Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport ...Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.展开更多
Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,an...Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.展开更多
Amyloid-beta(Aβ)-related alterations,similar to those found in the brains of patients with Alzheimer's disease,have been observed in the retina of patients with glaucoma.Decreased levels of brain-derived neurotro...Amyloid-beta(Aβ)-related alterations,similar to those found in the brains of patients with Alzheimer's disease,have been observed in the retina of patients with glaucoma.Decreased levels of brain-derived neurotrophic factor(BDNF)are believed to be associated with the neurotoxic effects of Aβpeptide.To investigate the mechanism underlying the neuroprotective effects of BDNF on Aβ_(1-40)-induced retinal injury in Sprague-Dawley rats,we treated rats by intravitreal administration of phosphate-buffered saline(control),Aβ_(1-40)(5 nM),or Aβ_(1-40)(5 nM)combined with BDNF(1μg/mL).We found that intravitreal administration of Aβ_(1-40)induced retinal ganglion cell apoptosis.Fluoro-Gold staining showed a significantly lower number of retinal ganglion cells in the Aβ_(1-40)group than in the control and BDNF groups.In the Aβ_(1-40)group,low number of RGCs was associated with increased caspase-3 expression and reduced TrkB and ERK1/2 expression.BDNF abolished Aβ_(1-40)-induced increase in the expression of caspase-3 at the gene and protein levels in the retina and upregulated TrkB and ERK1/2 expression.These findings suggest that treatment with BDNF prevents RGC apoptosis induced by Aβ_(1-40)by activating the BDNF-TrkB signaling pathway in rats.展开更多
Brain-derived neurotrophic factor is the most prevalent member of the nerve growth factor family.Since its discovery in 1978,this enigmatic molecule has spawned more than 27,000 publications,most of which are focused ...Brain-derived neurotrophic factor is the most prevalent member of the nerve growth factor family.Since its discovery in 1978,this enigmatic molecule has spawned more than 27,000 publications,most of which are focused on neurological disorders.Brain-derived neurotrophic factor is indispensable during embryogenesis and postnatally for the normal development and function of both the central and peripheral nervous systems.It is becoming increasingly clear,however,that brain-derived neurotrophic factor likewise plays crucial roles in a variety of other biological functions independently of sympathetic or parasympathetic involvement.Brain-derived neurotrophic factor is also increasingly recognized as a sophisticated environmental sensor and master coordinator of whole organismal physiology.To that point,we recently found that a common nonsynonymous(Val66→Met)single nucleotide polymorphism in the brain-derived neurotrophic factor gene(rs6265)not only substantially alters basal cardiac transcriptomics in mice but subtly influences heart gene expression and function differentially in males and females.In addition to a short description of recent results from associative neuropsychiatric studies,this review provides an eclectic assortment of research reports that support a modulatory role for rs6265 including and beyond the central nervous system.展开更多
The trigeminal root entry zone is the zone at which the myelination switches from peripheral Schwann cells to central oligodendrocytes.Its special anatomical and physiological structure renders it susceptible to nerve...The trigeminal root entry zone is the zone at which the myelination switches from peripheral Schwann cells to central oligodendrocytes.Its special anatomical and physiological structure renders it susceptible to nerve injury.The etiology of most primary trigeminal neuralgia is closely related to microvascular compression of the trigeminal root entry zone.This study aimed to develop an efficient in vitro model mimicking the glial environment of trigeminal root entry zone as a tool to investigate the effects of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor on the structural and functional integrity of trigeminal root entry zone and modulation of cellular interactions.Primary astrocytes and Schwann cells isolated from trigeminal root entry zone of postnatal rats were inoculated into a two-well silicon culture insert to mimic the trigeminal root entry zone microenvironment and treated with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor.In monoculture,glial cell line-derived neurotrophic factor promoted the migration of Schwann cells,but it did not have effects on the migration of astrocytes.In the co-culture system,glial cell line-derived neurotrophic factor promoted the bidirectional migration of astrocytes and Schwann cells.Brain-derived neurotrophic factor markedly promoted the activation and migration of astrocytes.However,in the co-culture system,brain-derived neurotrophic factor inhibited the migration of astrocytes and Schwann cells to a certain degree.These findings suggest that glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor are involved in the regulation of the astrocyte-Schwann cell interaction in the co-culture system derived from the trigeminal root entry zone.This system can be used as a cell model to study the mechanism of glial dysregulation associated with trigeminal nerve injury and possible therapeutic interventions.展开更多
BACKGROUND There are systematic differences in clinical features between women and men with schizophrenia(SCZ).The regulation of sex hormones may play a potential role in abnormal neurodevelopment in SCZ.Brain-derived...BACKGROUND There are systematic differences in clinical features between women and men with schizophrenia(SCZ).The regulation of sex hormones may play a potential role in abnormal neurodevelopment in SCZ.Brain-derived neurotrophic factor(BDNF)and sex hormones have complex interacting actions that contribute to the etiology of SCZ.AIM To investigate the influence of BDNF and sex hormones on cognition and clinical symptomatology in chronic antipsychotic-treated male SCZ patients.METHODS The serum levels of follicle-stimulating hormone,luteinizing hormone(LH),estradiol(E2),progesterone,testosterone(T),prolactin(PRL)and BDNF were compared between chronic antipsychotic-treated male(CATM)patients with SCZ(n=120)and healthy controls(n=120).The Positive and Negative Syndrome Scale was used to quantify SCZ symptoms,while neuropsychological tests were used to assess cognition.Neuropsychological tests,such as the Digit Cancellation Test(DCT),Semantic Verbal Fluency(SVF),Spatial Span Test(SS),Paced Auditory Serial Addition Test(PASAT),Trail Making Task(TMT-A),and Block Design Test(BDT),were used to assess executive functions(BDT),attention(DCT,TMT-A),memory(SS,PASAT),and verbal proficiency(SVF).RESULTS Although E2 levels were significantly lower in the patient group compared to the healthy controls,T,PRL,and LH levels were all significantly higher.Additionally,the analysis revealed that across the entire sample,there were positive correlations between E2 Levels and BDNF levels as well as BDNF levels and the digital cancellation time.In CATM patients with SCZ,a significant correlation between the negative symptoms score and PRL levels was observed.CONCLUSION Sex hormones and BDNF levels may also be linked to cognitive function in patients with chronic SCZ.展开更多
