RESUMEN
In neurons, fast axonal transport (FAT) of vesicles occurs over long distances and requires constant and local energy supply for molecular motors in the form of adenosine triphosphate (ATP). FAT is independent of mitochondrial metabolism. Indeed, the glycolytic machinery is present on vesicles and locally produces ATP, as well as nicotinamide adenine dinucleotide bonded with hydrogen (NADH) and pyruvate, using glucose as a substrate. It remains unclear whether pyruvate is transferred to mitochondria from the vesicles as well as how NADH is recycled into NAD+ on vesicles for continuous glycolysis activity. The optimization of a glycolytic activity test for subcellular compartments allowed the evaluation of the kinetics of vesicular glycolysis in the brain. This revealed that glycolysis is more efficient on vesicles than in the cytosol. We also found that lactate dehydrogenase (LDH) enzymatic activity is required for effective vesicular ATP production. Indeed, inhibition of LDH or the forced degradation of pyruvate inhibited ATP production from axonal vesicles. We found LDHA rather than the B isoform to be enriched on axonal vesicles suggesting a preferential transformation of pyruvate to lactate and a concomitant recycling of NADH into NAD+ on vesicles. Finally, we found that LDHA inhibition dramatically reduces the FAT of both dense-core vesicles and synaptic vesicle precursors in a reconstituted cortico-striatal circuit on-a-chip. Together, this shows that aerobic glycolysis is required to supply energy for vesicular transport in neurons, similar to the Warburg effect.
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Glucólisis , NAD , NAD/metabolismo , Glucólisis/fisiología , Axones/metabolismo , Adenosina Trifosfato/metabolismo , Piruvatos/metabolismoRESUMEN
We have previously shown that recovery of visual responses to a deprived eye during the critical period in mouse primary visual cortex requires phosphorylation of the TrkB receptor for BDNF [M. Kaneko, J. L. Hanover, P. M. England, M. P. Stryker, Nat. Neurosci. 11, 497-504 (2008)]. We have now studied the temporal relationship between the production of mature BDNF and the recovery of visual responses under several different conditions. Visual cortical responses to an eye whose vision has been occluded for several days during the critical period and is then re-opened recover rapidly during binocular vision or much more slowly following reverse occlusion, when the previously intact fellow eye is occluded in a model of "patch therapy" for amblyopia. The time to recovery of visual responses differed by more than 18 h between these two procedures, but in each, the production of mature BDNF preceded the physiological recovery. These findings suggest that a spurt of BDNF production is permissive for the growth of connections serving the deprived eye to restore visual responses. Attenuation of recovery of deprived-eye responses by interference with TrkB receptor activation or reduction of BDNF production by interference with homeostatic synaptic scaling had effects consistent with this suggestion.
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Ambliopía , Corteza Visual , Ratones , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Receptor trkB/metabolismo , Corteza Visual/fisiología , Visión Ocular , Privación Sensorial/fisiología , Plasticidad Neuronal/fisiologíaRESUMEN
The myocyte enhancer factor (MEF2) family of transcription factors, originally discovered for its pivotal role in muscle development and function, has emerged as an essential regulator in various aspects of brain development and neuronal plasticity. The MEF2 transcription factors are known to regulate numerous important genes in the nervous system, including brain-derived neurotrophic factor (BDNF), a small secreted neurotrophin responsible for promoting the survival, growth, and differentiation of neurons. The expression of the Bdnf gene is spatiotemporally controlled by various transcription factors binding to both its proximal and distal regulatory regions. While previous studies have investigated the connection between MEF2 transcription factors and Bdnf, the endogenous function of MEF2 factors in the transcriptional regulation of Bdnf remains largely unknown. Here, we aimed to deepen the knowledge of MEF2 transcription factors and their role in the regulation of Bdnf comparatively in rat cortical and hippocampal neurons. As a result, we demonstrate that the MEF2 transcription factor-dependent enhancer located at -4.8 kb from the Bdnf gene regulates the endogenous expression of Bdnf in hippocampal neurons. In addition, we confirm neuronal activity-dependent activation of the -4.8 kb enhancer in vivo. Finally, we show that specific MEF2 family transcription factors have unique roles in the regulation of Bdnf, with the specific function varying based on the particular brain region and stimuli. Altogether, we present MEF2 family transcription factors as crucial regulators of Bdnf expression, fine-tuning Bdnf expression through both distal and proximal regulatory regions.
