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Sample records for neurotrophic factor determined

  1. Optimizing neurotrophic factor combinations for neurite outgrowth

    NASA Astrophysics Data System (ADS)

    Deister, C.; Schmidt, C. E.

    2006-06-01

    Most neurotrophic factors are members of one of three families: the neurotrophins, the glial cell-line derived neurotrophic factor family ligands (GFLs) and the neuropoietic cytokines. Each family activates distinct but overlapping cellular pathways. Several studies have shown additive or synergistic interactions between neurotrophic factors from different families, though generally only a single combination has been studied. Because of possible interactions between the neurotrophic factors, the optimum concentration of a factor in a mixture may differ from the optimum when applied individually. Additionally, the effect of combinations of neurotrophic factors from each of the three families on neurite extension is unclear. This study examines the effects of several combinations of the neurotrophin nerve growth factor (NGF), the GFL glial cell-line derived neurotrophic factor (GDNF) and the neuropoietic cytokine ciliary neurotrophic factor (CNTF) on neurite outgrowth from young rat dorsal root ganglion (DRG) explants. The combination of 50 ng ml-1 NGF and 10 ng ml-1 of each GDNF and CNTF induced the highest level of neurite outgrowth at a 752 ± 53% increase over untreated DRGs and increased the longest neurite length to 2031 ± 97 µm compared to 916 ± 64 µm for untreated DRGs. The optimum concentrations of the three factors applied in combination corresponded to the optimum concentration of each factor when applied individually. These results indicate that the efficacy of future therapies for nerve repair would be enhanced by the controlled release of a combination of neurotrophins, GFLs and neuropoietic cytokines at higher concentrations than used in previous conduit designs.

  2. [Neurotrophic factors and their importance in attention deficit hyperactivity disorde].

    PubMed

    Ramos-Quiroga, Josep A; Sánchez-Mora, Cristina; Corominas, Margarida; Martínez, Iris; Barrau, Víctor; Prats, Laura; Casas, Miguel; Ribasés, Marta

    2014-02-24

    The existing literature that reports findings linked with the involvement of neurotrophic factors in attention deficit hyperactivity disorder (ADHD) is reviewed. Neurotrophins, a family of neurotrophic factors, are a kind of proteins that are specific to the nervous system and play an essential role in neuron survival, differentiation and proliferation during the development of the central and peripheral nervous system. These molecules stimulate axonal growth and exert an influence on the connections with the target tissue in order to establish the synaptic connections. The study of neurotrophins in ADHD, a neurodevelopmental disorder, is of interest mainly due to the functions that these proteins perform in the central nervous system. Studies on animal, pharmacological and molecular genetic models yield evidence that relates neurotrophins with the disorder. This work reviews the results from the studies conducted to date on ADHD and neurotrophic factors, especially brain-derived neurotrophic factor (BDNF). Thus, although pharmacological studies suggest that the response to atomoxetine in adults with ADHD is not directly mediated by the effect on the BDNF, reductions in BDNF levels in the plasma of adult patients with ADHD have been reported. Further studies with broader samples and greater control of environmental factors that can regulate neurotrophin expression, such as diet, physical exercise and situations of social risk, are needed to be able to determine the role they play in the aetiology of ADHD.

  3. Neurotrophic factors and female sexual development.

    PubMed

    Ojeda, S R; Dissen, G A; Junier, M P

    1992-04-01

    The concept is proposed that polypeptide neurotrophic factors contribute to the developmental regulation of ovarian and hypothalamic function in mammals. Nerve growth factor (NGF) and neurotrophin-3, two members of the neurotrophin family, have been identified in the rat ovary and one of its receptors has been localized to the innervation and thecal cells of developing follicles. Although NGF supports the sympathetic innervation of the gland, the extent to which follicles are innervated appears to be defined by the differential expression of NGF receptors in the theca of developing follicles. The presence of NGF receptors in steroid-producing cells suggests a direct involvement of neurotrophins in the regulation of gonadal endocrine function. Evidence is beginning to emerge suggesting that development of the reproductive hypothalamus is affected by insulin-like growth factor 1 secreted by peripheral tissues, and transforming growth factor alpha (TGF alpha) produced locally. In the rat hypothalamus, TGF alpha appears to be synthesized in both neurons and glial cells. In glial cells it may interact with epidermal growth factor (EGF) receptors to further enhance TGF alpha synthesis and to, perhaps, stimulate eicosanoid formation. In turn, one of these eicosanoids, prostaglandin E2, may act on luteinizing hormone-releasing hormone (LHRH) neurons to stimulate the release of LHRH in a genomic-independent manner. This provides the basis for the notion that during development LHRH secretion is regulated by a dual mechanism, one that involves transsynaptic effects exerted by neurotransmitters, the other that requires a glial-neuronal interaction and that may predominantly regulate release of the neuropeptide. An increased expression of the TGF alpha and EGF receptor genes in reactive astrocytes is postulated to contribute to the process by which hypothalamic injury causes sexual precocity. Morphological maturation of the reproductive hypothalamus is thought to occur during

  4. Neurotrophic factor - Characterization and partial purification

    NASA Technical Reports Server (NTRS)

    Popiela, H.; Ellis, S.

    1981-01-01

    Recent evidence suggests that neurotrophic activity is required for the normal proliferation and development of muscle cells. The present paper reports a study of the purification and characterization of a neurotrophic factor (NTF) from adult chicken ischiatic-peroneal nerves using two independent quantitative in vitro assay systems. The assays were performed by the measurement of the incorporation of tritiated thymidine or the sizes of single-cell clones by chick muscle cells grown in culture. The greatest amount of neutrotrophic activity is found to be extracted at a pH of 8; aqueous suspensions of the activity are stable to long-term storage at room temperature. The specific activity of the substance is doubled upon precipitation with ammonium sulfate or after gel filtration, and increase 4 to 5 fold after salt gradient elution from DEAE cellulose columns. The active fraction obtained after gel filtration and rechromatography on DEAE cellulose exhibits a 7 to 10-fold increase in specific activity. Electrophoresis of the most highly purified material yields a greatly concentrated band at around 80,000 daltons. Although NTF is purified almost 10-fold as indicated by the increase in specific activity, the maximum activity of the partially purified material is greatly reduced, possibly due to a requirement for a cofactor for the expression of maximum activity.

  5. [The research advance of brain derived neurotrophic factor].

    PubMed

    Liu, Z; Chen, J

    2000-12-01

    Recent research advances in neuroscience show that neurotrophic factors are proteins that affect selectively various kinds of neurons of CNS and PNS. Brain derived neurotrophic factor (BDNF) is another neurotrophic factor that was first reported by Barde, a German chemist, thirty years later after the nerve growth factor had been found out. BDNF plays an important role in the growth, development, differentiation, maintenance and regeneration of various types of neurons in the CNS and has potential application to the treatment of brain injury and neurodegenerative diseases such as Alzheimer's disease, Parkinson's syndrome, Huntington's chorea and amyotrophic lateral sclerosis. In this paper, the structure, function and potential clinical application of BDNF were reviewed.

  6. Neurotrophic Factors and Their Potential Applications in Tissue Regeneration.

    PubMed

    Xiao, Nan; Le, Quynh-Thu

    2016-04-01

    Neurotrophic factors are growth factors that can nourish neurons and promote neuron survival and regeneration. They have been studied as potential drug candidates for treating neurodegenerative diseases. Since their identification, there are more and more evidences to indicate that neurotrophic factors are also expressed in non-neuronal tissues and regulate the survival, anti-inflammation, proliferation and differentiation in these tissues. This mini review summarizes the characteristics of the neurotrophic factors and their potential clinical applications in the regeneration of neuronal and non-neuronal tissues.

  7. Neurotrophic Factors and Their Potential Applications in Tissue Regeneration

    PubMed Central

    Le, Quynh-Thu

    2016-01-01

    Neurotrophic factors are growth factors that can nourish neurons and promote neuron survival and regeneration. They have been studied as potential drug candidates for treating neurodegenerative diseases. Since their identification, there are more and more evidences to indicate that neurotrophic factors are also expressed in non-neuronal tissues and regulate the survival, anti-inflammation, proliferation and differentiation in these tissues. This mini review summarizes the characteristics of the neurotrophic factors and their potential clinical applications in the regeneration of neuronal and non-neuronal tissues. PMID:26611762

  8. Brain-derived Neurotrophic Factor in Megakaryocytes.

    PubMed

    Chacón-Fernández, Pedro; Säuberli, Katharina; Colzani, Maria; Moreau, Thomas; Ghevaert, Cedric; Barde, Yves-Alain

    2016-05-06

    The biosynthesis of endogenous brain-derived neurotrophic factor (BDNF) has thus far been examined in neurons where it is expressed at very low levels, in an activity-dependent fashion. In humans, BDNF has long been known to accumulate in circulating platelets, at levels far higher than in the brain. During the process of blood coagulation, BDNF is released from platelets, which has led to its extensive use as a readily accessible biomarker, under the assumption that serum levels may somehow reflect brain levels. To identify the cellular origin of BDNF in platelets, we established primary cultures of megakaryocytes, the progenitors of platelets, and we found that human and rat megakaryocytes express the BDNF gene. Surprisingly, the pattern of mRNA transcripts is similar to neurons. In the presence of thapsigargin and external calcium, the levels of the mRNA species leading to efficient BDNF translation rapidly increase. Under these conditions, pro-BDNF, the obligatory precursor of biologically active BDNF, becomes readily detectable. Megakaryocytes store BDNF in α-granules, with more than 80% of them also containing platelet factor 4. By contrast, BDNF is undetectable in mouse megakaryocytes, in line with the absence of BDNF in mouse serum. These findings suggest that alterations of BDNF levels in human serum as reported in studies dealing with depression or physical exercise may primarily reflect changes occurring in megakaryocytes and platelets, including the ability of the latter to retain and release BDNF.

