Changes In Brain-derived Neurotrophic Factor Research Articles

Chronic intermittent ethanol exposure leads to alterations in brain-derived neurotrophic factor within the frontal cortex and impaired behavioral flexibility in both adolescent and adult rats

Chronic intermittent exposure to ethanol (EtOH; CIE) that produces binge-like levels of intoxication has been associated with age-dependent deficits in cognitive functioning. Male Sprague–Dawley rats were exposed to CIE (5g/kg, 25% EtOH, 13 intragastric gavages) beginning at three ages: early adolescence (postnatal day [PD] 28), mid-adolescence (PD35) and adulthood (PD72). In experiment 1, rats were behaviorally tested following CIE. Spatial memory was not affected by CIE, but adult CIE rats were impaired at acquiring a non-spatial discrimination task and subsequent reversal tasks. Rats exposed to CIE during early or mid-adolescence were impaired on the first reversal, demonstrating transient impairment in behavioral flexibility. Blood EtOH concentrations negatively correlated with performance on reversal tasks. Experiment 2 examined changes in brain-derived neurotrophic factor (BDNF) levels within the frontal cortex (FC) and hippocampus (HPC) at four time points: during intoxication, 24 h after the final EtOH exposure (acute abstinence), 3 weeks following abstinence (recovery) and after behavioral testing. HPC BDNF levels were not affected by CIE at any time point. During intoxication, BDNF was suppressed in the FC, regardless of the age of exposure. However, during acute abstinence, reduced FC BDNF levels persisted in early adolescent CIE rats, whereas adult CIE rats displayed an increase in BDNF levels. Following recovery, neurotrophin levels in all CIE rats recovered. Our results indicate that intermittent binge-like EtOH exposure leads to acute disruptions in FC BDNF levels and long-lasting behavioral deficits. However, the type of cognitive impairment and its duration differ depending on the age of exposure.

Erratum to: Mesenchymal stem cells attenuate hydrogen peroxide-induced oxidative stress and enhance neuroprotective effects in retinal ganglion cells.

The apoptosis of retinal ganglion cells leads to visual impairment and blindness in ocular neurodegenerative diseases, especially in diabetic retinopathy (DR). Mounting evidence suggests that oxidative stress contributes to the pathogenesis of DR. In the present study, we investigated whether bone mesenchymal stem cells (BMSCs) have protective ability to relieve hydrogen peroxide (H2O2)-induced injury on retinal ganglion cells in vitro. An immortalized retinal ganglion cells, RGC-5 cells, were exposed to an indicated concentration of H2O2 for 24 h. Cell viability was analyzed by CCK-8 assay to find out a certain concentration to build H2O2 oxidative damage model. Morphological changes in RGC-5 cells were observed under optical microscope, and cell apoptosis was detected with Hoechst fluorescence staining. Then, BMSCs were co-cultured with RGC-5 cells in a transwell culture system for 24 h and 48 h. Flow cytometry was performed to qualify the apoptosis rate of RGC-5 cells. Conditioned medium was collected for evaluation the inflammatory cytokines by ELISA. The content of intracellular malondialdehyde (MDA) and superoxide dismutase (SOD) was assayed by thiobarbituric acid and xanthine oxidase method, respectively. qRT-PCR and ELISA were conducted for analysis of the expression changes in brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), respectively. After H2O2 exposure, the morphological varieties were observed as cytoplasm shrinking and paramorphia together with nuclear gathering. Meanwhile, the apoptotic cells had hyperfluorescence with Hoechst 33258 staining. Co-culture with BMSCs significantly inhibited retinal cell death. It was found that BMSCs reduced H2O2-induced inflammatory factors IL-1β and TNF-α, down-regulated intracellular oxidant factor MDA, up-regulated intracellular antioxidant factor SOD, and increased neurotrophins BDNF and CNTF expression. BMSCs may enhance protective effect of RGC-5 cells in H2O2-induced damage through improving antioxidant capacity, inhibiting pro-inflammatory cytokine secretion, and promoting neurotrophin expression.