Many studies have shown that fibronectin type III domain-containing protein 5(FDNC5) and brain-derived neurotrophic factor(BDNF) play vital roles in plasticity after brain injury. An enriched environment refers to an ...Many studies have shown that fibronectin type III domain-containing protein 5(FDNC5) and brain-derived neurotrophic factor(BDNF) play vital roles in plasticity after brain injury. An enriched environment refers to an environment that provides animals with multi-sensory stimulation and movement opportunities. An enriched environment has been shown to promote the regeneration of nerve cells, synapses, and blood vessels in the animal brain after cerebral ischemia;however, the exact mechanisms have not been clarified. This study aimed to determine whether an enriched environment could improve neurobehavioral functions after the experimental inducement of cerebral ischemia and whether neurobehavioral outcomes were associated with the expression of FDNC5 and BDNF. This study established ischemic mouse models using permanent middle cerebral artery occlusion(pMCAO) on the left side. On postoperative day 1, the mice were randomly assigned to either enriched environment or standard housing condition groups. Mice in the standard housing condition group were housed and fed under standard conditions. Mice in the enriched environment group were housed in a large cage, containing various toys, and fed with a standard diet. Sham-operated mice received the same procedure, but without artery occlusion, and were housed and fed under standard conditions. On postoperative days 7 and 14, a beam-walking test was used to assess coordination, balance, and spatial learning. On postoperative days 16–20, a Morris water maze test was used to assess spatial learning and memory. On postoperative day 15, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex were analyzed by western blot assay. The results showed that compared with the standard housing condition group, the motor balance and coordination functions(based on beam-walking test scores 7 and 14 days after operation), spatial learning abilities(based on the spatial learning scores from the Morris water maze test 16–19 days after operation), and memory abilities(based on the memory scores of the Morris water maze test 20 days after operation) of the enriched environment group improved significantly. In addition, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex increased in the enriched environment group compared with those in the standard housing condition group. Furthermore, the Pearson correlation coefficient showed that neurobehavioral functions were positively associated with the expression levels of FDNC5 and BDNF(r = 0.587 and r = 0.840, respectively). These findings suggest that an enriched environment upregulates FDNC5 protein expression in the ipsilateral cerebral cortex after cerebral ischemia, which then activates BDNF protein expression, improving neurological function. BDNF protein expression was positively correlated with improved neurological function. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University, China(approval Nos. 20160858 A232, 20160860 A234) on February 24, 2016.展开更多
Macrophage migration inhibitory factor(MIF)is a chemokine that plays an essential role in immune system function.Previous studies suggested that MIF protects neurons in ischemic conditions.However,few studies are repo...Macrophage migration inhibitory factor(MIF)is a chemokine that plays an essential role in immune system function.Previous studies suggested that MIF protects neurons in ischemic conditions.However,few studies are reported on the role of MIF in neurological recovery after ischemic stroke.The purpose of this study is to identify the molecular mechanism of neuroprotection mediated by MIF.Human neuroblastoma cells were incubated in Dulbecco’s modified Eagle’s medium under oxygen-glucose deprivation(OGD)for 4 hours and then returned to normal aerobic environment for reperfusion(OGD/R).30 ng/mL MIF recombinant(30 ng/mL)or ISO-1(MIF antagonist;50μM)was administered to human neuroblastoma cells.Then cell cultures were assigned to one of four groups:control,OGD/R,OGD/R with MIF,OGD/R with ISO-1.Cell viability was analyzed using WST-1 assay.Expression levels of brain-derived neurotrophic factor(BDNF),microtubule-associated protein 2(MAP2),Caspase-3,Bcl2,and Bax were detected by western blot assay and immunocytochemistry in each group to measure apoptotic activity.WST-1 assay results revealed that compared to the OGD/R group,cell survival rate was significantly higher in the OGD/R with MIF group and lower in the OGD/R with ISO-1 group.Western blot assay and immunocytochemistry results revealed that expression levels of BDNF,Bcl2,and MAP2 were significantly higher,and expression levels of Caspase-3 and Bax were significantly lower in the MIF group than in the OGD/R group.Expression levels of BDNF,Bcl2,and MAP2 were significantly lower,and expression levels of Caspase-3 and Bax were significantly higher in the ISO-1 group than in the OGD/R group.MIF administration promoted neuronal cell survival and induced high expression levels of BDNF,MAP2,and Bcl2(anti-apoptosis)and low expression levels of Caspase-3 and Bax(pro-apoptosis)in an OGD/R model.These results suggest that MIF administration is effective for inducing expression of BDNF and leads to neuroprotection of neuronal cells against hypoxic injury.展开更多
Brain-derived neurotrophic factor(BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated fac...Brain-derived neurotrophic factor(BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The m RNA expression levels of BDNF and its processing enzymes and receptors(Furin, matrix metallopeptidase 9, tissuetype plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury;however, the expression levels of these m RNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia(approval No. U12-18) on July 30, 2018.展开更多
BACKGROUND: Because bone marrow mesenchymal stem cells (BMSCs) do not secrete sufficient brain-derived neurotrophic factor (BDNF), the use of exogenous BDNF could improve microenvironments in injured regions for BMSCs...BACKGROUND: Because bone marrow mesenchymal stem cells (BMSCs) do not secrete sufficient brain-derived neurotrophic factor (BDNF), the use of exogenous BDNF could improve microenvironments in injured regions for BMSCs differentiation. OBJECTIVE: To analyze recovery of the injured spinal cord following BMSCs venous transplantation in combination with consecutive injections of BDNF. DESIGN, TIME AND SETTING: A randomized, controlled animal experiment was performed at the Central Laboratory of First Hospital and Anatomical Laboratory, Fujian Medical University from October 2004 to May 2006. MATERIALS: Human BDNF was purchased from Sigma, USA. METHODS: A total of 44 New Zealand rabbits were randomly assigned to model (n = 8), BDNF (n = 12), BMSC (n = 12), and BMSC+BDNF (n = 12) groups. Spinal cord (L2) injury was established with the dropping method. The model group rabbits were injected with 1 mL normal saline via the ear margin vein; the BDNF group was subdurally injected with 100 μg/d human BDNF for 1 week; the BMSC group was injected with 1 mL BMSCs suspension (2 × 106/mL) via the ear margin vein; and the BMSC+BDNF group rabbits were subdurally injected with 100 μg/d BDNF for 1 week, in addition to BMSCs suspension via the ear margin vein. MAIN OUTCOME MEASURES: BMSCs surface markers were detected by flow cytometry. BMSCs differentiation in the injured spinal cord was detected by immunofluorescence histochemistry. Functional and structural recovery, as well as morphological changes, in the injured spinal cord were respectively detected by Tarlov score, horseradish peroxidase retrograde tracing, and hematoxylin & eosin staining methods at 1, 3, and 5 weeks following transplantation. RESULTS: Transplanted BMSCs differentiated into neuronal-like cells in the injured spinal cord at 3 and 5 weeks following transplantation. Neurological function and pathological damage improved following BMSC + BDNF treatment compared with BDNF or BMSC alone (P < 0.01 or P < 0.05). CONCLUSION: BMSCs venous transplantation in combination with BDNF subdural injection benefits neuronal-like cell differentiation and significantly improves structural and function of injured spinal cord compared with BMSCs or BDNF alone.展开更多
Previous studies suggest that serotonin(5-HT) might interact with brain-derived neurotrophic factor(BDNF) during the stress response.However,the relationship between 5-HT and BDNF expression under purely psychological...Previous studies suggest that serotonin(5-HT) might interact with brain-derived neurotrophic factor(BDNF) during the stress response.However,the relationship between 5-HT and BDNF expression under purely psychological stress is unclear.In this study,one hour before psychological stress exposure,the 5-HT1 A receptor agonist 8-OH-DPAT or antagonist MDL73005,or the 5-HT2 A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress.Immunohistochemistry and in situ hybridization revealed that after psychological stress,with the exception of the ventral tegmental area,BDNF protein and m RNA expression levels were higher in the 5-HT1 A and the 5-HT2 A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus,prefrontal cortex,central amygdaloid nucleus,dorsomedial hypothalamic nucleus,dentate gyrus,shell of the nucleus accumbens and the midbrain periaqueductal gray.There was no significant difference between the two agonist groups.In contrast,after stress exposure,BDNF protein and m RNA expression levels were lower in the 5-HT1 A and 5-HT2 A receptor antagonist groups than in the solvent control non-stress group,with the exception of the ventral tegmental area.Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.展开更多