  9. Novel CDNF/MANF family of neurotrophic factors.

    PubMed

    Lindholm, Päivi; Saarma, Mart

    2010-04-01

    Current therapeutic interventions for neurodegenerative diseases alleviate only disease symptoms, while treatments that could stop or reverse actual degenerative processes are not available. Parkinson's disease (PD) is a movement disorder with characteristic degeneration of dopaminergic neurons in the midbrain. Few neurotrophic factors (NTFs) that promote survival, maintenance, and differentiation of affected brain neurons are considered as potential therapeutic agents for the treatment of neurodegenerative diseases. Thus, it is important to search and study new NTFs that could also be used in therapy. In this review, we discuss novel evolutionary conserved family of NTFs consisting of two members in the vertebrates, cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF). Invertebrates, including Drosophila and Caenorhabditis have a single protein homologous to vertebrate CDNF/MANF. Characteristic feature of these proteins is eight structurally conserved cysteine residues, which determine the protein fold. The crystal structure analysis revealed that CDNF and MANF consist of two domains; an amino-terminal saposin-like domain that may interact with lipids or membranes, and a presumably unfolded carboxy-terminal domain that may protect cells against endoplasmic reticulum stress. CDNF and MANF protect midbrain dopaminergic neurons and restore motor function in 6-hydroxydopamine rat model of PD in vivo. In line, Drosophila MANF is needed for the maintenance of dopaminergic neurites and dopamine levels in the fly, suggesting that the function of CDNF/MANF proteins is evolutionary conserved. Future studies will reveal the receptors and mode of action of these novel factors, which are potential therapeutic proteins for the treatment of PD.

  10. Oligodendroglia and neurotrophic factors in neurodegeneration

    PubMed Central

    Bankston, Andrew N.; Mandler, Mariana D.; Feng, Yue

    2014-01-01

    Myelination by oligodendroglial cells (OLs) enables the propagation of action potentials along neuronal axons, which is essential for rapid information flow in the central nervous system (CNS). Besides saltatory conduction, the myelin sheath also protects axons against inflammatory and oxidative insults, and loss of myelin results in axonal damage and ultimately neuronal loss in demyelinating disorders. However, accumulating evidence indicates that OLs also provide support to neurons via mechanisms beyond the insulating function of myelin. More importantly, an increasing volume of reports indicates defects of OLs in numerous neurodegenerative diseases, sometimes even preceding neuronal loss in pre-symptomatic episodes, suggesting that OL pathology may be an important mechanism contributing to the initiation and/or progression of neurodegeneration. This review focuses on the emerging picture of neuronal support by OLs in the pathogenesis of neurodegenerative disorders through diverse molecular and cellular mechanisms, including direct neuron-myelin interaction, metabolic support by OLs, and neurotrophic factors produced by and/or acting on OLs. PMID:23558590

  11. Neurotrophic factor intervention restores auditory function in deafened animals

    NASA Astrophysics Data System (ADS)

    Shinohara, Takayuki; Bredberg, Göran; Ulfendahl, Mats; Pyykkö, Ilmari; Petri Olivius, N.; Kaksonen, Risto; Lindström, Bo; Altschuler, Richard; Miller, Josef M.

    2002-02-01

    A primary cause of deafness is damage of receptor cells in the inner ear. Clinically, it has been demonstrated that effective functionality can be provided by electrical stimulation of the auditory nerve, thus bypassing damaged receptor cells. However, subsequent to sensory cell loss there is a secondary degeneration of the afferent nerve fibers, resulting in reduced effectiveness of such cochlear prostheses. The effects of neurotrophic factors were tested in a guinea pig cochlear prosthesis model. After chemical deafening to mimic the clinical situation, the neurotrophic factors brain-derived neurotrophic factor and an analogue of ciliary neurotrophic factor were infused directly into the cochlea of the inner ear for 26 days by using an osmotic pump system. An electrode introduced into the cochlea was used to elicit auditory responses just as in patients implanted with cochlear prostheses. Intervention with brain-derived neurotrophic factor and the ciliary neurotrophic factor analogue not only increased the survival of auditory spiral ganglion neurons, but significantly enhanced the functional responsiveness of the auditory system as measured by using electrically evoked auditory brainstem responses. This demonstration that neurotrophin intervention enhances threshold sensitivity within the auditory system will have great clinical importance for the treatment of deaf patients with cochlear prostheses. The findings have direct implications for the enhancement of responsiveness in deafferented peripheral nerves.

  12. Neurotrophic factors and the pathophysiology of schizophrenic psychoses.

    PubMed

    Durany, Nuria; Thome, Johannes

    2004-09-01

    The aim of this review is to summarize the present state of findings on altered neurotrophic factor levels in schizophrenic psychoses, on variations in genes coding for neurotrophic factors, and on the effect of antipsychotic drugs on the expression level of neurotrophic factors. This is a conceptual paper that aims to establish the link between the neuromaldevelopment theory of schizophrenia and neurotrophic factors. An extensive literature review has been done using the Pub Med database, a service of the National Library of Medicine, which includes over 14 million citations for biomedical articles back to the 1950s. The majority of studies discussed in this review support the notion of alterations of neurotrophic factors at the protein and gene level, respectively, and support the hypothesis that these alterations could, at least partially, explain some of the morphological, cytoarchitectural and neurobiochemical abnormalities found in the brain of schizophrenic patients. However, the results are not always conclusive and the clinical significance of these alterations is not fully understood. It is, thus, important to further neurotrophic factor research in order to better understand the etiopathogenesis of schizophrenic psychoses and, thus, potentially develop new treatment strategies urgently needed for patients suffering from these devastating disorders.

  13. Hippocampal neurogenesis, neurotrophic factors and depression: possible therapeutic targets?

    PubMed

    Serafini, Gianluca; Hayley, Shawn; Pompili, Maurizio; Dwivedi, Yogesh; Brahmachari, Goutam; Girardi, Paolo; Amore, Mario

    2014-01-01

    Major depression is one of the leading causes of disability and psychosocial impairment worldwide. Although many advances have been made in the neurobiology of this complex disorder, the pathophysiological mechanisms are still unclear. Among the proposed theories, impaired neuroplasticity and hippocampal neurogenesis have received considerable attention. The possible association between hippocampal neurogenesis, neurotrophic factors, major depression, and antidepressant responses was critically analyzed using a comprehensive search of articles/book chapters in English language between 1980 and 2014. One common emerging theme was that chronic stress and major depression are associated with structural brain changes such as a loss of dendritic spines and synapses, as well as reduced dendritic arborisation, together with diminished glial cells in the hippocampus. Both central monoamines and neurotrophic factors were associated with a modulation of hippocampal progenitor proliferation and cell survival. Accordingly, antidepressants are generally suggested to reverse stress-induced structural changes augmenting dendritic arborisation and synaptogenesis. Such antidepressant consequences are supposed to stem from their stimulatory effects on neurotrophic factors, and possibly modulation of glial cells. Of course, accumulating evidence also suggested that glutamatergic systems are implicated in not only basic neuroplastic processes, but also in the core features of depression. Hence, it is critical that antidepressant strategies focus on links between the various neurotransmitter systems, neurotrophic processes of hippocampal neurogenesis, and neurotrophic factors with regards to depressive symptomology. The identification of novel alternative antidepressant medications that target these systems is discussed in this review.

  14. Poxue Huayu and Tianjing Busui Decoction for cerebral hemorrhage (Upregulation of neurotrophic factor expression): Upregulation of neurotrophic factor expression

    PubMed Central

    Ren, Jixiang; Zhou, Xiangyu; Wang, Jian; Zhao, Jianjun; Zhang, Pengguo

    2013-01-01

    This study established a rat model of cerebral hemorrhage by injecting autologous anticoagulated blood. Rat models were intragastrically administered 5, 10, 20 g/kg Poxue Huayu and Tianjing Busui Decoction, supplemented with Hirudo, raw rhubarb, raw Pollen Typhae, gadfly, Fructrs Trichosanthis, Radix Notoginseng, Rhizoma Acori Talarinowii, and glue of tortoise plastron, once a day, for 14 consecutive days. Results demonstrated that brain water content significantly reduced in rats with cerebral hemorrhage, and intracerebral hematoma volume markedly reduced after treatment. Immunohistochemical staining revealed that brain-derived neurotrophic factor, tyrosine kinase B and vascular endothelial growth factor expression noticeably increased around the surrounding hematoma. Reverse transcription-PCR revealed that brain-derived neurotrophic factor and tyrosine kinase B mRNA expression significantly increased around the surrounding hematoma. Neurologic impairment obviously reduced. These results indicated that Poxue Huayu and Tianjing Busui Decoction exert therapeutic effects on cerebral hemorrhage by upregulating the expression of brain-derived neurotrophic factor. PMID:25206512

  15. Immunohistochemical localization of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in the superior olivary complex of mice after radiofrequency exposure.

    PubMed

    Maskey, Dhiraj; Kim, Myeung Ju

    2014-04-03

    Raising health concerns about the biological effects from radiofrequency exposure, even with conflicting results, has prompted calls for formulation of a guideline of the biological safety level. Given the close proximity between a mobile phone and the ear, it has been suggested that the central auditory system may be detrimentally influenced by radiofrequency exposure. In the auditory system, neurotrophins are important in the regulation of neuron survival, especially mammalian cochlear neurons. Neurotrophic factors like brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) present in the auditory system are responsible for the maintenance of auditory neurons. BDNF and GDNF may protect against acoustic trauma and prevent from hearing defect. The present study applied radiofrequency at a specific absorption rate (SAR) of 1.6W/kg (E1.6) or 0W/kg group to determine the distribution of BDNF and GDNF in the nuclei of superior olivary complex (SOC). In the E1.6 group, significant decrements of BDNF immunoreactivity (IR) were noted in the lateral superior olive, medial superior olive, superior paraolivary nucleus and medial nucleus of the trapezoid body. GDNF IR was also significantly decreased (p<0.001) in all SOC nuclei of the E1.6 group. The decrease in the IR of these neurotrophic factors in the SOC of the E1.6 group suggests a detrimental effect of RF exposure in the auditory nuclei.

  16. Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease

    PubMed Central

    Mattson, Mark P.