Therapeutic Hypothermia Provides Variable Protection against Behavioral Deficits after Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor

Background: Despite treatment with therapeutic hypothermia (TH), infants who survive hypoxic ischemic (HI) encephalopathy (HIE) have persistent neurological abnormalities at school age. Protection by TH against HI brain injury is variable in both humans and animal models. Our current preclinical model of hypoxia-ischemia (HI) and TH displays this variability of outcomes in neuropathological and neuroimaging end points with some sexual dimorphism. The detailed behavioral phenotype of this model is unknown. Whether there is sexual dimorphism in certain behavioral domains is also not known. Brain-derived neurotrophic factor (BDNF) supports neuronal cell survival and repair but may also be a marker of injury. Here, we characterize the behavioral deficits after HI and TH stratified by sex, as well as late changes in BDNF and its correlation with memory impairment. Methods: HI was induced in C57BL6 mice on postnatal day 10 (p10) (modified Vannucci model). Mice were randomized to TH (31°C) or normothermia (NT, 36°C) for 4 h after HI. Controls were anesthesia-exposed, age- and sex-matched littermates. Between p16 and p39, growth was followed, and behavioral testing was performed including reflexes (air righting, forelimb grasp and negative geotaxis) and sensorimotor, learning, and memory skills (open field, balance beam, adhesive removal, Y-maze tests, and object location task [OLT]). Correlations between mature BDNF levels in the forebrain and p42 memory outcomes were studied. Results: Both male and female HI mice had an approximately 8-12% lower growth rate (g/day) than shams (p ≤ 0.01) by p39. TH ameliorated this growth failure in females but not in males. In female mice, HI injury prolonged the time spent at the periphery (open field) at p36 (p = 0.004), regardless of treatment. TH prevented motor impairments in the balance beam and adhesive removal tests in male and female mice, respectively (p ≤ 0.05). Male and female HI mice visited the new arm of the Y-maze 12.5% (p = 0.05) and 10% (p = 0.03) less often than shams, respectively. Male HI mice also had 35% lower exploratory preference score than sham (p ≤ 0.001) in the OLT. TH did not prevent memory impairments found with Y-maze testing or OLT in either sex (p ≤ 0.01) at p26. At p42, BDNF levels in the forebrain ipsilateral to the HI insult were 1.7- to 2-fold higher than BDNF levels in the sham forebrain, and TH did not prevent this increase. Higher BDNF levels in the forebrain ipsilateral to the insult correlated with worse performance in the Y-maze in both sexes and in OLT in male mice (p = 0.01). Conclusions: TH provides benefit in specific domains of behavior following neonatal HI. In general, these benefits accrued to both males and females, but not in all areas. In some domains, such as memory, no benefit of TH was found. Late differences in individual BDNF levels may explain some of these findings.

Trigeminal Neuralgia Induced by Cobra Venom Leads to Cognitive Deficits Associated with Downregulation of CREB/BDNF Pathway

Background: Chronic pain often results in cognitive impairment. Our previous study showed that trigeminal neuralgia induced by cobra venom leads to spatial learning and memory deficits, although the underlying mechanism remains unclear. However, recent evidence indicates that the c-AMP-responsive element binding protein (CREB)/brain derived neurotrophic factor (BDNF) pathway plays a critical role in various etiologies of cognitive deficits. Objectives: Our aim was to explore the CREB/BDNF pathway to determine the molecular mechanisms involved in the pathogenesis of cognitive impairment caused by cobra venominduced trigeminal neuralgia. Study Design: A randomized, controlled animal study. Setting: Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University. Methods: Fifty male Sprague–Dawley rats were randomly divided into 3 groups: cobra venom group, sham group, and control group. Cobra venom or saline was injected into the sheath of the infraorbital nerve (ION), respectively. Video recordings and mechanical thresholds were used to analyze changes in behavioral activity 3 days before surgery and 4, 7, 14, 21, 28, and 56 days after surgery. Morris water maze tests were conducted at 4- and 8-week time points after surgery to evaluate spatial learning and memory. We also investigated expression changes of phosphorylated CREB (p-CREB) and BDNF in the hippocampus and prefrontal cortex (PFC) using western blotting and immunohistochemistry. Results: Cobra venom-treated rats exhibited significant changes in face grooming, as well as exploratory and resting behaviors, compared with the control group and sham group (both P < 0.001). Rats in the cobra venom group exhibited slightly impaired acquisition (P < 0.05) without memory deficits (P > 0.05) in the first water maze protocol. In the second water maze test, rats in the cobra venom group exhibited spatial learning and memory deficits, with fewer platform site crossings during the probe trial (P < 0.05). Moreover, results showed decreased p-CREB and BDNF expressions in the hippocampus and PFC in the cobra venom group, with significant differences at 9 weeks post-surgery (P < 0.05). Limitations: No signaling inhibitor or genetic manipulation was administered to further confirm upstream factors of the CREB/BDNF pathway in cognitive deficits caused by chronic trigeminal neuralgia. Conclusions: The findings suggest that cognitive impairment caused by cobra venom-induced trigeminal neuralgia is associated with downregulation of the CREB/BDNF pathway in the hippocampus and PFC. Key words: Cognitive impairment, the CREB/BDNF pathway, cobra venom, trigeminal neuralgia, hippocampus, prefrontal cortex, free behavior, Morris water maze