Major depressive disorder is a debilitating disorder affecting millions of people each year.Brain-derived neurotrophic factor(BDNF)and inflammation are two prominent biologic risk factors in the pathogenesis of depres...Major depressive disorder is a debilitating disorder affecting millions of people each year.Brain-derived neurotrophic factor(BDNF)and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention.Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression.However,less is known about potential interaction between BDNF and inflammation,particularly within the central nervous system.Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and antidepressant response.Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF,and BDNF may play an important negative regulatory role on inflammation within the brain.Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities.Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.展开更多
BACKGROUND:Studies have demonstrated that brain-derived neurotrophic factor(BDNF) has a dual effect on epilepsy.However,the relationship between epilepsy-induced brain injury and BDNF remains poorly understood.OBJECTI...BACKGROUND:Studies have demonstrated that brain-derived neurotrophic factor(BDNF) has a dual effect on epilepsy.However,the relationship between epilepsy-induced brain injury and BDNF remains poorly understood.OBJECTIVE:According to ultrastructural and molecular parameters,to detect the degree of neuronal injury and BDNF expression changes at different brain regions and different kindling times to determine the effects of BDNF on epilepsy-induced brain injury.DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment based on neuropathology and molecular biology was performed at the Department of Physiology and Department of Pathology,Basic Medical College of Jilin University in 2003.MATERIALS:UltraSensitive SP kit for immunohistochemistry(Fuzhou Maxim Biotechnology,China),BDNF antibody(concentrated type,Wuhan Boster Biological Technology,China),JEM-1000SX transmission electron microscopy(JEOL,Japan),and BH-2 light microscope(Olympus,Japan) were used in the present study.METHODS:Wistar rats were randomly assigned to control(n = 6),sham-surgery(n = 6),and model(n = 60) groups.The control group rats were not treated;an electrode was embedded into the amygdala in rats from the sham-surgery and model groups;an amygdala kindling epilepsy model was established in the model group.MAIN OUTCOME MEASURES:Pathological changes in the temporal lobe and hippocampus were observed by light and electron microscopy at 1,3,7,14,and 21 days following kindling,and BDNF expression in the various brain regions was determined by immunohistochemistry.RESULTS:In the model group,temporal lobe cortical and hippocampal neurons were swollen and the nuclei were laterally deviated.There were also some apoptotic neurons 3 days after kindling.The nucleoli disappeared and the nuclei appeared broken or lysed,as well as slight microglia hyperplasia,at 7 days.Electron microscopic observation displayed chromatin aggregation in the nuclei and slight mitochondrion swelling 3 days after kindling.Injury changes were aggravated at 7 days,characterized by broken cytoplasmic membrane and pyknosis.With the development of seizure,the number of BDNF-positive neurons in the hippocampus and temporal lobe increased and peaked at 7 days.Moreover,hippocampal and cortical temporal lobe injury continued.Following termination of electrical stimulation after 7 days of kindling,BDNF expression decreased,but continued to be expressed,up to 21 days of kindling.In addition,the number of temporal and hippocampal BDNF-positive neurons was greater than the control group.CONCLUSION:Brain injury and BDNF expression peaked at 7 days after kindling,and hippocampal changes were significant.展开更多
BACKGROUND:Previous studies have shown that nerve regeneration factor (NRF) provides neuroprotective effects. However,the neuroprotective effects on retinal ganglion cells in an animal model of glaucoma remain uncerta...BACKGROUND:Previous studies have shown that nerve regeneration factor (NRF) provides neuroprotective effects. However,the neuroprotective effects on retinal ganglion cells in an animal model of glaucoma remain uncertain. OBJECTIVE:To determine the neuroprotective effects of NRF on retinal ganglion cells in a rabbit model of acute hyper-intraocular pressure and to compare the effects on brain-derived neurotrophic factor (BDNF). DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at Jiangsu Provincial Key Laboratory of Neural Regeneration from September 2006 to August 2007. MATERIALS:Sterone,a major component of NRF,was provided by the Key Laboratory of Neural Regeneration,Nantong University in China; BDNF was provided by BioDesign Inc.,USA. METHODS:A total of 24 healthy rabbits were randomly assigned to NRF,BDNF,and phosphate buffered saline groups,with 8 rabbits per group. The left eyes were considered normal controls,and acute hyper-intraocular pressure was induced in the right eyes via anterior chamber perfusion. The right camera vitrea bulbi was injected with 4.5 μg NRF,3.75 μg BDNF,or 5 μL 0.1 mol/L phosphate buffered saline,respectively. MAIN OUTCOME MEASURES:Retinal ganglion cells were reverse-labeled using horseradish peroxidase to quantify cell density at 2,4,and 6 mm from the optic disc edge. RESULTS:NRF increased the number of surviving retinal ganglion cells at the optic disc edge (P < 0.01 or P < 0.05). The density of surviving retinal ganglion cells decreased with increasing distance from the optic disc. The number of retinal ganglion cells in the BDNF group was similar to the NRF group (P > 0.05). At 2,4,and 6 mm away from the optic disc edge,there was no significant difference in retinal ganglion cell density between NRF and BDNF groups (P > 0.05). CONCLUSION:NRF provided protection to retinal ganglion cells in a rabbit model of acute hyper-intraocular pressure,i.e.,NRF enhanced the survival rate of retinal ganglion cells. The neuroprotective effect was similar to BDNF.展开更多
Epigenetic changes have been shown to be associated with both aging process and aging-related diseases.There is evidence regarding the benefits of physical activity on the functionality,cognition,and quality of life o...Epigenetic changes have been shown to be associated with both aging process and aging-related diseases.There is evidence regarding the benefits of physical activity on the functionality,cognition,and quality of life of institutionalized older adults,however,the molecular mechanisms involved are not elucidated.The purpose of this pilot study was to investigate the effects of a multimodal exercise intervention on functional outcomes,cognitive performance,quality of life(QOL),epigenetic markers and brain-derived neurotrophic factor(BDNF)levels among institutionalized older adult individuals.Participants(n=8)without dementia who were aged 73.38±11.28 years and predominantly female(87.5%)were included in this quasi-experimental pilot study.A multimodal exercise protocol(cardiovascular capacity,strength,balance/agility andflexibility,perception and cognition)consisted of twice weekly sessions(60 minutes each)over 8 weeks.Balance(Berg Scale),mobility(Timed Up and Go test),functional capacity(Six-Minute Walk test),cognitive function(Mini-Mental State Examination)and QOL(the World Health Organization Quality of Life-BREF Scale questionnaire)were evaluated before and after the intervention.Blood sample(15 mL)was also collected before and after intervention for analysis of biomarkers global histone H3 acetylation and brain-derived neurotrophic factor levels.Significant improvements were observed in cognitive function,balance,mobility,functional capacity and QOL after the intervention.In addition,a tendency toward an increase in global histone H3 acetylation levels was observed,while brain-derived neurotrophic factor level remained unchanged.This study provided evidence that an 8-week multimodal exercise protocol has a significant effect on ameliorating functional outcomes and QOL in institutionalized older adult individuals.In addition,it was also able to promote cognitive improvement,which seems to be partially related to histone hyperacetylation status.The Ethics Research Committee of Centro Universitário Metodista-IPA,Brazil approved the current study on June 6,2019(approval No.3.376.078).展开更多