    2008-01-01

    Glutamate’s role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis and neuron survival in the developing and adult mammalian nervous system. Cell surface glutamate receptors are coupled to Ca2+ influx and release from endoplasmic reticulum stores which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF) which, in turn, modifies neuronal glutamate sensitivity, Ca2+ homeostasis and plasticity. Neurotrophic factors may modify glutamate signalling directly, by changing the expression of glutamate receptor subunits and Ca2+-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins and anti-apoptotic Bcl2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer’s disease to psychiatric disorders. By enhancing neurotrophic factor signalling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signalling and protect against neurological disorders. PMID:19076369

  17. Neurotrophic factors improve muscle reinnervation from embryonic neurons.

    PubMed

    Casella, Gizelda T B; Almeida, Vania W; Grumbles, Robert M; Liu, Yang; Thomas, Christine K

    2010-11-01

    Motoneurons die in diseases like amyotrophic lateral sclerosis and after spinal cord trauma, inducing muscle denervation. We tested whether transplantation of embryonic cells with neurotrophic factors into peripheral nerve of adult rats improves muscle reinnervation and motor unit function more than cells alone. One week after sciatic nerve section, embryonic ventral spinal cord cells were transplanted into the tibial nerve with or without glial cell line-derived neurotrophic factor, hepatocyte growth factor, and insulin-like growth factor-1. These cells represented the only neuron source for muscle reinnervation. Ten weeks after transplantation, all medial gastrocnemius muscles contracted in response to electrical stimulation of cell transplants with factors. Only 80% of muscles responded with cells alone. Factors and cells resulted in survival of more motoneurons and reinnervation of more muscle fibers for a given axon (motor unit) number. Greater reinnervation from embryonic cells may enhance muscle excitation by patterned electrical stimulation.

  18. Human milk and formulae: neurotrophic and new biological factors.

    PubMed

    Serpero, Laura D; Frigiola, Alessandro; Gazzolo, Diego

    2012-03-01

    Mother milk is widely accepted to be a unique product believed to contain biological factors involved in the regulation of newborn optimal growth including brain when compared to milk-formula milks. In this setting, there is growing evidence that in milk-formula neuro-oxidative stress biomarkers, neurotrophic proteins and calcium binding proteins, known to be involved in a cascade of events leading to brain, cardiac and vascular development/damage, are to date lacking or at a lower concentration than breast milk. Therefore, this review is aimed at offering additional insights to the role in human milk of some selected biomarkers such as: i) neurotrophic factors such as Activin A; ii) Calcium binding protein such as S100B and, iii) heat shock protein known to be involved in oxidative stress response (namely hemeoxygenase-1, HO-1 or Heat shock Protein 32, HSP32).

  19. Implementing neuronal plasticity in NeuroAIDS: the experience of brain-derived neurotrophic factor and other neurotrophic factors.

    PubMed

    Mocchetti, Italo; Bachis, Alessia; Campbell, Lee A; Avdoshina, Valeriya

    2014-03-01

    Human immunodeficiency virus type-1 (HIV) causes mild or severe neurological problems, termed HIV-associated neurocognitive disorder (HAND), even when HIV patients receive antiretroviral therapy. Thus, novel adjunctive therapies are necessary to reduce or abolish the neurotoxic effect of HIV. However, new therapies require a better understanding of the molecular and cellular mechanisms of HIV-induced neurotoxicity. HAND subjects are characterized by being profoundly depressed, and they experience deficits in memory, learning and movements. Experimental evidence has also shown that HIV reduces neurogenesis. These deficits resemble those occurring in premature brain aging or in a brain with impaired neural repair properties. Thus, it appears that HIV diminishes neuronal survival, along with reduced neuronal connections. These two phenomena should not occur in the adult and developing brain when synaptic plasticity is promoted by neurotrophic factors, polypeptides that are present in adult synapses. This review will outline experimental evidence as well as present emerging concepts for the use of neurotrophic factors and in particular brain-derived neurotrophic factor as an adjunct therapy to prevent HIV-mediated neuronal degeneration and restore the loss of synaptic connections.

  20. Serum brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 levels in children with attention-deficit/hyperactivity disorder.

    PubMed

    Bilgiç, Ayhan; Toker, Aysun; Işık, Ümit; Kılınç, İbrahim

    2017-03-01

    It has been suggested that neurotrophins are involved in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). This study aimed to investigate whether there are differences in serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NTF3) levels between children with ADHD and healthy controls. A total of 110 treatment-naive children with the combined presentation of ADHD and 44 healthy controls aged 8-18 years were enrolled in this study. The severity of ADHD symptoms was determined by scores on the Conners' Parent Rating Scale-Revised Short and Conners' Teacher Rating Scale-Revised Short. The severity of depression and anxiety symptoms of the children were evaluated by the self-report inventories. Serum levels of neurotrophins were measured using commercial enzyme-linked immunosorbent assay kits. The multivariate analysis of covariance (MANCOVA) revealed a significant main effect of groups in the levels of serum neurotrophins, an effect that was independent of age, sex, and the severity of the depression and anxiety. The analysis of covariance (ANCOVA) indicated that the mean serum GDNF and NTF3 levels of ADHD patients were significantly higher than that of controls. However, serum BDNF and NGF levels did not show any significant differences between groups. No correlations between the levels of serum neurotrophins and the severity of ADHD were observed. These results suggest that elevated serum GDNF and NTF3 levels may be related to ADHD in children.

  1. Effect of neurotrophic factor, MDP, on rats' nerve regeneration.

    PubMed

    Fornazari, A A; Rezende, M R de; Mattar Jr, R; Taira, R I; Santos, G B dos; Paulos, R G

    2011-04-01

    Our objective was to determine the immune-modulating effects of the neurotrophic factor N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) on median nerve regeneration in rats. We used male Wistar rats (120-140 days of age, weighing 250-332 g) and compared the results of three different techniques of nerve repair: 1) epineural neurorrhaphy using sutures alone (group S - 10 rats), 2) epineural neurorrhaphy using sutures plus fibrin tissue adhesive (FTA; group SF - 20 rats), and 3) sutures plus FTA, with MDP added to the FTA (group SFM - 20 rats). Functional assessments using the grasp test were performed weekly for 12 weeks to identify recovery of flexor muscle function in the fingers secondary to median nerve regeneration. Histological analysis was also utilized. The total number and diameter of myelinated fibers were determined in each proximal and distal nerve segment. Two indices, reported as percentage, were calculated from these parameters, namely, the regeneration index and the diameter change index. By the 8th week, superiority of group SFM over group S became apparent in the grasping test (P = 0.005). By the 12th week, rats that had received MDP were superior in the grasping test compared to both group S (P < 0.001) and group SF (P = 0.001). Moreover, group SF was better in the grasping test than group S (P = 0.014). However, no significant differences between groups were identified by histological analysis. In the present study, rats that had received MDP obtained better function, in the absence of any significant histological differences.

  2. Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation

    PubMed Central

    Guo, Qing; Sebastian, Lois; Sopher, Bryce L.; Miller, Miles W.; Glazner, Gordon W.; Ware, Carol B.; Martin, George M.; Mattson, Mark P.

    1999-01-01

    Although an excitotoxic mechanism of neuronal injury has been proposed to play a role in chronic neurodegenerative disorders such as Alzheimer’s disease, and neurotrophic factors have been put forward as potential therapeutic agents, direct evidence is lacking. Taking advantage of the fact that mutations in the presenilin-1 (PS1) gene are causally linked to many cases of early-onset inherited Alzheimer’s disease, we generated PS1 mutant knock-in mice and directly tested the excitotoxic and neurotrophic hypotheses of Alzheimer’s disease. Primary hippocampal neurons from PS1 mutant knock-in mice exhibited increased production of amyloid β-peptide 42/43 and increased vulnerability to excitotoxicity, which occurred in a gene dosage-dependent manner. Neurons expressing mutant PS1 exhibited enhanced calcium responses to glutamate and increased oxyradical production and mitochondrial dysfunction. Pretreatment with either basic fibroblast growth factor or activity-dependent neurotrophic factor protected neurons expressing mutant PS1 against excitotoxicity. Both basic fibroblast growth factor and activity-dependent neurotrophic factor stabilized intracellular calcium levels and abrogated the increased oxyradical production and mitochondrial dysfunction otherwise caused by the PS1 mutation. Our data indicate that neurotrophic factors can interrupt excitotoxic neurodegenerative cascades promoted by PS1 mutations. PMID:10097174

  3. Brain-derived neurotrophic factor and its clinical implications.

    PubMed

    Bathina, Siresha; Das, Undurti N

    2015-12-10

    Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. It is widely expressed in the CNS, gut and other tissues. BDNF binds to its high affinity receptor TrkB (tyrosine kinase B) and activates signal transduction cascades (IRS1/2, PI3K, Akt), crucial for CREB and CBP production, that encode proteins involved in β cell survival. BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes. Brain-derived neurotrophic factor regulates glucose and energy metabolism and prevents exhaustion of β cells. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Thus, BDNF may be useful in the prevention and management of several diseases including diabetes mellitus.

  4. Delayed onset muscle soreness: Involvement of neurotrophic factors.

    PubMed

    Mizumura, Kazue; Taguchi, Toru

    2016-01-01

    Delayed-onset muscle soreness (DOMS) is quite a common consequence of unaccustomed strenuous exercise, especially exercise containing eccentric contraction (lengthening contraction, LC). Its typical sign is mechanical hyperalgesia (tenderness and movement related pain). Its cause has been commonly believed to be micro-damage of the muscle and subsequent inflammation. Here we present a brief historical overview of the damage-inflammation theory followed by a discussion of our new findings. Different from previous observations, we have observed mechanical hyperalgesia in rats 1-3 days after LC without any apparent microscopic damage of the muscle or signs of inflammation. With our model we have found that two pathways are involved in inducing mechanical hyperalgesia after LC: activation of the B2 bradykinin receptor-nerve growth factor (NGF) pathway and activation of the COX-2-glial cell line-derived neurotrophic factor (GDNF) pathway. These neurotrophic factors were produced by muscle fibers and/or satellite cells. This means that muscle fiber damage is not essential, although it is sufficient, for induction of DOMS, instead, NGF and GDNF produced by muscle fibers/satellite cells play crucial roles in DOMS.