HuCNS-SC Human NSCs Fail to Differentiate, Form Ectopic Clusters, and Provide No Cognitive Benefits in a Transgenic Model of Alzheimer's Disease

SummaryTransplantation of neural stem cells (NSCs) can improve cognition in animal models of Alzheimer's disease (AD). However, AD is a protracted disorder, and prior studies have examined only short-term effects. We therefore used an immune-deficient model of AD (Rag-5xfAD mice) to examine long-term transplantation of human NSCs (StemCells Inc.; HuCNS-SCs). Five months after transplantation, HuCNS-SCs had engrafted and migrated throughout the hippocampus and exhibited no differences in survival or migration in response to β-amyloid pathology. Despite robust engraftment, HuCNS-SCs failed to terminally differentiate and over a quarter of the animals exhibited ectopic human cell clusters within the lateral ventricle. Unlike prior short-term experiments with research-grade HuCNS-SCs, we also found no evidence of improved cognition, no changes in brain-derived neurotrophic factor, and no increase in synaptic density. These data, while disappointing, reinforce the notion that individual human NSC lines need to be carefully assessed for efficacy and safety in appropriate long-term models.

Changes in fMRI activation in anterior hippocampus and motor cortex during memory retrieval after an intense exercise intervention

Strong evidence indicates that regular aerobic training induces beneficial effects on cognitive functions. The present controlled fMRI study was designed to investigate the impact of a short-term intense aerobic exercise on the pattern of functional activation during the retrieval of learned pair-associates in 17 young and healthy male adults compared to 17 matched control subjects. We further aimed to relate putative changes in hippocampal activation to postulated changes in the exercised-induced brain derived neurotrophic factor (BDNF). The supervised exercise program was performed on a bicycle ergometer and lasted six weeks, with three aerobic sessions per week.We found profound improvement of physical fitness in most subjects indicated by the target parameter ‘individual anaerobic threshold’. Significant improvements in the cognitive performance were detected in the exercise group, but also in the control group. We observed significant differences in the activation pattern of the left anterior hippocampus during the pair-associates task after the intervention. We could also show a significant positive correlation between changes in exercise-induced BDNF and left anterior hippocampal activation. Moreover, we observed the brain’s motor network to be significantly stronger activated after the exercise intervention. Thus, our results suggest BDNF dependent activation changes of the hippocampus in addition to previously described structural changes after exercise.

High-Intensity Locomotor Exercise Increases Brain-Derived Neurotrophic Factor in Individuals with Incomplete Spinal Cord Injury.

High-intensity locomotor exercise is suggested to contribute to improved recovery of locomotor function after neurological injury. This may be secondary to exercise-intensity-dependent increases in neurotrophin expression demonstrated previously in control subjects. However, rigorous examination of intensity-dependent changes in neurotrophin levels is lacking in individuals with motor incomplete spinal cord injury (SCI). Therefore, the primary aim of this study was to evaluate the effect of locomotor exercise intensity on peripheral levels of brain-derived neurotrophic factor (BDNF) in individuals with incomplete SCI. We also explored the impact of the Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene on intensity-dependent changes. Serum concentrations of BDNF and insulin-like growth factor-1 (IGF-1), as well as measures of cardiorespiratory dynamics, were evaluated across different levels of exercise intensity achieved during a graded-intensity, locomotor exercise paradigm in 11 individuals with incomplete SCI. Our results demonstrate a significant increase in serum BDNF at high, as compared to moderate, exercise intensities (p = 0.01) and 15 and 30 min post-exercise (p < 0.01 for both), with comparison to changes at low intensity approaching significance (p = 0.05). Serum IGF-1 demonstrated no intensity-dependent changes. Significant correlations were observed between changes in BDNF and specific indicators of exercise intensity (e.g., rating of perceived exertion; R = 0.43; p = 0.02). Additionally, the data suggest that Val66Met SNP carriers may not exhibit intensity-dependent changes in serum BDNF concentration. Given the known role of BDNF in experience-dependent neuroplasticity, these preliminary results suggest that exercise intensity modulates serum BDNF concentrations and may be an important parameter of physical rehabilitation interventions after neurological injury.

