Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner.
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SUBMITTER: Ionescu-Tucker A
PROVIDER: S-EPMC8712855 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aerobic exercise (AEx) exerts antidepressant effects, although the neurobiological mechanisms underlying such effects are not well understood. Reduced brain-derived neurotrophic factor (BDNF) and elevated cortisol have been implicated in the pathophysiology of depression and appear to normalize with antidepressant treatment. Thus, BDNF and cortisol may serve as biological targets for developing AEx as an antidepressant treatment. PURPOSE:This study examined the effects of AEx, of different intensities, on serum BDNF and cortisol in individuals with and without depression. METHODS:Thirteen participants with depression (10 females; age = 27.2 ± 6.9 yr; Montgomery-Äsberg Depression Rating Scale = 21.7 ± 4.7) and 13 control participants (10 females; age 27.2 ± 7.2 yr; Montgomery-Äsberg Depression Rating Scale = 0.5 ± 0.9) participated. Experimental visits consisted of 15 min of low-intensity cycling (LO) at 35% heart rate reserve, high-intensity cycling (HI) at 70% heart rate reserve, or sitting (CON). During each visit, blood samples were obtained at baseline, immediately postexercise (IP), and then every 15 min postexercise for 1 h (15P, 30P, 45P, and 60P). Group, condition, and time differences in BDNF and cortisol were assessed. RESULTS:There were no group differences in cortisol and BDNF. Secondary analysis revealed that BDNF increased in an intensity-dependent nature at IP, and cortisol was significantly elevated at 15P after HI. Changes in BDNF and cortisol showed significant linear relationships with changes in HR. CONCLUSION:HI AEx can elicit acute, transient increases in BDNF and cortisol in young, healthy, and physically active, nondepressed and mild to moderately depressed individuals. This work suggests that AEx has potential to significantly affect the central nervous system function, and the magnitude of such effect may be directly driven by exercise intensity.
| S-EPMC6629513 | biostudies-literature
Project description:Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo.In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay.Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-κB-signaling pathway.These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-κB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis.
| S-EPMC5545027 | biostudies-other
Project description:The precursor of brain derived neurotrophic factor (proBDNF), the unprocessed BDNF gene product, binds to its receptors and exerts the opposing biologic functions of mature BDNF. proBDNF is expressed in the peripheral tissues but the functions of peripheral proBDNF remain elusive. Here we showed that proBDNF and its predominant receptor, p75 pan-neurotrophin receptor were upregulated in the nerve fibers and inflammatory cells in the local tissue in inflammatory pain. Neutralization of proBDNF by polyclonal antibody attenuated pain in different models of inflammatory pain. Unilateral intra-plantar supplementation of proBDNF by injecting exogenous proBDNF or ectopic overexpression resulted in pain hypersensitivity and induced spinal phosphorylated extracellular signal-regulated kinase activation. Exogenous proBDNF injection induced the infiltration of inflammatory cells and the activation of proinflammatory cytokines, suggesting that inflammatory reaction contributed to the pro-algesic effect of proBDNF. Finally, we generated monoclonal anti-proBDNF antibody that could biologically block proBDNF. Administration of monoclonal Ab-proBDNF attenuated various types of inflammatory pain and surgical pain. Thus, peripheral proBDNF is a potential pain mediator and anti-proBDNF pretreatment may alleviate the development of inflammatory pain.
| S-EPMC4890020 | biostudies-literature
Project description:In adult skeletal muscle, brain-derived neurotrophic factor (BDNF) is expressed in myogenic progenitors known as satellite cells. To functionally address the role of BDNF in muscle satellite cells and regeneration in vivo, we generated a mouse in which BDNF is specifically depleted from skeletal muscle cells. For comparative purposes, and to determine the specific role of muscle-derived BDNF, we also examined muscles of the complete BDNF(-/-) mouse. In both models, expression of the satellite cell marker Pax7 was significantly decreased. Furthermore, proliferation and differentiation of primary myoblasts was abnormal, exhibiting delayed induction of several markers of differentiation as well as decreased myotube size. Treatment with exogenous BDNF protein was sufficient to rescue normal gene expression and myotube size. Because satellite cells are responsible for postnatal growth and repair of skeletal muscle, we next examined whether regenerative capacity was compromised. After injury, BDNF-depleted muscle showed delayed expression of several molecular markers of regeneration, as well as delayed appearance of newly regenerated fibers. Recovery of wild-type BDNF levels was sufficient to restore normal regeneration. Together, these findings suggest that BDNF plays an important role in regulating satellite cell function and regeneration in vivo, particularly during early stages.
| S-EPMC2893983 | biostudies-literature
Project description:Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). When analyzing results across paradigms, sex significantly moderated the effect of exercise on BDNF levels, such that studies with more women showed less BDNF change resulting from exercise. Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans, but indicates that the magnitude of these effects may be lower in females relative to males.
| S-EPMC4314337 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women. Moderate aerobic exercise intervention is considered an initial treatment strategy for managing PCOS. Brain-derived neurotrophic factor (BDNF) is an important molecular mediator and a beneficial response to exercise. We aimed to investigate the expression pattern and underlying molecular mechanisms of this neurotrophic factor during follicle development in ovarian tissues. The PCOS model was established by subcutaneous injection of 60 mg/kg dehydroepiandrosterone (DHEA) into the neck of Sprague Dawley rats for 35 consecutive days. PCOS rats then received aerobic exercise for 8 weeks. Body/ovarian weight and peripheral serum hormone levels were observed. Immunohistochemistry combined with Western blot analysis and fluorescence quantitative polymerase chain reaction were used to detect the changes in BDNF-TrkB/p75NTR pathway, apoptosis, and inflammatory factors. We show that moderate aerobic exercise not only reverses the PCOS phenotype but also activates the BDNF-TrkB pathway and initiates downstream targets. p-TrkB upregulates and phosphorylates phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) to inhibit apoptosis. In addition, aerobic exercise therapy reduces the high expression of p75NTR in the ovarian tissue of PCOS rats and initiates the anti-apoptotic effect from the downstream pathway of NF-κB/JNK. Our in vitro results state that treatment with BDNF ameliorated dihydrotestosterone (DHT)-induced granulosa cells (GCs) apoptosis by provoking p-TrkB activation and upregulating the PI3K/AKT pathway. The present study suggests that moderate aerobic exercise regulates follicular dysfunction in PCOS-like rats. One possible mechanism is to initiate the BDNF-mediated anti-apoptotic signaling pathway.