  5. Assembly of Neuronal Connectivity by Neurotrophic Factors and Leucine-Rich Repeat Proteins

    PubMed Central

    Ledda, Fernanda; Paratcha, Gustavo

    2016-01-01

    Proper function of the nervous system critically relies on sophisticated neuronal networks interconnected in a highly specific pattern. The architecture of these connections arises from sequential developmental steps such as axonal growth and guidance, dendrite development, target determination, synapse formation and plasticity. Leucine-rich repeat (LRR) transmembrane proteins have been involved in cell-type specific signaling pathways that underlie these developmental processes. The members of this superfamily of proteins execute their functions acting as trans-synaptic cell adhesion molecules involved in target specificity and synapse formation or working in cis as cell-intrinsic modulators of neurotrophic factor receptor trafficking and signaling. In this review, we will focus on novel physiological mechanisms through which LRR proteins regulate neurotrophic factor receptor signaling, highlighting the importance of these modulatory events for proper axonal extension and guidance, tissue innervation and dendrite morphogenesis. Additionally, we discuss few examples linking this set of LRR proteins to neurodevelopmental and psychiatric disorders. PMID:27555809

  6. Brain-derived neurotrophic factor and neuropsychiatric disorders.

    PubMed

    Autry, Anita E; Monteggia, Lisa M

    2012-04-01

    Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development.

  7. Secretion of nerve growth factor, brain-derived neurotrophic factor, and glial cell-line derived neurotrophic factor in co-culture of four cell types in cerebrospinal fluid-containing medium.

    PubMed

    Feng, Sanjiang; Zhuang, Minghua; Wu, Rui

    2012-12-25

    The present study co-cultured human embryonic olfactory ensheathing cells, human Schwann cells, human amniotic epithelial cells and human vascular endothelial cells in complete culture medium-containing cerebrospinal fluid. Enzyme linked immunosorbent assay was used to detect nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor secretion in the supernatant of co-cultured cells. Results showed that the number of all cell types reached a peak at 7-10 days, and the expression of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor peaked at 9 days. Levels of secreted nerve growth factor were four-fold higher than brain-derived neurotrophic factor, which was three-fold higher than glial cell line-derived neurotrophic factor. Increasing concentrations of cerebrospinal fluid (10%, 20% and 30%) in the growth medium caused a decrease of neurotrophic factor secretion. Results indicated co-culture of human embryonic olfactory ensheathing cells, human Schwann cells, human amniotic epithelial cells and human vascular endothelial cells improved the expression of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor. The reduction of cerebrospinal fluid extravasation at the transplant site after spinal cord injury is beneficial for the survival and secretion of neurotrophic factors from transplanted cells.

  8. Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans

    PubMed Central

    Bezdjian, Aren; Kraaijenga, Véronique J. C.; Ramekers, Dyan; Versnel, Huib; Thomeer, Hans G. X. M.; Klis, Sjaak F. L.; Grolman, Wilko

    2016-01-01

    Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising. PMID:27898033

  9. Progesterone, brain-derived neurotrophic factor and neuroprotection.

    PubMed

    Singh, M; Su, C

    2013-06-03

    While the effects of progesterone in the CNS, like those of estrogen, have generally been considered within the context of reproductive function, growing evidence supports its importance in regulating non-reproductive functions including cognition and affect. In addition, progesterone has well-described protective effects against numerous insults in a variety of cell models, animal models and in humans. While ongoing research in several laboratories continues to shed light on the mechanism(s) by which progesterone and its related progestins exert their effects in the CNS, our understanding is still incomplete. Among the key mediators of progesterone's beneficial effects is the family of growth factors called neurotrophins. Here, we review the mechanisms by which progesterone regulates one important member of the neurotrophin family, brain-derived neurotrophic factor (BDNF), and provides support for its pivotal role in the protective program elicited by progesterone in the brain.

  10. Brain-Derived Neurotrophic Factor: Three Ligands, Many Actions.

    PubMed

    Hempstead, Barbara L

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of a family of neurotrophins which include nerve growth factor, neurotrophin 3, and neurotrophin 4. Studies over the last three decades have identified mature BDNF as a key regulator of neuronal differentiation, structure, and function; actions mediated by the TrkB receptor. More recently identified isoforms which are translated from the bdnf gene, including the uncleaved precursor, pro-BDNF, and the cleaved prodomain, have been found to elicit opposing functions in neurons through the activation of distinct receptors. This work emphasizes the critical roles for all three isoforms of BDNF in modulating neuronal activity that impact complex human behaviors including memory, anxiety, depression, and hyperphagia.

  11. Prolongation of Relaxation Time in Extraocular Muscles With Brain Derived Neurotrophic Factor in Adult Rabbit

    PubMed Central

    Nelson, Krysta R.; Stevens, Shanlee M.; McLoon, Linda K.

    2016-01-01

    Purpose We tested the hypothesis that short-term treatment with brain derived neurotrophic factor (BDNF) would alter the contractile characteristics of rabbit extraocular muscle (EOM). Methods One week after injections of BDNF in adult rabbit superior rectus muscles, twitch properties were determined in treated and control muscles in vitro. Muscles were also examined for changes in mean cross-sectional areas, neuromuscular junction size, and percent of myofibers expressing specific myosin heavy chain isoforms, and sarcoendoplasmic reticulum calcium ATPases (SERCA) 1 and 2. Results Brain derived neurotrophic factor–treated muscles had prolonged relaxation times compared with control muscles. Time to 50% relaxation, time to 100% relaxation, and maximum rate of relaxation were increased by 24%, 27%, and 25%, respectively. No significant differences were seen in time to peak force, twitch force, or maximum rate of contraction. Brain derived neurotrophic factor treatment significantly increased mean cross-sectional areas of slow twitch and tonic myofibers, with increased areas ranging from 54% to 146%. Brain derived neurotrophic factor also resulted in an increased percentage of slow twitch myofibers in the orbital layers, ranging from 54% to 77%, and slow-tonic myofibers, ranging from 44% to 62%. No significant changes were seen SERCA1 or 2 expression or in neuromuscular junction size. Conclusions Short-term treatment with BDNF significantly prolonged the duration and rate of relaxation time and increased expression of both slow-twitch and slow-tonic myosin-expressing myofibers without changes in neuromuscular junctions or SERCA expression. The changes induced by BDNF treatment might have potential therapeutic value in dampening/reducing uncontrolled eye oscillations in nystagmus. PMID:27802489

  12. Role of brain-derived neurotrophic factor in Huntington's disease.

    PubMed

    Zuccato, Chiara; Cattaneo, Elena

    2007-04-01

    Neurotrophic factors are essential contributors to the survival of peripheral and central nervous system (CNS) neurons, and demonstration of their reduced availability in diseased brains indicates that they play a role in various neurological disorders. This paper will concentrate on the role of brain-derived neurotrophic factor (BDNF) in the survival and activity of the neurons that die in Huntington's disease (HD) by reviewing the evidence indicating that it involves profound changes in BDNF levels and that attempts to restore these levels are therapeutically interesting. BDNF is a small dimeric protein that is widely expressed in adult mammalian brain and has been shown to promote the survival of all major neuronal types affected in Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, cortical BDNF production is required for the correct activity of the corticostriatal synapse and the survival of the GABA-ergic medium-sized spiny striatal neurons that die in HD. We will highlight the available data concerning changes in BDNF levels in HD cells, mice and human postmortem samples, describe the molecular evidence underlying this alteration, and review the data concerning the impact of the experimental manipulation of BDNF levels on HD progression. Such studies have revealed a major loss of BDNF protein in the striatum of HD patients which may contribute to the clinical manifestations of the disease. They have also opened up a molecular window into the underlying pathogenic mechanism and new therapeutic perspectives by raising the possibility that one of the mechanisms triggering the reduction in BDNF in HD may also affect the activity of many other neuronal proteins.

  13. Brain-Derived Neurotrophic Factor Gene Expression in Pediatric Bipolar Disorder: Effects of Treatment and Clinical Response

    ERIC Educational Resources Information Center

    Pandey, Ghanshyam N.; Rizavi, Hooriyah S.; Dwivedi, Yogesh; Pavuluri, Mani N.

    2008-01-01

    The study determines the gene expression of brain-derived neurotrophic factor (BDNF) in the lymphocytes of subjects with pediatric bipolar disorder (PBD) before and during treatment with mood stabilizers and in drug-free normal control subjects. Results indicate the potential of BDNF levels as a biomarker for PBD and as a treatment predictor and…

  14. Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia

    PubMed Central

    Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

    2013-01-01

    Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the decrease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance. PMID:25206547

  15. Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia.

    PubMed

    Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

    2013-09-05

    Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the decrease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance.

  16. Regulation of ciliary neurotrophic factor receptor alpha in sciatic motor neurons following axotomy.

    PubMed

    MacLennan, A J; Devlin, B K; Neitzel, K L; McLaurin, D L; Anderson, K J; Lee, N

    1999-01-01

    Spinal motor neurons are one of the few classes of neurons capable of regenerating axons following axotomy. Injury-induced expression of neurotrophic factors and corresponding receptors may play an important role in this rare ability. A wide variety of indirect data suggests that ciliary neurotrophic factor receptor alpha may critically contribute to the regeneration of injured spinal motor neurons. We used immunohistochemistry, in situ hybridization and retrograde tracing techniques to study the regulation of ciliary neurotrophic factor receptor alpha in axotomized sciatic motor neurons. Ciliary neurotrophic factor receptor alpha immunoreactivity, detected with two independent antisera, is increased in a subpopulation of caudal sciatic motor neuron soma one, two and six weeks after sciatic nerve transection and reattachment, while no changes are detected at one day and 15 weeks post-lesion. Ciliary neurotrophic factor receptor alpha messenger RNA levels are augmented in the same classes of neurons following an identical lesion, suggesting that increased synthesis contributes, at least in part, to the additional ciliary neurotrophic factor receptor alpha protein. Separating the proximal and distal nerve stumps with a plastic barrier does not noticeably affect the injury-induced change in ciliary neurotrophic factor receptor alpha regulation, thereby indicating that this injury response is not dependent on signals distal to the lesion traveling retrogradely through the nerve or signals generated by axonal growth through the distal nerve. The prolonged increases in ciliary neurotrophic factor receptor alpha protein and messenger RNA found in regenerating sciatic motor neurons contrast with the responses of non-regenerating central neurons, which are reported to display, at most, a short-lived increase in ciliary neurotrophic factor receptor alpha messenger RNA expression following injury. The present data are the first to demonstrate, in vivo, neuronal regulation of

  17. Role of neurotrophic factors in attention deficit hyperactivity disorder.

    PubMed

    Tsai, Shih-Jen

    2016-11-30

    Neurotrophins (NTs), a family of proteins including nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4, are essential for neural growth, survival, and differentiation, and are therefore crucial for brain development. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by problems of inattention and/or hyperactivity-impulsivity. ADHD is one of the most common childhood onset psychiatric disorders. Studies have suggested that both genetic and environmental factors influence the development of the disorder, although the precise causes of ADHD have not yet been identified. In this review, we assess the role of NTs in the pathophysiology of ADHD. Preclinical evidence indicates that BDNF knockout mice are hyperactive, and an ADHD rodent model exhibited decreased cerebral BDNF levels. Several lines of evidence from clinical studies, including blood level and genetic studies, have suggested that NTs are involved in the pathogenesis of ADHD and in the mechanism of biological treatments for ADHD. Future directions for research are proposed, such as using blood NTs as ADHD biomarkers, optimizing NT genetic studies in ADHD, considering NTs as a link between ADHD and other comorbid mental disorders, and investigating methods for optimally modulating NT signaling to discover novel therapeutics for treating ADHD.