Regular exercise promotes memory function and enhances hippocampal neuroplasticity in experimental autoimmune encephalomyelitis mice

Multiple sclerosis (MS) is a progressive condition affecting the central nervous system (CNS), and is characterized by the development of demyelinated lesions and plaques in the brain and spinal cord. Exercise is beneficial against dementia in elderly patients, so we investigated the effects of exercise on memory in relation to hippocampal demyelination and neuroplasticity in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Mice were randomly divided into three groups: Sham, EAE, and EAE and exercise (EAE+EX). EAE+EX mice exercised five times a week for 4weeks, and all mice performed step-down avoidance tasks in order to verify memory ability. We analyzed changes in myelin basic protein (MBP), 2′,3′-Cyclic nucleotide 3′-phosphodiesterase (CNPase), 5-bromo-2′-deoxyuridine (brdU), doublecortin (DCX), bcl-2, bax, TUNEL, caspase-3, and brain derived neurotrophic factor (BDNF) via immunoassay or histological staining. We found decreased memory ability in EAE mice, accompanied by impaired myelination, increased apoptosis and cell proliferation, and decreased BDNF in the hippocampus. The memory decline and changes in demyelination, apoptosis, BDNF, and cell proliferation were partially reversed in EAE+EX mice. Our findings suggest that in patients with MS, regular exercise may benefit cognitive function by rescuing some hippocampal cellular and molecular impairments.

Dual influences of early-life maternal deprivation on histone deacetylase activity and recognition memory in rats

Exposure to stress early in life may negatively impact nervous system functioning, including increasing the proneness to learning and memory impairments later in life. Maternal deprivation, a model of early-life stress, hinders memory in adult rats and lessens brain-derived neurotrophic factor (BDNF) levels in the hippocampus in a very heterogeneous way among individuals. The main goal of the present study was to investigate the possible epigenetic modulation underlying recognition memory impairment and reduced BDNF levels in the hippocampus of adult maternally deprived rats. We also evaluated the potential ameliorating properties of the histone deacetylase (HDAC) inhibitor, sodium butyrate, on memory deficits and BDNF changes related to maternal deprivation. Maternally deprived animals were categorized as ‘inferior learners’ and ‘superior learners’ according to their performance in object recognition memory task in comparison to controls. Results indicated that HDAC activity was higher in individuals submitted to maternal deprivation with the worst cognitive performance (inferior learners). Acute administration of sodium butyrate increased histone H3 acetylation and BDNF levels, and restored recognition memory in maternally deprived animals with the worst cognitive performance. Moreover, we also showed that there is a positive correlation between BDNF levels and memory performance. Taken together, the results indicated that HDAC inhibitors could be considered as a possible therapeutic agent to improve cognitive performance in inferior learners. Further studies need to be conducted for a better comprehension of the mechanisms related to persistent alterations observed in adult life induced by early stressful circumstances and those leading to resilience.

No Change in Brain-Derived Neurotrophic Factor Levels Following a Single Session of Light to-Moderate Intensity Walk in Chronic Stroke Patients

Background: Many studies show the beneficial effects of overground gait training in stroke patients. However, it is not know whether it is able to induce changes in brain-derived neurotrophic factor (BDNF) levels, which could positively influence neurophysiological mechanisms. Objective: To evaluate the effect of a single session of light-to-moderate intensity walk on BDNF serum levels and its precursors (proBDNF) in chronic ischemic stroke patients. Methods: Patients were asked to walk for 30 minutes in the target heart rate training zone (30-60% of maximal heart rate). Blood samples were collected immediately before and after a single session. Results: Fifteen individuals with 60.8 (7.7) years old participated of this study. There was no significant difference in proBDNF (p=0.573) and BDNF (p=0.563) serum levels between pre- and post-session. Conclusion: This study used light-to-moderate intensity because the goal is to approach the gait training in clinical setting. The lack of increase in BDNF levels can be explained by two reasons: the intensity zone of the heart rate selected during the session and not having a gradual increase in this intensity.