| S-EPMC9571561 | biostudies-literature
Project description:Stroke is associated with neuroinflammation, neuronal loss and blood-brain barrier (BBB) breakdown. Thus far, recombinant tissue-type plasminogen activator (rtPA), the only approved treatment for acute ischemic stroke, increases the risk of intracerebral hemorrhage and is poorly efficient in disaggregating platelet-rich thrombi. Therefore, the development of safer and more efficient therapies is highly awaited. Encouraging neuroprotective effects were reported in mouse models of ischemic stroke following administration of erythropoietin (EPO). However, previous preclinical studies did not investigate the effects of EPO in focal ischemic stroke induced by a platelet-rich thrombus and did not consider the implication of age. Here, we performed middle cerebral artery occlusion by inducing platelet-rich thrombus formation in chimeric 5- (i.e. young) and 20- (i.e. aged) months old C57BL/6 mice, in which hematopoietic stem cells carried the green fluorescent protein (GFP)-tag. Recombinant human EPO (rhEPO) was administered 24 hours post-occlusion and blood-circulating monocyte populations were studied by flow cytometry 3 hours post-rhEPO administration. Twenty-four hours following rhEPO treatment, neuronal loss and BBB integrity were assessed by quantification of Fluoro-Jade B (FJB)-positive cells and extravasated serum immunoglobulins G (IgG), respectively. Neuroinflammation was determined by quantifying infiltration of GFP-positive bone marrow-derived cells (BMDC) and recruitment of microglial cells into brain parenchyma, along with monocyte chemotactic protein-1 (MCP-1) brain protein levels. Here, rhEPO anti-inflammatory properties rescued ischemic injury by reducing neuronal loss and BBB breakdown in young animals, but not in aged littermates. Such age-dependent effects of rhEPO must therefore be taken into consideration in future studies aiming to develop new therapies for ischemic stroke.
| S-EPMC5094944 | biostudies-literature
Project description:BackgroundSleep homeostasis is characterized by a positive correlation between sleep length and intensity with the duration of the prior waking period. A causal role for brain-derived neurotrophic factor (BDNF) in sleep homeostasis has been suggested, but the underlying mechanisms remain unclear. Cortistatin, a neuropeptide expressed primarily in a subset of cortical GABAergic interneurons, is another molecule implicated in sleep homeostasis.ResultsWe confirmed that sleep deprivation leads to an increase in cortical cortistatin mRNA expression. Disruption of activity-dependent BDNF expression in a genetically modified mouse line impairs both baseline levels of cortistatin mRNA as well as its levels following sleep deprivation. Disruption of activity-dependent BDNF also leads to a decrease in sleep time during the active (dark) phase.ConclusionOur studies suggest that regulation of cortistatin-expressing interneurons by activity-dependent BDNF expression may contribute to regulation of sleep behavior.
| S-EPMC3061911 | biostudies-literature
Project description:Exogenous brain-derived neurotrophic factor (BDNF) enhances Ca(2+) signaling and cell proliferation in human airway smooth muscle (ASM), especially with inflammation. Human ASM also expresses BDNF, raising the potential for autocrine/paracrine effects. The mechanisms by which ASM BDNF secretion occurs are not known. Transient receptor potential channels (TRPCs) regulate a variety of intracellular processes including store-operated Ca(2+) entry (SOCE; including in ASM) and secretion of factors such as cytokines. In human ASM, we tested the hypothesis that TRPC3 regulates BDNF secretion. At baseline, intracellular BDNF was present, and BDNF secretion was detectable by enzyme linked immunosorbent assay (ELISA) of cell supernatants or by real-time fluorescence imaging of cells transfected with GFP-BDNF vector. Exposure to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) (20ng/ml, 48h) or a mixture of allergens (ovalbumin, house dust mite, Alternaria, and Aspergillus extracts) significantly enhanced BDNF secretion and increased TRPC3 expression. TRPC3 knockdown (siRNA or inhibitor Pyr3; 10μM) blunted BDNF secretion, and prevented inflammation effects. Chelation of extracellular Ca(2+) (EGTA; 1mM) or intracellular Ca(2+) (BAPTA; 5μM) significantly reduced secreted BDNF, as did the knockdown of SOCE proteins STIM1 and Orai1 or plasma membrane caveolin-1. Functionally, secreted BDNF had autocrine effects suggested by phosphorylation of high-affinity tropomyosin-related kinase TrkB receptor, prevented by chelating extracellular BDNF with chimeric TrkB-Fc. These data emphasize the role of TRPC3 and Ca(2+) influx in the regulation of BDNF secretion by human ASM and the enhancing effects of inflammation. Given the BDNF effects on Ca(2+) and cell proliferation, BDNF secretion may contribute to altered airway structure and function in diseases such as asthma.
| S-EPMC3835538 | biostudies-literature
Project description:Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.
| S-EPMC2834321 | biostudies-literature