  18. Brain-derived neurotrophic factor, food intake regulation, and obesity.

    PubMed

    Rosas-Vargas, Haydeé; Martínez-Ezquerro, José Darío; Bienvenu, Thierry

    2011-08-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a fundamental role in development and plasticity of the central nervous system (CNS). It is currently recognized as a major participant in the regulation of food intake. Multiple studies have shown that different regulators of appetite such as leptin, insulin and pancreatic polypeptide (PP) potentially exert anorexigenic effects through BDNF. Low circulating levels of BDNF are associated with a higher risk of eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). Strict food restriction reduces BDNF and may trigger binge-eating episodes and weight gain. The existence of mutations that cause haploinsufficiency of BDNF as well as some genetic variants, notably the BDNF p.Val66Met polymorphism, are also associated with the development of obese phenotypes and hyperphagia. However, association of the Met allele with AN and BN, which have different phenotypic characteristics, shows clearly the existence of other relevant factors that regulate eating behavior. This may, in part, be explained by the epigenetic regulation of BDNF through mechanisms like DNA methylation and histone acetylation. Environmental factors, primarily during early development, are crucial to the establishment of these stable but reversible changes that alter the transcriptional expression and are transgenerationally heritable, with potential concomitant effects on the development of eating disorders and body weight control.

  19. Neurotrophic Factors Rescue Basal Forebrain Cholinergic Neurons and Improve Performance on a Spatial Learning Test

    PubMed Central

    Lee, Yu-Shang; Danandeh, Andalib; Baratta, Janie; Lin, Ching-Yi; Yu, Jen; Robertson, Richard T.

    2013-01-01

    This study investigated whether animals sustaining experimental damage to the basal forebrain cholinergic system would benefit from treatment with exogenous neurotrophic factors. Specifically, we set out to determine whether neurotrophic factors would rescue damaged cholinergic neurons and improve behavioral performance on a spatial learning and memory task. Adult rats received bilateral injections of either saline (controls) or 192 IgG-saporin to damage basal forebrain cholinergic neurons (BFCNs). Two weeks later, animals received implants of an Alzet mini-pump connected to cannulae implanted bilaterally in the lateral ventricles. Animals received infusions of nerve growth factor (NGF), neurotrophin 3 (NT3), a combination of NGF and NT3, or a saline control over a 4-week period. Compared to saline-treated controls, animals sustaining saporin-induced damage to BFCNs took significantly more trials to learn a delayed match to position task and also performed more poorly on subsequent tests, with increasing delays between test runs. In contrast, animals infused with neurotrophins after saporin treatment performed significantly better than animals receiving saline infusions; no differences were detected for performance scores among animals infused with NGF, NT3, or a combination of NGF and NT3. Studies of ChAT immunnocytochemical labeling of BFCNs revealed a reduction in the numbers of ChAT-positive neurons in septum, nucleus of diagonal band, and nucleus basalis in animals treated with saporin followed by saline infusions, whereas animals treated with infusions of NGF, NT3 or a combination of NGF and NT3 showed only modest reductions in ChAT-positive neurons. Together, these data support the notion that administration of neurotrophic factors can rescue basal forebrain cholinergic neurons and improve learning and memory performance in rats. PMID:24017996

  20. Neurotrophic factors rescue basal forebrain cholinergic neurons and improve performance on a spatial learning test.

    PubMed

    Lee, Yu-Shang; Danandeh, Andalib; Baratta, Janie; Lin, Ching-Yi; Yu, Jen; Robertson, Richard T

    2013-11-01

    This study investigated whether animals sustaining experimental damage to the basal forebrain cholinergic system would benefit from treatment with exogenous neurotrophic factors. Specifically, we set out to determine whether neurotrophic factors would rescue damaged cholinergic neurons and improve behavioral performance on a spatial learning and memory task. Adult rats received bilateral injections of either saline (controls) or 192 IgG-saporin to damage basal forebrain cholinergic neurons (BFCNs). Two weeks later, animals received implants of an Alzet mini-pump connected to cannulae implanted bilaterally in the lateral ventricles. Animals received infusions of nerve growth factor (NGF), neurotrophin 3 (NT3), a combination of NGF and NT3, or a saline control over a 4-week period. Compared to saline-treated controls, animals sustaining saporin-induced damage to BFCNs took significantly more trials to learn a delayed match to position task and also performed more poorly on subsequent tests, with increasing delays between test runs. In contrast, animals infused with neurotrophins after saporin treatment performed significantly better than animals receiving saline infusions; no differences were detected for performance scores among animals infused with NGF, NT3, or a combination of NGF and NT3. Studies of ChAT immunnocytochemical labeling of BFCNs revealed a reduction in the numbers of ChAT-positive neurons in septum, nucleus of diagonal band, and nucleus basalis in animals treated with saporin followed by saline infusions, whereas animals treated with infusions of NGF, NT3 or a combination of NGF and NT3 showed only modest reductions in ChAT-positive neurons. Together, these data support the notion that administration of neurotrophic factors can rescue basal forebrain cholinergic neurons and improve learning and memory performance in rats.

  1. Brain-derived neurotrophic factor levels in Alzheimer's disease.

    PubMed

    O'Bryant, Sid E; Hobson, Valerie; Hall, James R; Waring, Stephen C; Chan, Wenyan; Massman, Paul; Lacritz, Laura; Cullum, C Munro; Diaz-Arrastia, Ramon

    2009-01-01

    The current search for biomarkers that are diagnostic and/or prognostic of Alzheimer's disease (AD) is of vital importance given the rapidly aging population. It was recently reported that brain-derived neurotrophic factor (BDNF) fluctuated according to AD severity, suggesting that BDNF might have utility for diagnostics and monitoring of therapeutic efficacy. The current study sought to examine whether BDNF levels varied according to AD severity, as previously reported. There were 196 participants (Probable AD, n = 98; Controls, n = 98) in the Texas Alzheimer's Research Consortium (TARC) Longitudinal Research Cohort available for analysis. BDNF levels were assayed via multiplex immunoassay. Regression analyses were utilized to examine the relation between BDNF levels, Mini-Mental Status Examination, and Clinical Dementia Rating scores adjusting for age and gender. In adjusted models, BDNF levels did not distinguish between AD patients and normal controls and did not significantly predict AD severity or global cognitive functioning. In conclusion, these findings do not support the notion that BDNF serves as a diagnostic marker for AD or disease severity. It is likely that the most accurate approach to identifying biomarkers of AD will be through an algorithmic approach that combines multiple markers reflective of various pathways.

  2. Chronic elevation of brain-derived neurotrophic factor by ampakines.

    PubMed

    Lauterborn, Julie C; Truong, Giang S; Baudry, Michel; Bi, Xiaoning; Lynch, Gary; Gall, Christine M

    2003-10-01

    The ampakine CX614 positively modulates alpha-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor-gated currents and increases brain-derived neurotrophic factor (BDNF) expression. In rat hippocampal slice cultures, CX614 rapidly increases BDNF gene expression but with time, mRNA levels fall despite the continued presence of active drug. The present study examined this apparent refractory period and the possibility that spaced ampakine treatments could sustain elevated BDNF protein levels. In cultured hippocampal slices, CX614, a second ampakine CX546, and the cholinergic agonist carbachol each increased BDNF mRNA levels with acute (3-h) treatment. After 4-day pretreatment with CX614, fresh ampakine (CX614 or CX546) did not induce BDNF mRNA, whereas carbachol did. Western blots confirmed that after an extended period of ampakine treatment, AMPA receptor protein levels are indeed reduced, suggesting that with longer treatments receptor down-regulation mediates ampakine insensitivity. Finally, using a "24-h on/24-h off" CX614 treatment protocol, the ampakine refractory state was circumvented, BDNF mRNA was induced with each ampakine application, and elevated BDNF protein levels were maintained through 5 days in vitro. These results suggest that spaced ampakine treatments can be used to sustain elevated neurotrophin levels and to test the utility of this manipulation for neuroprotection by endogenous neurotrophins.

  3. Tianeptine increases brain-derived neurotrophic factor expression in the rat amygdala.

    PubMed

    Reagan, Lawrence P; Hendry, Robert M; Reznikov, Leah R; Piroli, Gerardo G; Wood, Gwendolyn E; McEwen, Bruce S; Grillo, Claudia A

    2007-06-22

    Chronic restraint stress affects hippocampal and amygdalar synaptic plasticity as determined by electrophysiological, morphological and behavioral measures, changes that are inhibited by some but not all antidepressants. The efficacy of some classes of antidepressants is proposed to involve increased phosphorylation of cAMP response element binding protein (CREB), leading to increased expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). Conversely, some studies suggest that acute and chronic stress downregulate BDNF expression and activity. Accordingly, the aim of the current study was to examine total and phosphorylated CREB (pCREB), as well as BDNF mRNA and protein levels in the hippocampus and amygdala of rats subjected to chronic restraint stress in the presence and absence of the antidepressant tianeptine. In the hippocampus, chronic restraint stress increased pCREB levels without affecting BDNF mRNA or protein expression. Tianeptine administration had no effect upon these measures in the hippocampus. In the amygdala, BDNF mRNA expression was not modulated in chronic restraint stress rats given saline in spite of increased pCREB levels. Conversely, BDNF mRNA levels were increased in the amygdala of chronic restraint stress/tianeptine rats in the absence of changes in pCREB levels when compared to non-stressed controls. Amygdalar BDNF protein increased while pCREB levels decreased in tianeptine-treated rats irrespective of stress conditions. Collectively, these results demonstrate that tianeptine concomitantly decreases pCREB while increasing BDNF expression in the rat amygdala, increases in neurotrophic factor expression that may participate in the enhancement of amygdalar synaptic plasticity mediated by tianeptine.