Mood disorders are the most common mental disorders, affecting approximately350 million people globally. Recent studies have shown that neuroimmuneinteraction regulates mood disorders. Brain-derived neurotrophic facto...Mood disorders are the most common mental disorders, affecting approximately350 million people globally. Recent studies have shown that neuroimmuneinteraction regulates mood disorders. Brain-derived neurotrophic factor (BDNF)and its precursor pro-BDNF, are involved in the neuroimmune crosstalk duringthe development of mood disorders. BDNF is implicated in the pathophysiologyof psychiatric and neurological disorders especially in antidepressant pharmacotherapy.In this review, we describe the functions of BDNF/pro-BDNF signalingin the central nervous system in the context of mood disorders. In addition, wesummarize the developments for BDNF and pro-BDNF functions in mooddisorders. This review aims to provide new insights into the impact ofneuroimmune interaction on mood disorders and reveal a new basis for furtherdevelopment of diagnostic targets and mood disorders.展开更多
The aim of this paper is to describe the direction of the link between stress,depression,increased inflammation and brain-derived neurotrophic factor(BDNF)reduction.We hypothesize that severe stress or prolonged stres...The aim of this paper is to describe the direction of the link between stress,depression,increased inflammation and brain-derived neurotrophic factor(BDNF)reduction.We hypothesize that severe stress or prolonged stress can be the driving factor that promote the onset of depression.Both stress and depression,if not resolved over time,activate the production of transcription factors that will switch on pro-inflammatory genes and translate them into cytokines.This cascade fosters systemic chronic inflammation and reduced plasma BDNF levels.Since people with depression have a 60%increased risk of developing type 2diabetes(T2D)and show high levels of inflammation and low levels of BDNF,we hypothesize possible reasons that might explain why T2D,depression and dementia are often associated in the same patient.展开更多
Objective Expressing the human matured brain-derived neurotrophic factor (mBDNF) gene in E. Coli and determining its bioactivity. Methods The resulting gene of mBDNF was subcloned into the EcoRI-BamHI site or the expr...Objective Expressing the human matured brain-derived neurotrophic factor (mBDNF) gene in E. Coli and determining its bioactivity. Methods The resulting gene of mBDNF was subcloned into the EcoRI-BamHI site or the expression vector plasmid pBV220. The ligation products were used to transform the competent E. Coli DH5a. The proteins or mBDNF were experessed by temperature inducing. The expression products were dealed with solubilizing inclusion bodies and refolding protein. It was introduced into the embryonic chicken DRG to test whether the expressed mBDNF is a biologically active protein. Results The recombinant plasmid pBV/mBDNF was success- fully constructed. By temperature inducing, under the control of the bacteriophage λPL promoter, the experessed mBDNF protein was a 14Kd non-fusion protein,which existed in E. Coli as inclusion bodies. The size or expressed mBDNF is identical to the prediction. Bioactivity of the products was proved that it could support the cell survival and neurite growth in the primary cultures of embryonic 8-day-old chicken DRG neurons as compared to control. Conclusion Tke mBDNF gene can be expressed bioactively in E. Coli.展开更多
BACKGROUND: Under induction of retinoic acid (RA), bone marrow stromal cells (BMSCs) can differentiate into nerve cells or neuron-like cells, which do not survive for a long time, so those are restricted to an applica...BACKGROUND: Under induction of retinoic acid (RA), bone marrow stromal cells (BMSCs) can differentiate into nerve cells or neuron-like cells, which do not survive for a long time, so those are restricted to an application. Other neurotrophic factors can also differentiate into neuronal cells through inducing BMSCs; especially, brain-derived neurotrophic factor (BDNF) can delay natural death of neurons and play a key role in survival and growth of neurons. The combination of them is beneficial for differentiation of BMSCs. OBJECTIVE: To investigate the effects of BDNF combining with RA on inducing differentiation of BMSCs to nerve cells of adult rats and compare the results between common medium group and single BDNF group. DESIGN: Randomized controlled animal study.SETTING: Department of Neurology, Affiliated Hospital of Xuzhou Medical College. MATERIALS: The experiment was carried out in the Clinical Neurological Laboratory of Xuzhou Medical College from September 2003 to April 2005. A total of 24 SD rats, of either gender, 2 months old, weighing 130-150 g, were provided by Experimental Animal Center of Xuzhou Medical College [certification: SYXK (su) 2002-0038]. Materials and reagents: low-glucose DMEM medium, bovine serum, BDNF, RA, trypsin, separating medium of lymphocyte, monoclonal antibody of mouse-anti-nestin, neuro-specific enolase, glial fibrillary acidic protein (GFAP) antibody, SABC kit, and diaminobenzidine (DAB) color agent. All these mentioned above were mainly provided by SIGMA Company, GIBCO Company and Boshide Company. METHODS: Bone marrow of SD rats was selected for density gradient centrifugation. BMSCs were undertaken primary culture and subculture; and then, those cells were induced respectively in various mediums in total of 3 groups, including control group (primary culture), BDNF group (20 μg/L BDNF) and BDNF+RA group (20 μg/L BDNF plus 20 μg/L RA). On the 3rd and the 7th days after induction, BMSCs were stained immunocytochemically with nestin (sign of nerve stem cells), neuron-specific enolase (NSE, sign of diagnosing neurons) and GFAP (diagnosing astrocyte), and evaluated cellular property. MAIN OUTCOME MEASURES: Induction and differentiation in vitro of BMSCs in 3 groups. RESULTS: ① Induction and differentiation of BMSCs: Seven days after induction, cells having 2 or more apophyses were observed. Soma shaped like angle or erose form, which were similar to neurons and glial cells having strong refraction. ② Results of immunocytochemical detection: Three days after induction, rate of positive cells in BDNF+RA group was higher than that in BDNF group and control group [(86.15±4.58)%, (65.43±4.23)%, (4.18±1.09)%, P < 0.01]. Seven days after induction, rate of positive cells was lower in BDNF group and BDNF+RA group than that in both groups at 3 days after induction [(31.12±3.18)%, (29.35±2.69)%, P < 0.01]; however, amounts of positive cells of NSE and GFAP were higher than those at 3 days after induction (P < 0.01); meanwhile, the amount in BDNF+RA group was remarkably higher than that in BDNF group (P < 0.01). CONCLUSION: Combination of BDNF and RA can cooperate differentiation of BMSCs into neurons and astrocyte, and the effect is superior to single usage of BDNF.展开更多
<b>Objective:</b> To explore the pathogenesis of PTSD in the brain-derived neurotrophic factor (BDNF) gene methylation of patients with posttraumatic stress disorder (Posttraumatic Stress Disorder, PTSD) i...<b>Objective:</b> To explore the pathogenesis of PTSD in the brain-derived neurotrophic factor (BDNF) gene methylation of patients with posttraumatic stress disorder (Posttraumatic Stress Disorder, PTSD) in Hainan Province, the relationship between the influence of BDNF gene methylation and the influence of PTSD. <b>Methods:</b> A case-control study method was adopted, strictly in accordance with DSM-IV and PTSD diagnosis, and 150 Li PTSD patients matched with gender and age of 300 Han PTSD patients were selected as the research objects. The peripheral venous whole blood of the subjects was drawn, genomic DNA was extracted, modified with bisulfite, and directly sequenced to quantitatively detect the methylation status of the CpG island in the promoter region of brain-derived neurotrophic factor (BDNF). <b>Results:</b> The results showed that the methylation levels of CPGl, CPG2, CPG3, CPG4, CPG5, CPG6, CPG7, CPG9, CPGl2, CPGl3, CPGl4, CPGl5, CPGl6, CPGl7, and CPGl8 in THE BDNF promoter were significantly different between the HAN PTSD group and the Li PTSD group (<i>P</i> < 0.001). <b>Conclusion:</b> It is suggested that CPG methylation in the promoter region of BDNF gene is closely related to patients with PTSD. There is a statistical difference in the level of CpG methylation in the promoter region of BDNF gene in PTSD between Li and Han ethnic groups in Hainan Province. CpG methylation in the promoter region of BDNF gene may be used as a biomarker for the diagnosis of PTSD.展开更多
基金supported by the Community Development Office of Hunan Provincial Science and Technology DepartmentChina,Nos.2020SK53613(to DH),21JJ31006(to DH)the Fundamental Research Funds of Central South University,Nos.CX20220375(to TX),2023zzts215(to MZ)。
文摘Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.