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Factor Neurotrófico Derivado del Encéfalo , Elementos de Facilitación Genéticos , Hipocampo , Factores de Transcripción MEF2 , Neuronas , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Factores de Transcripción MEF2/metabolismo , Factores de Transcripción MEF2/genética , Animales , Hipocampo/metabolismo , Hipocampo/citología , Neuronas/metabolismo , Neuronas/citología , Ratas , Corteza Cerebral/metabolismo , Corteza Cerebral/citología , Regulación de la Expresión Génica , Células Cultivadas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, ß-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs in a pathophysiological relevant manner in the heart, especially in the ß-adrenergic receptor-desensitized postischemic myocardium. Nor is it fully understood whether and how TrkB agonists counter chronic postischemic left ventricle (LV) decompensation, a significant unmet clinical milestone. METHODS: We conducted in vitro studies using neonatal rat and adult murine cardiomyocytes, SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed myocardial ischemia (MI) impact in wild type, ß3AR knockout, or myocyte-selective BDNF knockout (myoBDNF KO) mice in vivo (via coronary ligation [MI]) or in isolated hearts with global ischemia-reperfusion (I/R). RESULTS: In wild type hearts, BDNF levels rose early after MI (<24 hours), plummeting at 4 weeks when LV dysfunction, adrenergic denervation, and impaired angiogenesis ensued. The TrkB agonist, LM22A-4, countered all these adverse effects. Compared with wild type, isolated myoBDNF KO hearts displayed worse infarct size/LV dysfunction after I/R injury and modest benefits from LM22A-4. In vitro, LM22A-4 promoted neurite outgrowth and neovascularization, boosting myocyte function, effects reproduced by 7,8-dihydroxyflavone, a chemically unrelated TrkB agonist. Superfusing myocytes with the ß3AR-agonist, BRL-37344, increased myocyte BDNF content, while ß3AR signaling underscored BDNF generation/protection in post-MI hearts. Accordingly, the ß1AR blocker, metoprolol, via upregulated ß3ARs, improved chronic post-MI LV dysfunction, enriching the myocardium with BDNF. Last, BRL-37344-imparted benefits were nearly abolished in isolated I/R injured myoBDNF KO hearts. CONCLUSIONS: BDNF loss underscores chronic postischemic heart failure. TrkB agonists can improve ischemic LV dysfunction via replenished myocardial BDNF content. Direct cardiac ß3AR stimulation, or ß-blockers (via upregulated ß3AR), is another BDNF-based means to fend off chronic postischemic heart failure.
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Insuficiencia Cardíaca , Isquemia Miocárdica , Neuroblastoma , Disfunción Ventricular Izquierda , Ratas , Ratones , Humanos , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Endoteliales/metabolismo , Neuroblastoma/metabolismo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Isquemia Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Receptores Adrenérgicos beta/metabolismoRESUMEN
Here, it was aimed to investigate the effects of intracerebroventricular (ICV) Brain Derived Neurotrophic Factor (BDNF) infusion for 7 days following cerebral ischemia (CI) on autophagy in neurons in the penumbra. Focal CI was created by the occlusion of the right middle cerebral artery. A total of 60 rats were used and divided into 4 groups as Control, Sham CI, CI and CI + BDNF. During the 7-day reperfusion period, aCSF (vehicle) was infused to Sham CI and CI groups, and BDNF infusion was administered to the CI + BDNF group via an osmotic minipump. By the end of the 7th day of reperfusion, Beclin-1, LC3, p62 and cleaved caspase-3 protein levels in the penumbra area were evaluated using Western blot and immunofluorescence. BDNF treatment for 7 days reduced the infarct area after CI, induced the autophagic proteins Beclin-1, LC3 and p62 and suppressed the apoptotic protein cleaved caspase-3. Furthermore, rotarod and adhesive removal test times of BDNF treatment started to improve from the 4th day, and the neurological deficit score from the 5th day. ICV BDNF treatment following CI reduced the infarct area by inducing autophagic proteins Beclin-1, LC3 and p62 and inhibiting the apoptotic caspase-3 protein while its beneficial effects were apparent in neurological tests from the 4th day.