  4. Beta hairpin peptide hydrogels as an injectable solid vehicle for neurotrophic growth factor delivery

    PubMed Central

    Lindsey, Stephan; Piatt, Joseph H.; Worthington, Peter; Sönmez, Cem; Satheye, Sameer; Schneider, Joel P.; Pochan, Darrin J.; Langhans, Sigrid A.

    2016-01-01

    There is intense interest in developing novel methods for the sustained delivery of low levels of clinical therapeutics. MAX8 is a peptide-based beta-hairpin hydrogel that has unique shear thinning properties that allow for immediate rehealing after the removal of shear forces, making MAX8 an excellent candidate for injectable drug delivery at a localized injury site. The current studies examined the feasibility of using MAX8 as a delivery system for Nerve Growth Factor (NGF) and Brain-derived neurotrophic factor (BDNF), two neurotrophic growth factors currently used in experimental treatments of spinal cord injuries. Experiments determined that encapsulation of NGF and BDNF within MAX8 did not negatively impact gel formation or rehealing and that shear thinning did not result in immediate growth factor release. We found that increased NGF/BDNF dosages increased the amount and rate of growth factor release and that NGF/BDNF release was inversely related to the concentration of MAX8, indicating that growth factor release can be tuned by adjusting MAX8 concentrations. Encapsulation within MAX8 protected NGF and BDNF from in vitro degradation for up to 28 days. Released NGF resulted in the formation of neurite-like extensions in PC12 pheochromocytoma cells, demonstrating that NGF remains biologically active after release from encapsulation. Direct physical contact of PC12 cells with NGF-containing hydrogel did not inhibit neurite-like extension formation. On a molecular level, encapsulated growth factors activated the NGF/BDNF signaling pathways. Taken together, our data show MAX8 acts as a time-release gel, continually releasing low levels of growth factor over 21 days. MAX8 allows for greater dosage control and sustained therapeutic growth factor delivery, potentially alleviating side effects and improving the efficacy of current therapies. PMID:26225909

  5. Brain-derived neurotrophic factor modulates the dopaminergic network in the rat retina after axotomy.

    PubMed

    Lee, Eun-Jin; Song, Myoung-Chul; Kim, Hyun-Ju; Lim, Eun-Jin; Kim, In-Beom; Oh, Su-Ja; Moon, Jung-I L; Chun, Myung-Hoon

    2005-11-01

    Dopaminergic cells in the retina express the receptor for brain-derived neurotrophic factor (BDNF), which is the neurotrophic factor that influences the plasticity of synapses in the central nervous system. We sought to determine whether BDNF influences the network of dopaminergic amacrine cells in the axotomized rat retina, by immunocytochemistry with an anti-tyrosine hydroxylase (TH) antiserum. In the control retina, we found two types of TH-immunoreactive amacrine cells, type I and type II, in the inner nuclear layer adjacent to the inner plexiform layer (IPL). The type I amacrine cell varicosities formed ring-like structures in contact with AII amacrine cell somata in stratum 1 of the IPL. In the axotomized retinas, TH-labeled processes formed loose networks of fibers, unlike the dense networks in the control retina, and the ring-like structures were disrupted. In the axotomized retinas treated with BDNF, strong TH-immunoreactive varicosities were present in stratum 1 of the IPL and formed ring-like structures. Our data suggest that BDNF affects the expression of TH immunoreactivity in the axotomized rat retina and may therefore influence the retinal dopaminergic system.

  6. Novel combinatorial screening identifies neurotrophic factors for selective classes of motor neurons.

    PubMed

    Schaller, Sébastien; Buttigieg, Dorothée; Alory, Alysson; Jacquier, Arnaud; Barad, Marc; Merchant, Mark; Gentien, David; de la Grange, Pierre; Haase, Georg

    2017-03-21

    Numerous neurotrophic factors promote the survival of developing motor neurons but their combinatorial actions remain poorly understood; to address this, we here screened 66 combinations of 12 neurotrophic factors on pure, highly viable, and standardized embryonic mouse motor neurons isolated by a unique FACS technique. We demonstrate potent, strictly additive, survival effects of hepatocyte growth factor (HGF), ciliary neurotrophic factor (CNTF), and Artemin through specific activation of their receptor complexes in distinct subsets of lumbar motor neurons: HGF supports hindlimb motor neurons through c-Met; CNTF supports subsets of axial motor neurons through CNTFRα; and Artemin acts as the first survival factor for parasympathetic preganglionic motor neurons through GFRα3/Syndecan-3 activation. These data show that neurotrophic factors can selectively promote the survival of distinct classes of embryonic motor neurons. Similar studies on postnatal motor neurons may provide a conceptual framework for the combined therapeutic use of neurotrophic factors in degenerative motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and spinobulbar muscular atrophy.

  7. Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors.

    PubMed

    Gray, J D; Milner, T A; McEwen, B S

    2013-06-03

    Brain-derived neurotrophic factor (BDNF) is a secreted protein that has been linked to numerous aspects of plasticity in the central nervous system (CNS). Stress-induced remodeling of the hippocampus, prefrontal cortex and amygdala is coincident with changes in the levels of BDNF, which has been shown to act as a trophic factor facilitating the survival of existing and newly born neurons. Initially, hippocampal atrophy after chronic stress was associated with reduced BDNF, leading to the hypothesis that stress-related learning deficits resulted from suppressed hippocampal neurogenesis. However, recent evidence suggests that BDNF also plays a rapid and essential role in regulating synaptic plasticity, providing another mechanism through which BDNF can modulate learning and memory after a stressful event. Numerous reports have shown BDNF levels are highly dynamic in response to stress, and not only vary across brain regions but also fluctuate rapidly, both immediately after a stressor and over the course of a chronic stress paradigm. Yet, BDNF alone is not sufficient to effect many of the changes observed after stress. Glucocorticoids and other molecules have been shown to act in conjunction with BDNF to facilitate both the morphological and molecular changes that occur, particularly changes in spine density and gene expression. This review briefly summarizes the evidence supporting BDNF's role as a trophic factor modulating neuronal survival, and will primarily focus on the interactions between BDNF and other systems within the brain to facilitate synaptic plasticity. This growing body of evidence suggests a more nuanced role for BDNF in stress-related learning and memory, where it acts primarily as a facilitator of plasticity and is dependent upon the coactivation of glucocorticoids and other factors as the determinants of the final cellular response.

  8. Reduced serum levels of oestradiol and brain derived neurotrophic factor in both diabetic women and HFD-feeding female mice.

    PubMed

    Zhang, Yi; Zhang, Shan-Wen; Khandekar, Neeta; Tong, Shi-Fei; Yang, He-Qin; Wang, Wan-Ru; Huang, Xu-Feng; Song, Zhi-Yuan; Lin, Shu

    2017-04-01

    The estrogen levels in the pre and post menstrual phases interact with brain-derived neurotrophic factor in a complex manner, which influences the overall state of the body. To study the role of oestradiol and brain-derived neurotrophic factor in modulating obesity related type 2 diabetes and the interactions between two factors, we enrolled 15 diabetic premenopausal women and 15 diabetic postmenopausal women respectively, the same number of healthy pre and postmenopausal women were recruited as two control groups. The fasting blood glucose, insulin, lipids, estrogen, and brain-derived neurotrophic factor levels were measured through clinical tests. Additionally, we set up obese female mouse model to mimic human trial stated above, to verify the relationship between estrogen and brain-derived neurotrophic factor. Our findings revealed that there is a moderately positive correlation between brain-derived neurotrophic factor and oestradiol in females, and decreased brain-derived neurotrophic factor may worsen impaired insulin function. The results further confirmed that high fat diet-fed mice which exhibited impaired glucose tolerance, showed lower levels of oestradiol and decreased expression of brain-derived neurotrophic factor mRNA in the ventromedial hypothalamus. The level of brain-derived neurotrophic factor reduced on condition that the level of oestradiol is sufficiently low, such as women in postmenopausal period, which aggravates diabetes through feeding-related pathways. Increasing the level of brain-derived neurotrophic factor may help to alleviate the progression of the disease in postmenopausal women with diabetes.

  9. Triggering neurotrophic factor actions through adenosine A2A receptor activation: implications for neuroprotection

    PubMed Central

    Sebastião, Ana M; Ribeiro, Joaquim A

    2009-01-01

    G protein coupled receptors and tropomyosin-related kinase (Trk) receptors have distinct structure and transducing mechanisms; therefore, cross-talk among them was unexpected. Evidence has, however, accumulated showing that tonic adenosine A2A receptor activity is a required step to allow synaptic actions of neurotrophic factors, namely upon synaptic transmission at both pre- and post-synaptic level as well as upon synaptic plasticity. An enhancement of A2A receptor tonus upon ageing may partially compensate the loss of TrkB receptors, rescuing to certain degree the facilitatory action of brain derived neurotrophic factor in aged animals, which might prove particularly relevant in the prevention of neurodegeneration upon ageing. A2A receptors also trigger synaptic actions of other neurotrophic factors, such as glial derived neurotrophic factor at dopaminergic striatal nerve endings. The growing evidence that tonic adenosine A2A receptor activity is a crucial step to allow actions of neurotrophic factors in neurones will be reviewed and discussed in the light of therapeutic strategies for neurodegenerative diseases. PMID:19508402

  10. Are the neurotrophic factors a suitable therapeutic target for the prevention of epileptogenesis?

    PubMed

    Simonato, Michele; Zucchini, Silvia

    2010-07-01

    Neurotrophic factors are involved in the survival of neurons as well as in the proliferation and differentiation of neuronal precursors. Therefore, modulating their levels in lesion areas may exert favorable effects on seizure-induced damage. However, it is unclear if damage limitation or repair may prevent epileptogenesis; it is also uncertain which neurotrophic factor should be administered for limiting or repairing damage while avoiding possible proepileptic effects. We used viral vectors to locally supplement fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF), when an epileptogenic damage was already in place. These vectors were tested in the pilocarpine model of status epilepticus-induced neurodegeneration and epileptogenesis. FGF-2/BDNF expressing vectors increased neuronogenesis, limited neuronal damage, and reduced the occurrence of spontaneous seizures. These findings are discussed with consideration of the hurdles that will have to be overcome before clinical application.