文摘Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.
基金supported by the Ministry of Higher Education,Government of Malaysia,No.FRGS/2/2014/SG03/UITM/02/2 UiTM IRMI file No.600-RMI/FRGS 5/3(111/2014),toⅡYayasan Penyelidikan Otak,Minda dan Neurosains Malaysia(YPOMNM),No.YPOMNM/2019-04(2)UiTM IRMI No.100-IRMI/PRI 16/6/2(010/2019),to MAML。
文摘Amyloid-beta(Aβ)-related alterations,similar to those found in the brains of patients with Alzheimer's disease,have been observed in the retina of patients with glaucoma.Decreased levels of brain-derived neurotrophic factor(BDNF)are believed to be associated with the neurotoxic effects of Aβpeptide.To investigate the mechanism underlying the neuroprotective effects of BDNF on Aβ_(1-40)-induced retinal injury in Sprague-Dawley rats,we treated rats by intravitreal administration of phosphate-buffered saline(control),Aβ_(1-40)(5 nM),or Aβ_(1-40)(5 nM)combined with BDNF(1μg/mL).We found that intravitreal administration of Aβ_(1-40)induced retinal ganglion cell apoptosis.Fluoro-Gold staining showed a significantly lower number of retinal ganglion cells in the Aβ_(1-40)group than in the control and BDNF groups.In the Aβ_(1-40)group,low number of RGCs was associated with increased caspase-3 expression and reduced TrkB and ERK1/2 expression.BDNF abolished Aβ_(1-40)-induced increase in the expression of caspase-3 at the gene and protein levels in the retina and upregulated TrkB and ERK1/2 expression.These findings suggest that treatment with BDNF prevents RGC apoptosis induced by Aβ_(1-40)by activating the BDNF-TrkB signaling pathway in rats.
基金supported by a Kentucky INBRE IDeA grant (P20GM103436)(to CLG)a New Investigator Start-up Grant from Ogden College of Science (to CLG)the WKU Ogden College of Science (to CLG)
文摘Brain-derived neurotrophic factor is the most prevalent member of the nerve growth factor family.Since its discovery in 1978,this enigmatic molecule has spawned more than 27,000 publications,most of which are focused on neurological disorders.Brain-derived neurotrophic factor is indispensable during embryogenesis and postnatally for the normal development and function of both the central and peripheral nervous systems.It is becoming increasingly clear,however,that brain-derived neurotrophic factor likewise plays crucial roles in a variety of other biological functions independently of sympathetic or parasympathetic involvement.Brain-derived neurotrophic factor is also increasingly recognized as a sophisticated environmental sensor and master coordinator of whole organismal physiology.To that point,we recently found that a common nonsynonymous(Val66→Met)single nucleotide polymorphism in the brain-derived neurotrophic factor gene(rs6265)not only substantially alters basal cardiac transcriptomics in mice but subtly influences heart gene expression and function differentially in males and females.In addition to a short description of recent results from associative neuropsychiatric studies,this review provides an eclectic assortment of research reports that support a modulatory role for rs6265 including and beyond the central nervous system.
基金supported by the National Natural Sclence Foundation of China in 2021No.82171213+1 种基金the Natural Science Foundation of Fujian Province in 2019No.2019J01289 (both to DSL)
文摘The trigeminal root entry zone is the zone at which the myelination switches from peripheral Schwann cells to central oligodendrocytes.Its special anatomical and physiological structure renders it susceptible to nerve injury.The etiology of most primary trigeminal neuralgia is closely related to microvascular compression of the trigeminal root entry zone.This study aimed to develop an efficient in vitro model mimicking the glial environment of trigeminal root entry zone as a tool to investigate the effects of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor on the structural and functional integrity of trigeminal root entry zone and modulation of cellular interactions.Primary astrocytes and Schwann cells isolated from trigeminal root entry zone of postnatal rats were inoculated into a two-well silicon culture insert to mimic the trigeminal root entry zone microenvironment and treated with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor.In monoculture,glial cell line-derived neurotrophic factor promoted the migration of Schwann cells,but it did not have effects on the migration of astrocytes.In the co-culture system,glial cell line-derived neurotrophic factor promoted the bidirectional migration of astrocytes and Schwann cells.Brain-derived neurotrophic factor markedly promoted the activation and migration of astrocytes.However,in the co-culture system,brain-derived neurotrophic factor inhibited the migration of astrocytes and Schwann cells to a certain degree.These findings suggest that glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor are involved in the regulation of the astrocyte-Schwann cell interaction in the co-culture system derived from the trigeminal root entry zone.This system can be used as a cell model to study the mechanism of glial dysregulation associated with trigeminal nerve injury and possible therapeutic interventions.
基金Supported by This study was supported by the Suzhou Municipal Sci-Tech Bureau Program,No.SS202070Scientific and Technological Program of Suzhou,No.SS202069+5 种基金Suzhou clinical Medical Center for mood disorders,No.Szlcyxzx202109Suzhou Clinical Key Disciplines for Geriatric Psychiatry,No.SZXK202116Suzhou Key Technologies Program,No.SKY2021063Jiangsu Province social development project,No.BE2020764Research Project of Jiangsu Commission of Health,No.M2020031Elderly Health Research Project of Jiangsu Commission of Health,No.LR2022015 and No.LKZ2023020.
文摘BACKGROUND There are systematic differences in clinical features between women and men with schizophrenia(SCZ).The regulation of sex hormones may play a potential role in abnormal neurodevelopment in SCZ.Brain-derived neurotrophic factor(BDNF)and sex hormones have complex interacting actions that contribute to the etiology of SCZ.AIM To investigate the influence of BDNF and sex hormones on cognition and clinical symptomatology in chronic antipsychotic-treated male SCZ patients.METHODS The serum levels of follicle-stimulating hormone,luteinizing hormone(LH),estradiol(E2),progesterone,testosterone(T),prolactin(PRL)and BDNF were compared between chronic antipsychotic-treated male(CATM)patients with SCZ(n=120)and healthy controls(n=120).The Positive and Negative Syndrome Scale was used to quantify SCZ symptoms,while neuropsychological tests were used to assess cognition.Neuropsychological tests,such as the Digit Cancellation Test(DCT),Semantic Verbal Fluency(SVF),Spatial Span Test(SS),Paced Auditory Serial Addition Test(PASAT),Trail Making Task(TMT-A),and Block Design Test(BDT),were used to assess executive functions(BDT),attention(DCT,TMT-A),memory(SS,PASAT),and verbal proficiency(SVF).RESULTS Although E2 levels were significantly lower in the patient group compared to the healthy controls,T,PRL,and LH levels were all significantly higher.Additionally,the analysis revealed that across the entire sample,there were positive correlations between E2 Levels and BDNF levels as well as BDNF levels and the digital cancellation time.In CATM patients with SCZ,a significant correlation between the negative symptoms score and PRL levels was observed.CONCLUSION Sex hormones and BDNF levels may also be linked to cognitive function in patients with chronic SCZ.