Effects of isolation rearing and early antipsychotic intervention on oxidative stress-induced apoptosis and brain-derived neurotrophic factor in hippocampus in a rat model of schizophrenia

Background: Oxidative stress-induced neuronal dysfunction has been considered an essential factor for the development of schizophrenia. However, a longitudinal and causal relation between the impacts of developmental stress and oxidative stress remains unsolved. The present study aimed to examine whether the oxidative stress-relevant dysfunctions of the apoptotic index can be induced in rats of isolation rearing (IR, a rodent model of schizophrenia) and to see if the intervention of antipsychotics can reverse these dysfunctions. Materials and Methods: Pharmacological manipulation (risperidone [RIS] [1 mg/kg/day], olanzapine [OLA] [2.5 mg/kg/day], or saline [SAL] vehicle) was introduced 4 weeks (adolescence) or 8 weeks (young adulthood) after IR (i.e., rats were 7- or 11-week-old). The regime of RIS, OLA, or SAL was continued for 9 weeks. Locomotor activity was employed to validate the IR effect. Rats' hippocampus immediately after sacrifice was removed to measure messenger RNA expression of Bax, Bcl-2, brain-derived neurotrophic factor (BDNF) and the plasma level of nitric oxide (NO). Results: The results showed: (i) IR rats were more hyperactive. (ii) RIS may exert anti-apoptotic effects on IR rats, particularly at their adolescent age (as indexed by increased Bcl-2 and decreased Bax/Bcl-2 ratio). (iii) The therapeutic potential of RIS can be also observed in the change of BDNF in an age-independent manner, in which RIS effectively increased the BDNF level in IR but not social (SOC) rats. (iv) Plasma NO was not altered. Conclusion: The study results support the utility of the IR paradigm in exploring mental disorders with neurodevelopmental origin in which early pharmacological intervention may provide a therapeutic benefit in the overloaded oxidative stress and the dysfunction of BDNF.

Different levels of brain-derived neurotrophic factor and cortisol in healthy heavy smokers.

Studies suggest that brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis modulate dopaminergic activity in response to nicotine and that the concentrations of BDNF and cortisol seem to be dependent on the amount and duration of smoking. Therefore, we investigated BDNF and cortisol levels in smokers ranked by daily cigarette consumption. Twenty-seven adult males (13 non-smokers and 14 smokers) participated in the study. The smokers were divided in two groups: light (n=7) and heavy smokers (n=7). Anthropometric parameters and age were paired between the groups, and plasma BDNF and salivary cortisol levels were measured. Saliva samples were collected on awakening, 30 min after awakening, at 10:00 and 12:00 am, 5:00 and 10:00 pm. Additionally, cotinine serum levels were measured in smokers. Heavy smokers had higher mean values of BDNF compared to the control group (P=0.01), whereas no difference was observed in light smokers. Moreover, heavy smokers presented lower cortisol levels in the last collection (10:00 pm) than the control group (P=0.02) and presented statically higher values of cotinine than the light smokers (P=0.002). In conclusion, changes in BDNF and cortisol levels (10:00 pm) appear to be dependent on heavy cigarette smoking and can be involved in activation and in the relationship between the mesolimbic system and the HPA axis.

Anxiolytic effects of muscarinic acetylcholine receptors agonist oxotremorine in chronically stressed rats and related changes in BDNF and FGF2 levels in the hippocampus and prefrontal cortex.

In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2mg/kg Oxo, and unstressed group treated with Oxo. After 21days of CRS, the groups were treated for 10days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex CONCLUSIONS: The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.

Stress-induced change in serum BDNF is related to quantitative family history of alcohol use disorder and age at first alcohol use

Previous research in animal models suggests that brain-derived neurotrophic factor (BDNF) is involved in stress-modulated alcohol consumption. However, relatively few studies have investigated this issue in humans, and results of existing studies have been heterogeneous. The primary aim of the current study was to examine the within-subjects effect of acute stress (timed math plus cold pressor) on serum BDNF levels (ΔBDNF: post- minus pre-stress) in healthy social drinkers (N=68, 20 male). A secondary aim was to explore which heritable and environmental factors in our limited sample might exert the greatest influences on ΔBDNF. Importantly, presence versus absence of the BDNF Val66Met polymorphism (rs6265), which has often been discounted in studies of human serum BDNF, was included as a between-subjects control variable in all statistical analyses. Our results indicated that acute stress decreased serum BDNF. Further, multiple regression analyses revealed that quantitative family history of alcohol use disorder (qFH) and age at first alcohol use together accounted for 15% of the variance in ΔBDNF. Thus, the influences of qFH and age at first alcohol use may explain some of the heterogeneity that exists in previous studies of human serum BDNF. These results parallel findings in animal models and suggest that stress-related changes in serum BDNF are influenced by both heritable (qFH) and environmental (early alcohol consumption) factors.