  11. Vascular function and brain-derived neurotrophic factor: The functional capacity factor.

    PubMed

    Alomari, Mahmoud A; Khabour, Omar F; Maikano, Abubakar; Alawneh, Khaldoon

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) is essential for neurocognitive function. This study aims at establishing a plausible link between level of serum BDNF, functional capacity (FC), and vascular function in 181 young (age 25.5±9.1 years old), apparently healthy adults. Fasting blood samples were drawn from participants' antecubital veins into plain glass tubes while they were in a sitting position to evaluate serum BDNF using enzyme-linked immunosorbent assay (ELISA). Mercury-in-silastic strain-gauge plethysmography was used to determine arterial function indices, blood flow and vascular resistance at rest and following 5 minutes of arterial ischemia. The 6-minute walk distance (6MWD) test was used to determine FC, according to the American Thoracic Society Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories guidelines. It was conducted in an enclosed corridor on a flat surface with a circular track 33 meters long. The walking course was demarcated with bright colored cones. The 6MWD correlated with BDNF (r=0.3, p=0.000), as well as with forearm blood inflow (r=0.5, p=0.000) and vascular resistance (r = -0.4, p=0.000). Subsequent comparison showed that BDNF and blood inflow were greater (p<0.05) while vascular resistance was less (p<0.05) in participants who achieved a longer 6MWD. Similarly, BDNF correlated with forearm blood inflow (r=0.4, p=0.000) and vascular resistance (r = -0.4, p=0.000). Subsequent comparison showed improved vascular function (p<0.05) in the participants with greater BDNF. In conclusion, these findings might suggest that improved vascular function in individuals with greater FC is mediated, at least partially, by an enhanced serum BDNF level.

  12. Brain derived neurotrophic factor inhibits apoptosis in enteric glia during gut inflammation

    PubMed Central

    Steinkamp, Martin; Schulte, Nadine; Spaniol, Ulrike; Pflüger, Carolin; Hartmann, Christoph; Kirsch, Joachim; von Boyen, Georg

    2012-01-01

    Summary Background Enteric glia cells (EGCs) are essential for the integrity of the bowel. A loss of EGCs leads to a severe inflammation of the intestines. As a diminished EGC network is postulated in Crohn’s disease (CD), we aimed to investigate if EGCs could be a target of apoptosis during inflammation in CD, which can be influenced by Brain derived neurotrophic factor (BDNF). Material/Methods GFAP, BDNF and cCaspase-3 were detected in the gut of patients with CD. Primary EGC cultures were established and cultivated. Tyrosine receptor kinase (TrkB) receptors on these cells were investigated by western blot and immunofluorescence. Rate of apoptosis was induced by tumor necrosis factor (TNF-α) and interferon (IFN-γ). Apoptosis was determined by a fluorometric caspase 3/7 activation assay after preincubation of these cells with BDNF or neutralizing anti-BDNF antibodies. Results Mucosal GFAP-positive EGCs undergo apoptosis revealed by cCaspase-3 in the gut of patients with CD expressing BDNF highly. The combination of TNF-α and IFN-γ was able to induce apoptosis in primary EGCs, whereas these factors alone did not. Brain derived neurotrophic factor (BDNF) attenuate glia cell apoptosis to a small extent, but neutralizing antibodies against BDNF dramatically increased apoptosis. Conclusions Mucosal EGC apoptosis is an important finding in the gut of patients with CD. Proinflammatory cytokines, which are highly increased in CD, induce EGC apoptosis, whereas the neurotrophin BDNF might be protective for EGC. Since EGCs are implicated in the maintenance of the enteric mucosal integrity, EGC apoptosis may contribute to the pathophysiological changes in CD. PMID:22460084

  13. Aerobic exercise interacts with neurotrophic factors to predict cognitive functioning in adolescents.

    PubMed

    Lee, Tatia M C; Wong, Mark Lawrence; Lau, Benson Wui-Man; Lee, Jada Chia-Di; Yau, Suk-Yu; So, Kwok-Fai

    2014-01-01

    Recent findings have suggested that aerobic exercise may have a positive effect on brain functioning, in addition to its well-recognized beneficial effects on human physiology. This study confirmed the cognitive effects of aerobic exercise on the human brain. It also examined the relationships between exercise and the serum levels of neurotrophic factors (BDNF, IGI-1, and VEGF). A total of 91 healthy teens who exercised regularly participated in this study. A between-group design was adopted to compare cognitive functioning subserved by the frontal and temporal brain regions and the serum levels of neurotrophic factors between 45 regular exercisers and 46 matched controls. The exercisers performed significantly better than the controls on the frontal and temporal functioning parameters measured. This beneficial cognitive effect was region-specific because no such positive cognitive effect on task-tapping occipital functioning was observed. With respect to the serum levels of the neurotrophic factors, a negative correlation between neurotrophic factors (BDNF and VEGF) with frontal and medial-temporal lobe function was revealed. Furthermore, the levels of BDNF and VEGF interacted with exercise status in predicting frontal and temporal lobe function. This is the first report of the interaction effects of exercise and neurotrophic factors on cognitive functioning. Herein, we report preliminary evidence of the beneficial effects of regular aerobic exercise in improving cognitive functions in teens. These beneficial effects are region-specific and are associated with the serum levels of neurotrophic factors. Our findings lay the path for future studies looking at ways to translate these beneficial effects to therapeutic strategies for adolescents.

  14. Cell-based delivery of brain-derived neurotrophic factor in experimental allergic encephalomyelitis.

    PubMed

    Makar, Tapas K; Nimmagadda, Vamshi K C; Trisler, David; Bever, Christopher T

    2014-08-01

    Brain-derived neurotrophic factor (BDNF) is a pleiotropic cytokine with neuroprotective properties that has been identified as a potential therapeutic agent for diseases of the central nervous system (CNS). The use of BDNF has been limited by a short serum half-life and poor penetration of the blood-brain barrier. To address this limitation we have explored cell-based approaches to delivery. We have used experimental allergic encephalomyelitis (EAE), an inflammatory disease of the CNS, as a model system. We engineered hematopoietic stem cells to produce BDNF to determine the feasibility and effectiveness of cell-based delivery of BDNF into the CNS in EAE. We review those studies here.

  15. Parasite-Derived Neurotrophic Factor/trans-Sialidase of Trypanosoma cruzi Links Neurotrophic Signaling to Cardiac Innate Immune Response

    PubMed Central

    Salvador, Ryan; Aridgides, Daniel

    2014-01-01

    The Chagas' disease parasite Trypanosoma cruzi elicits a potent inflammatory response in acutely infected hearts that keeps parasitism in check and triggers cardiac abnormalities. A most-studied mechanism underlying innate immunity in T. cruzi infection is Toll-like receptor (TLR) activation by lipids and other parasite molecules. However, yet-to-be-identified pathways should exist. Here, we show that T. cruzi strongly upregulates monocyte chemoattractant protein 1 (MCP-1)/CCL2 and fractalkine (FKN)/CX3CL1 in cellular and mouse models of heart infection. Mechanistically, upregulation of MCP-1 and FKN stems from the interaction of parasite-derived neurotrophic factor (PDNF)/trans-sialidase with neurotrophic receptors TrkA and TrkC, as assessed by pharmacological inhibition, neutralizing antibodies, and gene silencing studies. Administration of a single dose of intravenous PDNF to naive mice results in a dose-dependent increase in MCP-1 and FKN in the heart and liver with pulse-like kinetics that peak at 3 h postinjection. Intravenous PDNF also augments MCP-1 and FKN in TLR signaling-deficient MyD88-knockout mice, underscoring the MyD88-independent action of PDNF. Although single PDNF injections do not increase MCP-1 and FKN receptors, multiple PDNF injections at short intervals up the levels of receptor transcripts in the heart and liver, suggesting that sustained PDNF triggers cell recruitment at infection sites. Thus, given that MCP-1 and FKN are chemokines essential to the recruitment of immune cells to combat inflammation triggers and to enhance tissue repair, our findings uncover a new mechanism in innate immunity against T. cruzi infection mediated by Trk signaling akin to an endogenous inflammatory and fibrotic pathway resulting from cardiomyocyte-TrkA recognition by matricellular connective tissue growth factor (CTGF/CCN2). PMID:24935974

  16. Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.

    PubMed

    Schulz, Karl-Heinz; Gold, Stefan M; Witte, Jan; Bartsch, Katharina; Lang, Undine E; Hellweg, Rainer; Reer, Rüdiger; Braumann, Klaus-Michael; Heesen, Christoph

    2004-10-15

    In recent years it has become clear that multiple sclerosis (MS) patients benefit from physical exercise as performed in aerobic training but little is known about the effect on functional domains and physiological factors mediating these effects. We studied immunological, endocrine and neurotrophic factors as well as coordinative function and quality of life during an 8-week aerobic bicycle training in a waitlist control design. In the immune-endocrine study (1) 28 patients were included, the coordinative extension study (2) included 39 patients. Training was performed at 60% VO(2)max after determining individual exertion levels through step-by-step ergometry. Metabolic (lactate), endocrine (cortisol, adrendocortico-releasing hormone, epinephrine, norepinephrine), immune (IL-6, soluble IL-6 receptor), and neurotrophic (brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF)) parameters were compared from a prestudy and a poststudy endurance test at 60% VO(2)max for 30 min. In study (1), lowered lactate levels despite higher workload levels indicated a training effect. Disease-specific quality of life (as measured by the Hamburg Quality of Life Questionnaire for Multiple Sclerosis, HAQUAMS) significantly increased in the training group. No significant training effects were seen for endocrine and immune parameters or neurotrophins. In study (2), two out of three coordinative parameters of the lower extremities were significantly improved. In summary, low-level aerobic training in MS improves not only quality of life but also coordinative function and physical fitness.