基金supported by the National Natural Science Foundation of China,Nos.81601961(to KWY),81672242(to YW)the Key Construction Projects of Shanghai Health and Family Planning on Weak Discipline,China,No.2015ZB0401(to YW)
文摘Many studies have shown that fibronectin type III domain-containing protein 5(FDNC5) and brain-derived neurotrophic factor(BDNF) play vital roles in plasticity after brain injury. An enriched environment refers to an environment that provides animals with multi-sensory stimulation and movement opportunities. An enriched environment has been shown to promote the regeneration of nerve cells, synapses, and blood vessels in the animal brain after cerebral ischemia;however, the exact mechanisms have not been clarified. This study aimed to determine whether an enriched environment could improve neurobehavioral functions after the experimental inducement of cerebral ischemia and whether neurobehavioral outcomes were associated with the expression of FDNC5 and BDNF. This study established ischemic mouse models using permanent middle cerebral artery occlusion(pMCAO) on the left side. On postoperative day 1, the mice were randomly assigned to either enriched environment or standard housing condition groups. Mice in the standard housing condition group were housed and fed under standard conditions. Mice in the enriched environment group were housed in a large cage, containing various toys, and fed with a standard diet. Sham-operated mice received the same procedure, but without artery occlusion, and were housed and fed under standard conditions. On postoperative days 7 and 14, a beam-walking test was used to assess coordination, balance, and spatial learning. On postoperative days 16–20, a Morris water maze test was used to assess spatial learning and memory. On postoperative day 15, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex were analyzed by western blot assay. The results showed that compared with the standard housing condition group, the motor balance and coordination functions(based on beam-walking test scores 7 and 14 days after operation), spatial learning abilities(based on the spatial learning scores from the Morris water maze test 16–19 days after operation), and memory abilities(based on the memory scores of the Morris water maze test 20 days after operation) of the enriched environment group improved significantly. In addition, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex increased in the enriched environment group compared with those in the standard housing condition group. Furthermore, the Pearson correlation coefficient showed that neurobehavioral functions were positively associated with the expression levels of FDNC5 and BDNF(r = 0.587 and r = 0.840, respectively). These findings suggest that an enriched environment upregulates FDNC5 protein expression in the ipsilateral cerebral cortex after cerebral ischemia, which then activates BDNF protein expression, improving neurological function. BDNF protein expression was positively correlated with improved neurological function. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University, China(approval Nos. 20160858 A232, 20160860 A234) on February 24, 2016.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education,No.2016R1A2B4012772(to DYK)
文摘Macrophage migration inhibitory factor(MIF)is a chemokine that plays an essential role in immune system function.Previous studies suggested that MIF protects neurons in ischemic conditions.However,few studies are reported on the role of MIF in neurological recovery after ischemic stroke.The purpose of this study is to identify the molecular mechanism of neuroprotection mediated by MIF.Human neuroblastoma cells were incubated in Dulbecco’s modified Eagle’s medium under oxygen-glucose deprivation(OGD)for 4 hours and then returned to normal aerobic environment for reperfusion(OGD/R).30 ng/mL MIF recombinant(30 ng/mL)or ISO-1(MIF antagonist;50μM)was administered to human neuroblastoma cells.Then cell cultures were assigned to one of four groups:control,OGD/R,OGD/R with MIF,OGD/R with ISO-1.Cell viability was analyzed using WST-1 assay.Expression levels of brain-derived neurotrophic factor(BDNF),microtubule-associated protein 2(MAP2),Caspase-3,Bcl2,and Bax were detected by western blot assay and immunocytochemistry in each group to measure apoptotic activity.WST-1 assay results revealed that compared to the OGD/R group,cell survival rate was significantly higher in the OGD/R with MIF group and lower in the OGD/R with ISO-1 group.Western blot assay and immunocytochemistry results revealed that expression levels of BDNF,Bcl2,and MAP2 were significantly higher,and expression levels of Caspase-3 and Bax were significantly lower in the MIF group than in the OGD/R group.Expression levels of BDNF,Bcl2,and MAP2 were significantly lower,and expression levels of Caspase-3 and Bax were significantly higher in the ISO-1 group than in the OGD/R group.MIF administration promoted neuronal cell survival and induced high expression levels of BDNF,MAP2,and Bcl2(anti-apoptosis)and low expression levels of Caspase-3 and Bax(pro-apoptosis)in an OGD/R model.These results suggest that MIF administration is effective for inducing expression of BDNF and leads to neuroprotection of neuronal cells against hypoxic injury.
基金supported by the National Natural Science Foundation of China,No. 82001604 (to LLX)the Joint Subject of Southwest Medical University and Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University of China,No. 2018XYLH-004 (to LLX)+1 种基金the National Construction Project of Regional Chinese Medicine Treatment Centre of China,No. 2018205 (to XB)the National Construction Project of the Second Clinical Research Base of Chinese Medicine of China,No. 2018131 (to XB)。
文摘Brain-derived neurotrophic factor(BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The m RNA expression levels of BDNF and its processing enzymes and receptors(Furin, matrix metallopeptidase 9, tissuetype plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury;however, the expression levels of these m RNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia(approval No. U12-18) on July 30, 2018.
基金the Major Program of Fujian Provincial Science and Technology Department, No. 2002Y014
文摘BACKGROUND: Because bone marrow mesenchymal stem cells (BMSCs) do not secrete sufficient brain-derived neurotrophic factor (BDNF), the use of exogenous BDNF could improve microenvironments in injured regions for BMSCs differentiation. OBJECTIVE: To analyze recovery of the injured spinal cord following BMSCs venous transplantation in combination with consecutive injections of BDNF. DESIGN, TIME AND SETTING: A randomized, controlled animal experiment was performed at the Central Laboratory of First Hospital and Anatomical Laboratory, Fujian Medical University from October 2004 to May 2006. MATERIALS: Human BDNF was purchased from Sigma, USA. METHODS: A total of 44 New Zealand rabbits were randomly assigned to model (n = 8), BDNF (n = 12), BMSC (n = 12), and BMSC+BDNF (n = 12) groups. Spinal cord (L2) injury was established with the dropping method. The model group rabbits were injected with 1 mL normal saline via the ear margin vein; the BDNF group was subdurally injected with 100 μg/d human BDNF for 1 week; the BMSC group was injected with 1 mL BMSCs suspension (2 × 106/mL) via the ear margin vein; and the BMSC+BDNF group rabbits were subdurally injected with 100 μg/d BDNF for 1 week, in addition to BMSCs suspension via the ear margin vein. MAIN OUTCOME MEASURES: BMSCs surface markers were detected by flow cytometry. BMSCs differentiation in the injured spinal cord was detected by immunofluorescence histochemistry. Functional and structural recovery, as well as morphological changes, in the injured spinal cord were respectively detected by Tarlov score, horseradish peroxidase retrograde tracing, and hematoxylin & eosin staining methods at 1, 3, and 5 weeks following transplantation. RESULTS: Transplanted BMSCs differentiated into neuronal-like cells in the injured spinal cord at 3 and 5 weeks following transplantation. Neurological function and pathological damage improved following BMSC + BDNF treatment compared with BDNF or BMSC alone (P < 0.01 or P < 0.05). CONCLUSION: BMSCs venous transplantation in combination with BDNF subdural injection benefits neuronal-like cell differentiation and significantly improves structural and function of injured spinal cord compared with BMSCs or BDNF alone.