The correlation between plasma brain-derived neurotrophic factor and cognitive function in bipolar disorder is modulated by the BDNF Val66Met polymorphism.

We explored the effect of the Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) on correlation between changes in plasma BDNF levels with cognitive function and quality of life (QoL) after 12 weeks of treatment in bipolar disorder (BD). Symptom severity and plasma BDNF levels were assessed upon recruitment and during weeks 1, 2, 4, 8 and 12. QoL, the Wisconsin Card Sorting Test (WCST), and the Conners’ Continuous Performance Test (CPT) were assessed at baseline and endpoint. The BDNF Val66Met polymorphism was genotyped. Changes in cognitive function and QoL over 12 weeks were reduced using factor analysis for the evaluation of their correlations with changes in plasma BDNF. Five hundred forty-one BD patients were recruited and 65.6% of them completed the 12-week follow-up. Changes in plasma BDNF levels with factor 1 (WCST) were significantly negatively correlated (r = −0.25, p = 0.00037). After stratification of BD subtypes and BDNF genotypes, this correlation was significant only in BP-I and the Val/Met genotype (r = −0.54, p = 0.008). We concluded that changes in plasma BDNF levels significantly correlated with changes in WCST scores in BD and is moderated by the BDNF Val66Met polymorphism and the subtype of BD.

Mesenchymal stem cells attenuate hydrogen peroxide-induced oxidative stress and enhance neuroprotective effects in retinal ganglion cells

The apoptosis of retinal ganglion cells leads to visual impairment and blindness in ocular neurodegenerative diseases, especially in diabetic retinopathy (DR). Mounting evidence suggests that oxidative stress contributes to the pathogenesis of DR. In the present study, we investigated whether bone mesenchymal stem cells (BMSCs) have protective ability to relieve hydrogen peroxide (H2O2)-induced injury on retinal ganglion cells in vitro. An immortalized retinal ganglion cells, RGC-5 cells, were exposed to anindicated concentration of H2O2 for 24h. Cell viability was analyzed by CCK-8 assay to find out a certain concentration to build H2O2 oxidative damage model. Morphological changes in RGC-5 cells were observed under optical microscope, and cell apoptosis was detected with Hoechst fluorescence staining. Then, BMSCs were co-cultured with RGC-5 cells in a transwell culture system for 24 h and 48h. Flow cytometry was performed to qualify the apoptosis rate of RGC-5 cells. Conditioned medium was collected for evaluation the inflammatory cytokines by ELISA. The content of intracellular malondialdehyde (MDA) and superoxide dismutase (SOD) was assayed by thiobarbituric acid and xanthine oxidase method, respectively. qRT-PCR and ELISA were conducted for analysis of the expression changes in brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), respectively. After H2O2 exposure, the morphological varieties were observed as cytoplasm shrinking and paramorphia together with nuclear gathering. Meanwhile, the apoptotic cells had hyperfluorescence with Hoechst 33258 staining. Co-culture with BMSCs significantly inhibited retinal cell death. It was found that BMSCs reduced H2O2-induced inflammatory factors IL-1β and TNF-α, down-regulated intracellular oxidant factor MDA, up-regulated intracellular antioxidant factor SOD, and increased neurotrophins BDNF and CNTF expression. BMSCs may enhance protective effect of RGC-5 cells in H2O2-induced damage through improving antioxidant capacity, inhibiting pro-inflammatory cytokine secretion, and promoting neurotrophin expression.

Running during adolescence rescues a maternal separation-induced memory impairment in female mice: Potential role of differential exon-specific BDNF expression.

