neuronal repair in the long term. The mechanism may be through stimulating BDNF and GFAP secretion in the injured motor cortex.

Reversible Changes in BDNF Expression in MK-801-Induced Hippocampal Astrocytes Through NMDAR/PI3K/ERK Signaling.

Dizocilpine (MK-801), a non-competitive N-methyl-D-aspartic acid receptor (NMDA-R) antagonist, can induce schizophrenia-like symptoms in healthy individuals, implicating NMDA-R hypofunction in disease pathogenesis. Brain-derived neurotrophic factor (BDNF) is also implicated in schizophrenia, and expression is regulated by NMDA-R activity, suggesting a functional link. We previously found that BDNF signaling was upregulated by MK-801 in cultured hippocampal astrocytes, but the underlying mechanism is not clear. To address this issue, the levels of BDNF expression and secretion were evaluated in hippocampal astrocytes incubated with MK-801 by ELISA and qPCR, with and without NMDA co-incubation or pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. The apoptosis, viability, and proliferation of the astrocytes were also examined. In the current study, we demonstrate that MK-801 treatment (20 μM for 5 days) enhances the proliferation of rat cultured hippocampal astrocytes. Expression of BDNF mRNA was enhanced after 24 h in MK-801, but returned to near baseline over the next 24 h in the continued presence of MK-801. However, two successive 24-h treatments enhanced BDNF expression. These application regimens had no effect on apoptosis or proliferation rate. Co-addition of NMDA significantly inhibited MK-801-induced upregulation of BDNF. Similarly, MK-801-induced BDNF upregulation was blocked by pretreatment with inhibitors of PI3K and ERK1/2, but not by inhibitors of p38 and JNK. These findings suggested that astrocytes may contribute to the acute neurological and behavioral response to MK-801 treatment via a transient increase in BDNF expression involving NMDA-R–PI3K–ERK signaling.

Brain-Derived Neurotrophic Factor Val66Met and Behavioral Adjustment after Early Childhood Traumatic Brain Injury.

The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on behavioral adjustment in children with traumatic brain injury (TBI) relative to children with orthopedic injury (OI). Participants were drawn from a prospective, longitudinal study of children who sustained a TBI (n = 69) or OI (n = 72) between 3 and 7 years of age. Parents completed the Child Behavior Checklist (CBCL) at the immediate post-acute period, 6, 12, and 18 months after injury, and an average of 3.5 and 7 years after injury. Longitudinal mixed models examined the BDNF Val66Met allele status (Met carriers vs. Val/Val homozygotes) × injury group (TBI vs. OI) interaction in association with behavioral adjustment. After adjusting for continental ancestry, socioeconomic status, time post-injury, and pre-injury functioning, the allele status × injury group interaction was statistically significant for Internalizing, Externalizing, and Total Behavior problems. Post hoc within-group analysis suggested a consistent trend of poorer behavioral adjustment in Met carriers relative to Val/Val homozygotes in the TBI group; in contrast, the opposite trend was observed in the OI group. These within-group differences, however, did not reach statistical significance. The results support a differential effect of the BDNF Val66Met polymorphism on behavioral adjustment in children with early TBI relative to OI, and suggest that the Met allele associated with reduced activity-dependent secretion of BDNF may impart risk for poorer long-term behavioral adjustment in children with TBI.