基金supported by grants from the Natural Science Foundation of Shandong Province of China(ZR2011HM023 to GYL)the “11th Five-Year Plan”,National Supporting Program(2007BAI17B02 to GYL)+5 种基金the Science and Technology Project of Higher Education of Shandong Province of China(J10LF01 to GYL)a grant from Medical Science and Technology Development Project of Shandong Province of China(2011HZ011 to GYL)the China Postdoctoral Science Foundation of China(2012M 520585 to CJZ)the Fund of Tianjin Health Bureau of China(2014KR02 to CJZ)the Foundation of Hainan Li Ou Pharmaceutical Co.,Ltd.the Foundation of Xuzhou Enhua Pharmaceutical Co.,Ltd. of China
文摘Previous studies suggest that serotonin(5-HT) might interact with brain-derived neurotrophic factor(BDNF) during the stress response.However,the relationship between 5-HT and BDNF expression under purely psychological stress is unclear.In this study,one hour before psychological stress exposure,the 5-HT1 A receptor agonist 8-OH-DPAT or antagonist MDL73005,or the 5-HT2 A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress.Immunohistochemistry and in situ hybridization revealed that after psychological stress,with the exception of the ventral tegmental area,BDNF protein and m RNA expression levels were higher in the 5-HT1 A and the 5-HT2 A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus,prefrontal cortex,central amygdaloid nucleus,dorsomedial hypothalamic nucleus,dentate gyrus,shell of the nucleus accumbens and the midbrain periaqueductal gray.There was no significant difference between the two agonist groups.In contrast,after stress exposure,BDNF protein and m RNA expression levels were lower in the 5-HT1 A and 5-HT2 A receptor antagonist groups than in the solvent control non-stress group,with the exception of the ventral tegmental area.Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.
基金Supported by National Institutes of Health,No.TL1 TR002647Veterans Affairs,No.I01BX003195。
文摘Major depressive disorder is a debilitating disorder affecting millions of people each year.Brain-derived neurotrophic factor(BDNF)and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention.Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression.However,less is known about potential interaction between BDNF and inflammation,particularly within the central nervous system.Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and antidepressant response.Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF,and BDNF may play an important negative regulatory role on inflammation within the brain.Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities.Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.
基金Supported by a Grant from the Health Department of Jilin Province,No. 2000029
文摘BACKGROUND:Studies have demonstrated that brain-derived neurotrophic factor(BDNF) has a dual effect on epilepsy.However,the relationship between epilepsy-induced brain injury and BDNF remains poorly understood.OBJECTIVE:According to ultrastructural and molecular parameters,to detect the degree of neuronal injury and BDNF expression changes at different brain regions and different kindling times to determine the effects of BDNF on epilepsy-induced brain injury.DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment based on neuropathology and molecular biology was performed at the Department of Physiology and Department of Pathology,Basic Medical College of Jilin University in 2003.MATERIALS:UltraSensitive SP kit for immunohistochemistry(Fuzhou Maxim Biotechnology,China),BDNF antibody(concentrated type,Wuhan Boster Biological Technology,China),JEM-1000SX transmission electron microscopy(JEOL,Japan),and BH-2 light microscope(Olympus,Japan) were used in the present study.METHODS:Wistar rats were randomly assigned to control(n = 6),sham-surgery(n = 6),and model(n = 60) groups.The control group rats were not treated;an electrode was embedded into the amygdala in rats from the sham-surgery and model groups;an amygdala kindling epilepsy model was established in the model group.MAIN OUTCOME MEASURES:Pathological changes in the temporal lobe and hippocampus were observed by light and electron microscopy at 1,3,7,14,and 21 days following kindling,and BDNF expression in the various brain regions was determined by immunohistochemistry.RESULTS:In the model group,temporal lobe cortical and hippocampal neurons were swollen and the nuclei were laterally deviated.There were also some apoptotic neurons 3 days after kindling.The nucleoli disappeared and the nuclei appeared broken or lysed,as well as slight microglia hyperplasia,at 7 days.Electron microscopic observation displayed chromatin aggregation in the nuclei and slight mitochondrion swelling 3 days after kindling.Injury changes were aggravated at 7 days,characterized by broken cytoplasmic membrane and pyknosis.With the development of seizure,the number of BDNF-positive neurons in the hippocampus and temporal lobe increased and peaked at 7 days.Moreover,hippocampal and cortical temporal lobe injury continued.Following termination of electrical stimulation after 7 days of kindling,BDNF expression decreased,but continued to be expressed,up to 21 days of kindling.In addition,the number of temporal and hippocampal BDNF-positive neurons was greater than the control group.CONCLUSION:Brain injury and BDNF expression peaked at 7 days after kindling,and hippocampal changes were significant.
文摘BACKGROUND:Previous studies have shown that nerve regeneration factor (NRF) provides neuroprotective effects. However,the neuroprotective effects on retinal ganglion cells in an animal model of glaucoma remain uncertain. OBJECTIVE:To determine the neuroprotective effects of NRF on retinal ganglion cells in a rabbit model of acute hyper-intraocular pressure and to compare the effects on brain-derived neurotrophic factor (BDNF). DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at Jiangsu Provincial Key Laboratory of Neural Regeneration from September 2006 to August 2007. MATERIALS:Sterone,a major component of NRF,was provided by the Key Laboratory of Neural Regeneration,Nantong University in China; BDNF was provided by BioDesign Inc.,USA. METHODS:A total of 24 healthy rabbits were randomly assigned to NRF,BDNF,and phosphate buffered saline groups,with 8 rabbits per group. The left eyes were considered normal controls,and acute hyper-intraocular pressure was induced in the right eyes via anterior chamber perfusion. The right camera vitrea bulbi was injected with 4.5 μg NRF,3.75 μg BDNF,or 5 μL 0.1 mol/L phosphate buffered saline,respectively. MAIN OUTCOME MEASURES:Retinal ganglion cells were reverse-labeled using horseradish peroxidase to quantify cell density at 2,4,and 6 mm from the optic disc edge. RESULTS:NRF increased the number of surviving retinal ganglion cells at the optic disc edge (P < 0.01 or P < 0.05). The density of surviving retinal ganglion cells decreased with increasing distance from the optic disc. The number of retinal ganglion cells in the BDNF group was similar to the NRF group (P > 0.05). At 2,4,and 6 mm away from the optic disc edge,there was no significant difference in retinal ganglion cell density between NRF and BDNF groups (P > 0.05). CONCLUSION:NRF provided protection to retinal ganglion cells in a rabbit model of acute hyper-intraocular pressure,i.e.,NRF enhanced the survival rate of retinal ganglion cells. The neuroprotective effect was similar to BDNF.
文摘Epigenetic changes have been shown to be associated with both aging process and aging-related diseases.There is evidence regarding the benefits of physical activity on the functionality,cognition,and quality of life of institutionalized older adults,however,the molecular mechanisms involved are not elucidated.The purpose of this pilot study was to investigate the effects of a multimodal exercise intervention on functional outcomes,cognitive performance,quality of life(QOL),epigenetic markers and brain-derived neurotrophic factor(BDNF)levels among institutionalized older adult individuals.Participants(n=8)without dementia who were aged 73.38±11.28 years and predominantly female(87.5%)were included in this quasi-experimental pilot study.A multimodal exercise protocol(cardiovascular capacity,strength,balance/agility andflexibility,perception and cognition)consisted of twice weekly sessions(60 minutes each)over 8 weeks.Balance(Berg Scale),mobility(Timed Up and Go test),functional capacity(Six-Minute Walk test),cognitive function(Mini-Mental State Examination)and QOL(the World Health Organization Quality of Life-BREF Scale questionnaire)were evaluated before and after the intervention.Blood sample(15 mL)was also collected before and after intervention for analysis of biomarkers global histone H3 acetylation and brain-derived neurotrophic factor levels.Significant improvements were observed in cognitive function,balance,mobility,functional capacity and QOL after the intervention.In addition,a tendency toward an increase in global histone H3 acetylation levels was observed,while brain-derived neurotrophic factor level remained unchanged.This study provided evidence that an 8-week multimodal exercise protocol has a significant effect on ameliorating functional outcomes and QOL in institutionalized older adult individuals.In addition,it was also able to promote cognitive improvement,which seems to be partially related to histone hyperacetylation status.The Ethics Research Committee of Centro Universitário Metodista-IPA,Brazil approved the current study on June 6,2019(approval No.3.376.078).