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Isquemia Encefálica , Daño por Reperfusión , Ratas , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ratas Sprague-Dawley , Caspasa 3 , Beclina-1 , Isquemia Encefálica/metabolismo , Apoptosis , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Autofagia , Infarto , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológicoRESUMEN
Brain-derived neurotrophic factor (BDNF) promotes neuronal survival and growth during development. In the adult nervous system, BDNF is important for synaptic function in several biological processes such as memory formation and food intake. In addition, BDNF has been implicated in development and maintenance of the cardiovascular system. The Bdnf gene comprises several alternative untranslated 5' exons and two variants of 3' UTRs. The effects of these entire alternative UTRs on translatability have not been established. Using reporter and translating ribosome affinity purification analyses, we show that prevalent Bdnf 5' UTRs, but not 3' UTRs, exert a repressive effect on translation. However, contrary to previous reports, we do not detect a significant effect of neuronal activity on BDNF translation. In vivo analysis via knock-in conditional replacement of Bdnf 3' UTR by bovine growth hormone 3' UTR reveals that Bdnf 3' UTR is required for efficient Bdnf mRNA and BDNF protein production in the brain, but acts in an inhibitory manner in lung and heart. Finally, we show that Bdnf mRNA is enriched in rat brain synaptoneurosomes, with higher enrichment detected for exon I-containing transcripts. In conclusion, these results uncover two novel aspects in understanding the function of Bdnf UTRs. First, the long Bdnf 3' UTR does not repress BDNF expression in the brain. Second, exon I-derived 5' UTR has a distinct role in subcellular targeting of Bdnf mRNA.
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Factor Neurotrófico Derivado del Encéfalo , ARN Mensajero , Regiones no Traducidas , Animales , Bovinos , Ratas , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Exones , Neuronas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regiones no Traducidas/fisiologíaRESUMEN
BACKGROUND: BDNF (brain-derived neurotrophic factor) is widely implicated in the pathophysiological process of stroke, but the effect of BDNF on poststroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between baseline serum BDNF and the risk of PSCI at 3 months in a multicenter study based on a preplanned ancillary study of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke). METHODS: We examined serum BDNF levels at baseline and used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke. PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. Logistic regression analyses were performed to evaluate the association between serum BDNF and the risk of 3-month PSCI. RESULTS: In this ancillary study, a total of 660 patients with ischemic stroke with hypertension were included, and 593 patients (mean age, 59.90±10.44 years; 410 males and 183 females) were finally included in this analysis. According to mini-mental state examination score, after adjustment for age, sex, education, baseline National Institutes of Health Stroke Scale score, APOE É4 carriers, and other potential confounders, the odds ratio of PSCI for the highest tertile of BDNF was 0.60 ([95% CI, 0.39-0.94]; P=0.024) compared with the lowest tertile. Multiple-adjusted spline regression model showed a linear association of serum BDNF levels with PSCI at 3 months (P value for linearity=0.010). Adding serum BDNF to conventional prognostic factors slightly improved the risk reclassification of PSCI (net reclassification improvement: 27.46%, P=0.001; integrated discrimination index: 1.02%, P=0.015). Similar significant findings were observed when PSCI was defined by the Montreal Cognitive Assessment score. CONCLUSIONS: Elevated serum BDNF levels were associated with a decreased risk of PSCI at 3 months, suggesting that serum BDNF might be a potential predictive biomarker for PSCI among patients with ischemic stroke with hypertension.