Exposure to early life stress has been associated with memory impairments related to changes in brain-derived neurotrophic factor (BDNF) signaling. However, the potential impact of physical exercise to reverse these effects of maternal separation has been under investigated. Mice were subjected to maternal separation during the first 2 weeks of life and then exposed to a 3-week running protocol during adolescence. The spontaneous object recognition task was performed during adolescence followed by analysis of hippocampal expression of exons I, IV, and IX of the BDNF gene. As expected, maternal separation impaired recognition memory and this effect was reversed by exercise. In addition, running increased BDNF exon I expression, but decreased expression of BDNF exon IV in all groups, while exon IX expression increased only in MS animals exposed to exercise. Our data suggest that memory deficits can be attenuated by exercise and specific transcripts of the BDNF gene are dynamically regulated following both MS and exercise.

Psychobiological Responses to Preferred and Prescribed Intensity Exercise in Major Depressive Disorder.

This study aimed to compare psychological and biological responses to preferred and prescribed steady-state exercise intensities to a patient-selected preferred intensity. Female adults (N = 24, age = 38.6 ± 14.0 yr) diagnosed with MDD completed four 30-min sessions of cycling exercise at three prescribed intensities (RPE of 11, 13, and 15) and one session with a self-selected intensity (preferred). Order was randomized and counterbalanced. Depressed mood (DM) was evaluated before, 10 min, and 30 min postexercise using the Profile of Mood States. Serum brain-derived neurotrophic factor (BDNF) was measured before and within 10 min postexercise. Changes in BDNF and DM for the preferred session were compared with the following prescribed sessions: 1) performed at the most similar intensity (matched on RPE; closest) and 2) with the greatest improvement in DM (greatest). Compared with the preferred session, improvement in DM was significantly larger after the greatest session (30 min postexercise: -11.8 ± 7.4 vs -3.4 ± 4.8), and the BDNF response was significantly greater after the closest session (5.4 ± 6.9 vs -1.4 ± 9.8 ng·mL). Permitting patients to select their own exercise intensity did not maximize improvements in mood. Further, preferred intensity exercise was also associated with a smaller BDNF response. Overall, the results suggest that exercise undertaken to improve mood should be prescribed on an individual basis in MDD and not necessarily based on the patient's preferred intensity. Clinicians, psychologists, and other practitioners should consider providing clear exercise intensity recommendations for symptom management in depression rather than allowing patients to self-select their intensity.

BDNF expression is up-regulated by progesterone in human umbilical cord mesenchymal stem cells

Objective: To investigate whether promotion of neuronal differentiation of human umbilical cord mesenchymal stem cells (HUMSCs) by progesterone (PROG) involves changes in brain-derived neurotrophic factor (BDNF) levels.Methods: We used rat brain tissue extracts to mimic the brain microenvironment. Quantitative sandwich enzyme-linked immunosorbent assay was performed to measure levels of BDNF in cultured medium with or without PROG.Results: Progesterone increased levels of BDNF in HUMSCs.Conclusion: Progesterone enhancement of brain-derived neurotrophic factor levels may be involved in PROG activated-pathways to promote neuronal differentiation of HUMSCs.

Effect of Maternal Stress Prior to Conception on Hippocampal BDNF Signaling in Rat Offspring.

Environmental factors, especially stress, can remain pervasive effects across the lifespan. Traumatic experiences are risk factors for the behavioral and emotional disorders. Since brain-derived neurotrophic factor (BDNF) is the important regulator of neural survival, development, and its genetic and epigenetic alterations which have been linked with several neuropsychiatric disorders, the present study investigated the effect of maternal adulthood stress on molecular changes of BDNF and tyrosine kinase-coupled receptor (TrkB) in the hippocampus of 30-day-old offspring. To induce stress, we employed a repeated forced swimming model for female rats across 21days. Then, they were divided into two parental breeding groups: stressed mother (SM) and non-stressed mother (NSM) or control group. Anxiety-like behavior was tested in adult female rats and 30-day-old pups by using the elevated plus maze (EPM). The level of serum corticosterone was also measured by ELISA. BDNF and TrkB gene methylation and protein expression in the hippocampus were detected using real-time PCR and Western blotting in all groups. Thirty-day-old male and female pups from SM groups had a significantly more serum corticosterone concentration, DNA methylation levels of BDNF and TrKB, and lower expression of these genes compared to pups from the control groups. Also, male pups from stressed mother exhibited significant anxiety-like behavior compared to male pups from the control mothers. These findings suggest that molecular changes formed by maternal stress experience even before conception persist to the next generation and will negatively influence on phenotypes of offspring.