基金Supported by National Natural Science Foundation of China,No. 82071347 and No. 81771354 (to Dai RP)
文摘Mood disorders are the most common mental disorders, affecting approximately350 million people globally. Recent studies have shown that neuroimmuneinteraction regulates mood disorders. Brain-derived neurotrophic factor (BDNF)and its precursor pro-BDNF, are involved in the neuroimmune crosstalk duringthe development of mood disorders. BDNF is implicated in the pathophysiologyof psychiatric and neurological disorders especially in antidepressant pharmacotherapy.In this review, we describe the functions of BDNF/pro-BDNF signalingin the central nervous system in the context of mood disorders. In addition, wesummarize the developments for BDNF and pro-BDNF functions in mooddisorders. This review aims to provide new insights into the impact ofneuroimmune interaction on mood disorders and reveal a new basis for furtherdevelopment of diagnostic targets and mood disorders.
文摘The aim of this paper is to describe the direction of the link between stress,depression,increased inflammation and brain-derived neurotrophic factor(BDNF)reduction.We hypothesize that severe stress or prolonged stress can be the driving factor that promote the onset of depression.Both stress and depression,if not resolved over time,activate the production of transcription factors that will switch on pro-inflammatory genes and translate them into cytokines.This cascade fosters systemic chronic inflammation and reduced plasma BDNF levels.Since people with depression have a 60%increased risk of developing type 2diabetes(T2D)and show high levels of inflammation and low levels of BDNF,we hypothesize possible reasons that might explain why T2D,depression and dementia are often associated in the same patient.
文摘Objective Expressing the human matured brain-derived neurotrophic factor (mBDNF) gene in E. Coli and determining its bioactivity. Methods The resulting gene of mBDNF was subcloned into the EcoRI-BamHI site or the expression vector plasmid pBV220. The ligation products were used to transform the competent E. Coli DH5a. The proteins or mBDNF were experessed by temperature inducing. The expression products were dealed with solubilizing inclusion bodies and refolding protein. It was introduced into the embryonic chicken DRG to test whether the expressed mBDNF is a biologically active protein. Results The recombinant plasmid pBV/mBDNF was success- fully constructed. By temperature inducing, under the control of the bacteriophage λPL promoter, the experessed mBDNF protein was a 14Kd non-fusion protein,which existed in E. Coli as inclusion bodies. The size or expressed mBDNF is identical to the prediction. Bioactivity of the products was proved that it could support the cell survival and neurite growth in the primary cultures of embryonic 8-day-old chicken DRG neurons as compared to control. Conclusion Tke mBDNF gene can be expressed bioactively in E. Coli.
文摘BACKGROUND: Under induction of retinoic acid (RA), bone marrow stromal cells (BMSCs) can differentiate into nerve cells or neuron-like cells, which do not survive for a long time, so those are restricted to an application. Other neurotrophic factors can also differentiate into neuronal cells through inducing BMSCs; especially, brain-derived neurotrophic factor (BDNF) can delay natural death of neurons and play a key role in survival and growth of neurons. The combination of them is beneficial for differentiation of BMSCs. OBJECTIVE: To investigate the effects of BDNF combining with RA on inducing differentiation of BMSCs to nerve cells of adult rats and compare the results between common medium group and single BDNF group. DESIGN: Randomized controlled animal study.SETTING: Department of Neurology, Affiliated Hospital of Xuzhou Medical College. MATERIALS: The experiment was carried out in the Clinical Neurological Laboratory of Xuzhou Medical College from September 2003 to April 2005. A total of 24 SD rats, of either gender, 2 months old, weighing 130-150 g, were provided by Experimental Animal Center of Xuzhou Medical College [certification: SYXK (su) 2002-0038]. Materials and reagents: low-glucose DMEM medium, bovine serum, BDNF, RA, trypsin, separating medium of lymphocyte, monoclonal antibody of mouse-anti-nestin, neuro-specific enolase, glial fibrillary acidic protein (GFAP) antibody, SABC kit, and diaminobenzidine (DAB) color agent. All these mentioned above were mainly provided by SIGMA Company, GIBCO Company and Boshide Company. METHODS: Bone marrow of SD rats was selected for density gradient centrifugation. BMSCs were undertaken primary culture and subculture; and then, those cells were induced respectively in various mediums in total of 3 groups, including control group (primary culture), BDNF group (20 μg/L BDNF) and BDNF+RA group (20 μg/L BDNF plus 20 μg/L RA). On the 3rd and the 7th days after induction, BMSCs were stained immunocytochemically with nestin (sign of nerve stem cells), neuron-specific enolase (NSE, sign of diagnosing neurons) and GFAP (diagnosing astrocyte), and evaluated cellular property. MAIN OUTCOME MEASURES: Induction and differentiation in vitro of BMSCs in 3 groups. RESULTS: ① Induction and differentiation of BMSCs: Seven days after induction, cells having 2 or more apophyses were observed. Soma shaped like angle or erose form, which were similar to neurons and glial cells having strong refraction. ② Results of immunocytochemical detection: Three days after induction, rate of positive cells in BDNF+RA group was higher than that in BDNF group and control group [(86.15±4.58)%, (65.43±4.23)%, (4.18±1.09)%, P < 0.01]. Seven days after induction, rate of positive cells was lower in BDNF group and BDNF+RA group than that in both groups at 3 days after induction [(31.12±3.18)%, (29.35±2.69)%, P < 0.01]; however, amounts of positive cells of NSE and GFAP were higher than those at 3 days after induction (P < 0.01); meanwhile, the amount in BDNF+RA group was remarkably higher than that in BDNF group (P < 0.01). CONCLUSION: Combination of BDNF and RA can cooperate differentiation of BMSCs into neurons and astrocyte, and the effect is superior to single usage of BDNF.
文摘<b>Objective:</b> To explore the pathogenesis of PTSD in the brain-derived neurotrophic factor (BDNF) gene methylation of patients with posttraumatic stress disorder (Posttraumatic Stress Disorder, PTSD) in Hainan Province, the relationship between the influence of BDNF gene methylation and the influence of PTSD. <b>Methods:</b> A case-control study method was adopted, strictly in accordance with DSM-IV and PTSD diagnosis, and 150 Li PTSD patients matched with gender and age of 300 Han PTSD patients were selected as the research objects. The peripheral venous whole blood of the subjects was drawn, genomic DNA was extracted, modified with bisulfite, and directly sequenced to quantitatively detect the methylation status of the CpG island in the promoter region of brain-derived neurotrophic factor (BDNF). <b>Results:</b> The results showed that the methylation levels of CPGl, CPG2, CPG3, CPG4, CPG5, CPG6, CPG7, CPG9, CPGl2, CPGl3, CPGl4, CPGl5, CPGl6, CPGl7, and CPGl8 in THE BDNF promoter were significantly different between the HAN PTSD group and the Li PTSD group (<i>P</i> < 0.001). <b>Conclusion:</b> It is suggested that CPG methylation in the promoter region of BDNF gene is closely related to patients with PTSD. There is a statistical difference in the level of CpG methylation in the promoter region of BDNF gene in PTSD between Li and Han ethnic groups in Hainan Province. CpG methylation in the promoter region of BDNF gene may be used as a biomarker for the diagnosis of PTSD.