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Isquemia Encefálica , Disfunción Cognitiva , Hipertensión , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Masculino , Femenino , Humanos , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular Isquémico/complicaciones , Factor Neurotrófico Derivado del Encéfalo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/complicaciones , Hipertensión/epidemiología , Hipertensión/complicacionesRESUMEN
BACKGROUND: Myokines play vital roles in both stable coronary artery disease (SCAD) and depression. Meanwhile, there is a pressing necessity to find effective biomarkers for early predictor of major adverse cardiovascular events (MACE) in SCAD patients with depressive symptoms. METHODS: A single-center, 5-year follow-up study was investigated. MACE was defined as composite end points, including cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, coronary artery revascularization, or hospitalization for unstable angina. RESULTS: A total of 116 SCAD patients were enrolled, consisting of 30 cases (25.9%) without depressive symptoms and 86 cases (74.1%) with depressive symptoms. During the follow-up, 3 patients (2.6%) were lost. Out of 113 patients, 51 (45.1%) experienced MACE. In the subgroup of 84 SCAD patients with depressive symptoms, 44 cases (52.4%) of MACE were observed. Finally, mature brain-derived neurotrophic factor (mBDNF), pro-brain-derived neurotrophic factor, receptor activator of nuclear factor-κB ligand, smoking history, hypertension and cystatin C were incorporated into the predictive model. CONCLUSIONS: Depressive symptoms represent an independent risk factor for MACE in patients with SCAD. Additionally, low mBDNF expression may be an important early predictor for MACE in SCAD patients with depressive symptoms. The predictive model may exhibit a commendable predictive performance for MACE in SCAD patients with depressive symptoms.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Enfermedad de la Arteria Coronaria , Depresión , Humanos , Masculino , Femenino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Enfermedad de la Arteria Coronaria/psicología , Persona de Mediana Edad , Estudios de Seguimiento , Depresión/metabolismo , Anciano , Valor Predictivo de las Pruebas , BiomarcadoresRESUMEN
Tropomyosin receptor kinase B (TrkB) and its primary ligand brain-derived neurotrophic factor (BDNF) are expressed in the neuromuscular system, where they affect neuronal survival, differentiation, and functions. Changes in BDNF levels and full-length TrkB (TrkB-FL) signaling have been revealed in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), two common forms of motor neuron diseases that are characterized by defective neuromuscular junctions in early disease stages and subsequently progressive muscle weakness. This review summarizes the current understanding of BDNF/TrkB-FL-related research in SMA and ALS, with an emphasis on their alterations in the neuromuscular system and possible BDNF/TrkB-FL-targeting therapeutic strategies. The limitations of current studies and future directions are also discussed, giving the hope of discovering novel and effective treatments.
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Esclerosis Amiotrófica Lateral , Atrofia Muscular Espinal , Humanos , Factor Neurotrófico Derivado del Encéfalo , Neuronas Motoras/fisiología , Tropomiosina , Receptor trkBRESUMEN
Synaptic changes are early manifestations of neuronal dysfunction in Huntington's disease (HD). However, the mechanisms by which mutant HTT protein impacts synaptogenesis and function are not well understood. Herein we explored HD pathogenesis in the BACHD mouse model by examining synaptogenesis and function in long term primary cortical cultures. At DIV14 (days in vitro), BACHD cortical neurons showed no difference from WT neurons in synaptogenesis as revealed by colocalization of a pre-synaptic (Synapsin I) and a post-synaptic (PSD95) marker. From DIV21 to DIV35, BACHD neurons showed progressively reduced colocalization of Synapsin I and PSD95 relative to WT neurons. The deficits were effectively rescued by treatment of BACHD neurons with BDNF. The recombinant apical domain of CCT1 (ApiCCT1) yielded a partial rescuing effect. BACHD neurons also showed culture age-related significant functional deficits as revealed by multielectrode arrays (MEAs). These deficits were prevented by BDNF, whereas ApiCCT1 showed a less potent effect. These findings are evidence that deficits in BACHD synapse and function can be replicated in vitro and that BDNF or a TRiC-inspired reagent can potentially be protective against these changes in BACHD neurons. Our findings support the use of cellular models to further explicate HD pathogenesis and potential treatments.
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Factor Neurotrófico Derivado del Encéfalo , Corteza Cerebral , Modelos Animales de Enfermedad , Enfermedad de Huntington , Neuronas , Sinapsis , Animales , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Sinapsis/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Ratones , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Ratones Transgénicos , Células Cultivadas , Sinapsinas/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Ratones Endogámicos C57BLRESUMEN
Brain-derived neurotrophic factor (Bdnf) plays a critical role in brain development, dendritic growth, synaptic plasticity, as well as learning and memory. The rodent Bdnf gene contains nine 5' non-coding exons (I-IXa), which are spliced to a common 3' coding exon (IX). Transcription of individual Bdnf variants, which all encode the same BDNF protein, is initiated at unique promoters upstream of each non-coding exon, enabling precise spatiotemporal and activity-dependent regulation of Bdnf expression. Although prior evidence suggests that Bdnf transcripts containing exon I (Bdnf I) or exon IV (Bdnf IV) are uniquely regulated by neuronal activity, the functional significance of different Bdnf transcript variants remains unclear. To investigate functional roles of activity-dependent Bdnf I and IV transcripts, we used a CRISPR activation system in which catalytically dead Cas9 fused to a transcriptional activator (VPR) is targeted to individual Bdnf promoters with single guide RNAs, resulting in transcript-specific Bdnf upregulation. Bdnf I upregulation is associated with gene expression changes linked to dendritic growth, while Bdnf IV upregulation is associated with genes that regulate protein catabolism. Upregulation of Bdnf I, but not Bdnf IV, increased mushroom spine density, volume, length, and head diameter, and also produced more complex dendritic arbors in cultured rat hippocampal neurons. In contrast, upregulation of Bdnf IV, but not Bdnf I, in the rat hippocampus attenuated contextual fear expression. Our data suggest that while Bdnf I and IV are both activity-dependent, BDNF produced from these promoters may serve unique cellular, synaptic, and behavioral functions.
RESUMEN
Monocyte aberrations have been increasingly recognized as contributors to renal damage in systemic lupus erythematosus (SLE), however, recognition of the underlying mechanisms and modulating strategies is at an early stage. Our studies have demonstrated that brain-derived neurotrophic factor precursor (proBDNF) drives the progress of SLE by perturbing antibody-secreting B cells, and proBDNF facilitates pro-inflammatory responses in monocytes. By utilizing peripheral blood from patients with SLE, GEO database and spontaneous MRL/lpr lupus mice, we demonstrated in the present study that CX3CR1+ patrolling monocytes (PMo) numbers were decreased in SLE. ProBDNF was specifically expressed in CX3CR1+ PMo and was closely correlated with disease activity and the degree of renal injury in SLE patients. In MRL/lpr mice, elevated proBDNF was found in circulating PMo and the kidney, and blockade of proBDNF restored the balance of circulating and kidney-infiltrating PMo. This blockade also led to the reversal of pro-inflammatory responses in monocytes and a noticeable improvement in renal damage in lupus mice. Overall, the results indicate that the upregulation of proBDNF in PMo plays a crucial role in their infiltration into the kidney, thereby contributing to nephritis in SLE. Targeting of proBDNF offers a potential therapeutic role in modulating monocyte-driven renal damage in SLE.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Animales , Humanos , Ratones , Riñón , Ratones Endogámicos MRL lpr , Monocitos , Regulación hacia Arriba , Precursores de ProteínasRESUMEN
The adapter protein SH2B1 is recruited to neurotrophin receptors, including TrkB (also known as NTRK2), the receptor for brain-derived neurotrophic factor (BDNF). Herein, we demonstrate that the four alternatively spliced isoforms of SH2B1 (SH2B1α-SH2B1δ) are important determinants of neuronal architecture and neurotrophin-induced gene expression. Primary hippocampal neurons from Sh2b1-/- [knockout (KO)] mice exhibit decreased neurite complexity and length, and BDNF-induced expression of the synapse-related immediate early genes Egr1 and Arc. Reintroduction of each SH2B1 isoform into KO neurons increases neurite complexity; the brain-specific δ isoform also increases total neurite length. Human obesity-associated variants, when expressed in SH2B1δ, alter neurite complexity, suggesting that a decrease or increase in neurite branching may have deleterious effects that contribute to the severe childhood obesity and neurobehavioral abnormalities associated with these variants. Surprisingly, in contrast to SH2B1α, SH2B1ß and SH2B1γ, which localize primarily in the cytoplasm and plasma membrane, SH2B1δ resides primarily in nucleoli. Some SH2B1δ is also present in the plasma membrane and nucleus. Nucleolar localization, driven by two highly basic regions unique to SH2B1δ, is required for SH2B1δ to maximally increase neurite complexity and BDNF-induced expression of Egr1, Arc and FosL1.
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Proteínas Adaptadoras Transductoras de Señales/genética , Neuronas/citología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Ratones , Neuritas/metabolismo , Neuronas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMEN
IMPORTANCE: Human cytomegalovirus (HCMV) infection is the leading cause of non-heritable birth defects worldwide. HCMV readily infects the early progenitor cell population of the developing brain, and we have found that infection leads to significantly downregulated expression of key neurodevelopmental transcripts. Currently, there are no approved therapies to prevent or mitigate the effects of congenital HCMV infection. Therefore, we used human-induced pluripotent stem cell-derived organoids and neural progenitor cells to elucidate the glycoproteins and receptors used in the viral entry process and whether antibody neutralization was sufficient to block viral entry and prevent disruption of neurodevelopmental gene expression. We found that blocking viral entry alone was insufficient to maintain the expression of key neurodevelopmental genes, but neutralization combined with neurotrophic factor treatment provided robust protection. Together, these studies offer novel insight into mechanisms of HCMV infection in neural tissues, which may aid future therapeutic development.
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Anticuerpos Neutralizantes , Infecciones por Citomegalovirus , Citomegalovirus , Expresión Génica , Factores de Crecimiento Nervioso , Humanos , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Citomegalovirus/efectos de los fármacos , Citomegalovirus/inmunología , Citomegalovirus/fisiología , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/metabolismo , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Células Madre Pluripotentes Inducidas/citología , Factores de Crecimiento Nervioso/farmacología , Factores de Crecimiento Nervioso/uso terapéutico , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/virología , Organoides/citología , Organoides/metabolismo , Organoides/virología , Receptores Virales/antagonistas & inhibidores , Receptores Virales/metabolismo , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/metabolismo , Internalización del Virus/efectos de los fármacosRESUMEN
BACKGROUND: Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. METHODS: Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. RESULTS: Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). CONCLUSIONS: These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.
RESUMEN
BACKGROUND: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions. METHODS: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss-/- mice, Ctss+/+ mice and Ctss+/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions. RESULTS: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis. CONCLUSION: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.
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Factor Neurotrófico Derivado del Encéfalo , Catepsinas , Cognición , Animales , Masculino , Ratones , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Catepsinas/efectos de los fármacos , Catepsinas/genética , Catepsinas/metabolismo , Cognición/efectos de los fármacos , Cognición/fisiología , Ratones Noqueados , Receptor trkB/metabolismo , Receptor trkB/genética , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
Activity-induced muscle pain increases interleukin-1ß (IL-1ß) release from muscle macrophages and the development of hyperalgesia is prevented by blockade of IL-1ß in muscle. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1ß and mediates both inflammatory and neuropathic pain. Thus, we hypothesize that in activity-induced pain, fatigue metabolites combined with IL-1ß activate sensory neurons to increase BDNF release, peripherally in muscle and centrally in the spinal dorsal horn, to produce hyperalgesia. We tested the effect of intrathecal or intramuscular injection of BDNF-Tropomyosin receptor kinase B (TrkB) inhibitors, ANA-12 or TrkB-Fc, on development of activity-induced pain. Both inhibitors prevented the hyperalgesia when given before or 24hr after induction of the model in male but not female mice. BDNF messenger ribonucleic acid (mRNA) and protein were significantly increased in dorsal root ganglion (DRG) 24hr after induction of the model in both male and female mice. Blockade of IL-1ß in muscle had no effect on the increased BNDF mRNA observed in the activity-induced pain model, while IL-1ß applied to cultured DRG significantly induced BDNF expression, suggesting IL-1ß is sufficient but not necessary to induce BNDF. Thus, fatigue metabolites, combined with IL-1ß, upregulate BDNF in primary DRG neurons in both male and female mice, but contribute to activity-induced pain only in males.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Ganglios Espinales , Hiperalgesia , Interleucina-1beta , Mialgia , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Femenino , Ratones , Ganglios Espinales/metabolismo , Interleucina-1beta/metabolismo , Mialgia/metabolismo , Hiperalgesia/metabolismo , Ratones Endogámicos C57BL , Receptor trkB/metabolismo , Músculo Esquelético/metabolismo , Factores Sexuales , Caracteres Sexuales , Benzamidas/farmacología , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , AzepinasRESUMEN
The neurotrophic growth factor brain-derived neurotrophic factor (BDNF) plays a crucial role in various neurodegenerative and psychiatric diseases, such as Alzheimer's disease, schizophrenia and depression. BDNF has been proposed as a potential biomarker for diagnosis, prognosis and monitoring therapy. Understanding the factors influencing BDNF levels and whether they follow a circadian rhythm is essential for interpreting fluctuations in BDNF measurements. We aimed to investigate the circadian rhythm of BDNF by collecting multiple peripheral venous blood samples from young, healthy male participants at 12 different time points over 24 h. In addition, vital parameters, cortisol and insulin like growth factor 1 (IGF1) were measured to explore potential regulatory mechanisms, interfering variables and their correlations with BDNF concentration. The findings revealed that plasma BDNF did not exhibit any significant fluctuations over 24 h, suggesting the absence of a circadian rhythm. However, serum BDNF levels decreased during sleep. Furthermore, serum BDNF showed a positive correlation with heart rate but a negative correlation with IGF1. No significant correlation was observed between cortisol and BDNF or IGF1. Although plasma BDNF suggests steady-state conditions, the decline of serum BDNF during the nocturnal period could be attributed to physical inactivity and associated with reduced haemodynamic blood flow (heart rate reduction during sleep). The type of sample collection (peripheral venous cannula vs. blood sampling using a butterfly system) does not significantly affect the measured BDNF levels. The sample collection during the day did not significantly affect BDNF analysis, emphasizing the importance of considering activity levels rather than timing when designing standardized protocols for BDNF assessments.
RESUMEN
Epilepsy is a neurological disease characterized by repeated seizures. Despite of that the brain-derived neurotrophic factor (BDNF) is implicated in the pathogenesis of epileptogenesis and epilepsy, BDNF may have a neuroprotective effect against epilepsy. Thus, the goal of the present review was to highlight the protective and detrimental roles of BDNF in epilepsy. In this review, we also try to find the relation of BDNF with other signaling pathways and cellular processes including autophagy, mTOR pathway, progranulin (PGN), and α-Synuclein (α-Syn) which negatively and positively regulate BDNF/tyrosine kinase receptor B (TrkB) signaling pathway. Therefore, the assessment of BDNF levels in epilepsy should be related to other neuronal signaling pathways and types of epilepsy in both preclinical and clinical studies. In conclusion, there is a strong controversy concerning the potential role of BDNF in epilepsy. Therefore, preclinical, molecular, and clinical studies are warranted in this regard.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Epilepsia , Humanos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Epilepsia/metabolismo , Convulsiones/metabolismo , Transducción de Señal/fisiología , Receptor trkB/metabolismoRESUMEN
Postoperative cognitive dysfunction (POCD) occurs after surgery and severely impairs patients' quality of life. Finding POCD-associated variables can aid in its diagnosis and prognostication. POCD is associated with noncoding RNAs, such as microRNAs (miRNAs), involved in metabolic function, immune response alteration, and cognitive ability impairment; however, the underlying mechanisms remain unclear. The aim of this study was to investigate hub miRNAs (i.e., miRNAs that have an important regulatory role in diseases) regulating postoperative cognitive function and the associated mechanisms. Hub miRNAs were identified by bioinformatics, and their expression in mouse hippocampus tissues was determined using real-time quantitative polymerase chain reaction. Hub miRNAs were overexpressed or knocked down in cell and animal models to test their effects on neuroinflammation and postoperative cognitive function. Six differentially expressed hub miRNAs were identified. miR-206-3p was the only broadly conserved miRNA, and it was used in follow-up studies and animal experiments. Its inhibitors reduced the release of proinflammatory cytokines in BV-2 microglia by regulating its target gene, brain-derived neurotrophic factor (BDNF), and the downstream signaling pathways. miR-206-3p inhibition suppressed microglial activation in the hippocampi of mice and improved learning and cognitive decline. Therefore, miR-206-3p significantly affects POCD, implying its potential as a therapeutic target.