  17. Identification of Mesencephalic Astrocyte-Derived Neurotrophic Factor as a Novel Neuroprotective Factor for Retinal Ganglion Cells

    PubMed Central

    Gao, Feng-Juan; Wu, Ji-Hong; Li, Ting-Ting; Du, Shan-Shan; Wu, Qiang

    2017-01-01

    Mesencephalic astrocyte-derived neurotrophic factor (MANF), a newly discovered secreted neurotrophic factor, has been proven to not only protect dopaminergic neurons and other cell types but also regulate neuroinflammation and the immune response to promote tissue repair and regeneration. However, to date, there is no information regarding the relationship between MANF and retinal ganglion cells (RGCs) in the eye. In the current study, we first determined the expression of MANF in the retina and vitreous. Then, we examined the effect of MANF on RGCs using both in vivo and in vitro models and simultaneously explored the underlying neuroprotective mechanisms of MANF. Finally, we measured the concentrations of MANF in the vitreous of patients with different retinopathies. We demonstrated that MANF was highly expressed in RGCs and that exogenous MANF could protect RGCs from hypoxia-induced cell injury and apoptosis both in vitro and in vivo by preventing endoplasmic reticulum stress-mediated apoptosis. Furthermore, MANF can be detected in the vitreous humor, and the concentration changed under pathological conditions. Our results provide important evidence that MANF may be a potential therapeutic protein for a range of retinal pathologies in either the preclinical stage or after diagnosis to promote the survival of RGCs. Vitreous MANF may be a promising protein biomarker for the indirect assessment of retinal disorders, which could provide indirect evidence of retinal pathology. PMID:28367115

  18. Polylactic-co-glycolic acid microspheres containing three neurotrophic factors promote sciatic nerve repair after injury.

    PubMed

    Zhao, Qun; Li, Zhi-Yue; Zhang, Ze-Peng; Mo, Zhou-Yun; Chen, Shi-Jie; Xiang, Si-Yu; Zhang, Qing-Shan; Xue, Min

    2015-09-01

    A variety of neurotrophic factors have been shown to repair the damaged peripheral nerve. However, in clinical practice, nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor are all peptides or proteins that may be rapidly deactivated at the focal injury site; their local effective concentration time following a single medication cannot meet the required time for spinal axons to regenerate and cross the glial scar. In this study, we produced polymer sustained-release microspheres based on the polylactic-co-glycolic acid copolymer; the microspheres at 300-μm diameter contained nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor. Six microspheres were longitudinally implanted into the sciatic nerve at the anastomosis site, serving as the experimental group; while the sciatic nerve in the control group was subjected to the end-to-end anastomosis using 10/0 suture thread. At 6 weeks after implantation, the lower limb activity, weight of triceps surae muscle, sciatic nerve conduction velocity and the maximum amplitude were obviously better in the experimental group than in the control group. Compared with the control group, more regenerating nerve fibers were observed and distributed in a dense and ordered manner with thicker myelin sheaths in the experimental group. More angiogenesis was also visible. Experimental findings indicate that polylactic-co-glycolic acid composite microspheres containing nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor can promote the restoration of sciatic nerve in rats after injury.

  19. Polylactic-co-glycolic acid microspheres containing three neurotrophic factors promote sciatic nerve repair after injury

    PubMed Central

    Zhao, Qun; Li, Zhi-yue; Zhang, Ze-peng; Mo, Zhou-yun; Chen, Shi-jie; Xiang, Si-yu; Zhang, Qing-shan; Xue, Min

    2015-01-01

    A variety of neurotrophic factors have been shown to repair the damaged peripheral nerve. However, in clinical practice, nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor are all peptides or proteins that may be rapidly deactivated at the focal injury site; their local effective concentration time following a single medication cannot meet the required time for spinal axons to regenerate and cross the glial scar. In this study, we produced polymer sustained-release microspheres based on the polylactic-co-glycolic acid copolymer; the microspheres at 300-μm diameter contained nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor. Six microspheres were longitudinally implanted into the sciatic nerve at the anastomosis site, serving as the experimental group; while the sciatic nerve in the control group was subjected to the end-to-end anastomosis using 10/0 suture thread. At 6 weeks after implantation, the lower limb activity, weight of triceps surae muscle, sciatic nerve conduction velocity and the maximum amplitude were obviously better in the experimental group than in the control group. Compared with the control group, more regenerating nerve fibers were observed and distributed in a dense and ordered manner with thicker myelin sheaths in the experimental group. More angiogenesis was also visible. Experimental findings indicate that polylactic-co-glycolic acid composite microspheres containing nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor can promote the restoration of sciatic nerve in rats after injury. PMID:26604912

  20. Brain-derived neurotrophic factor deficiency restricts proliferation of oligodendrocyte progenitors following cuprizone-induced demyelination.

    PubMed

    Tsiperson, Vladislav; Huang, Yangyang; Bagayogo, Issa; Song, Yeri; VonDran, Melissa W; DiCicco-Bloom, Emanuel; Dreyfus, Cheryl F

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that through its neurotrophic tyrosine kinase, receptor, type 2 (TrkB) receptor, increases 5-bromo-2-deoxyuridine incorporation in oligodendrocyte progenitor cells (OPCs) in culture. Roles in vivo are less well understood; however, increases in numbers of OPCs are restricted in BDNF+/- mice following cuprizone-elicited demyelination. Here, we investigate whether these blunted increases in OPCs are associated with changes in proliferation. BDNF+/+ and BDNF+/- mice were fed cuprizone-containing or control feed. To assess effects on OPC numbers, platelet-derived growth factor receptor alpha (PDGFRα)+ or NG2+ cells were counted. To monitor DNA synthesis, 5-ethynyl-2'-deoxyuridine (EdU) was injected intraperitoneally and colocalized with PDGFRα+ cells. Alternatively, proliferating cell nuclear antigen (PCNA) was colocalized with PDGFRα or NG2. Labeling indices were determined in the BDNF+/+ and BDNF+/- animals. After 4 or 5 weeks of control feed, BDNF+/- mice exhibit similar numbers of OPCs compared with BDNF+/+ animals. The labeling indices for EdU and PCNA also were not significantly different, suggesting that neither the DNA synthesis phase (S phase) nor the proliferative pool size was different between genotypes. In contrast, when mice were challenged by cuprizone for 4 or 5 weeks, increases in OPCs observed in BDNF+/+ mice were reduced in the BDNF+/- mice. This difference in elevations in cell number was accompanied by decreases in EdU labeling and PCNA labeling without changes in cell death, indicating a reduction in the DNA synthesis and the proliferative pool. Therefore, levels of BDNF influence the proliferation of OPCs resulting from a demyelinating lesion.

  1. Absence of hippocampal mossy fiber sprouting in transgenic mice overexpressing brain-derived neurotrophic factor.

    PubMed

    Qiao, X; Suri, C; Knusel, B; Noebels, J L

    2001-05-01

    Excess neuronal activity upregulates the expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in adult hippocampus. Nerve growth factor has been shown to contribute the induction of aberrant hippocampal mossy fiber sprouting in the inner molecular layer of the dentate gyrus, however the role of prolonged brain-derived neurotrophic factor exposure is uncertain. We examined the distribution and plasticity of mossy fibers in transgenic mice with developmental overexpression of brain-derived neurotrophic factor. Despite 2--3-fold elevated BDNF levels in the hippocampus sufficient to increase the intensity of neuropeptide Y immunoreactivity in interneurons, no visible changes in mossy fiber Timm staining patterns were observed in the inner molecular layer of adult mutant hippocampus compared to wild-type mice. In addition, no changes of the mRNA expression of two growth-associated proteins, GAP-43 and SCG-10 were found. These data suggest that early and persistent elevations of brain-derived neurotrophic factor in granule cells are not sufficient to elicit this pattern of axonal plasticity in the hippocampus.

  2. Interplay Between Nitric Oxide and Brain-Derived Neurotrophic Factor in Neuronal Plasticity.

    PubMed

    Biojone, Caroline; Casarotto, Plinio Cabrera; Joca, Samia Regiane; Castrén, Eero

    2015-01-01

    Nitric oxide is a gaseous neuromodulator that displays a core role in several neuronal processes. Beyond regulating the release of neurotransmitters, nitric oxide also plays a role in cell differentiation and maturation in the central nervous system. Although the mode of action of nitric oxide is not fully understood, it involves the activation of soluble guanylate cyclase as well as the nitration and S-nitrosylation of specific amino acid residues in other proteins. Brain-derived neurotrophic factor is a member of neurotrophic factor family and, acting through its receptor tropomyosinrelated kinase B, increases the production of nitric oxide, modulates neuronal differentiation and survival, and plays a crucial role in synaptic plasticity, such as long-term potentiation. Furthermore, nitric oxide is an important regulator of the production of these factors. The aim of the present review is to present a condensed view of the evidence related to the interaction between nitric oxide and brain-derived neurotrophic factor. Additionally, we conducted bioinformatics analysis based on the amino acid sequences of brain-derived neurotrophic factor and tropomyosin-related kinase receptors, and proposed that nitric oxide might nitrate/S-nitrosylate these proteins. Thus, we suggest a putative direct mode of action between these molecules to be further explored.

  3. Effect of glatiramer acetate on peripheral blood brain-derived neurotrophic factor and phosphorylated TrkB levels in relapsing-remitting multiple sclerosis.

    PubMed

    Vacaras, Vitalie; Major, Zsigmond Z; Muresanu, Dafin F; Krausz, Tibor L; Marginean, Ioan; Buzoianu, Dana A

    2014-01-01

    Glatiramer acetate (GA) is one of the most widely used disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis; is assumed to have inductor effects on neurotrophic factor expression. One of these neurotrophic factor systems is the brain-derived neurotrophic factor (BDNF)/receptor tyrosine kinase B (TrkB) pathway. Peripheral blood is thought to contain soluble BDNF, and some blood cells express TrkB. We attempted to determine whether GA treatment leads to changes in plasma BDNF levels and TrkB activation. Such a phenomenon are relapsing-remitting multiple sclerosis patients is significantly reduced; GA treatment is not influencing peripheral BDNF levels, after one year of sustained therapy, not from the point of view of total free BDNF nor the phosphorylated TrkB.

  4. Decreased plasma brain-derived neurotrophic factor and vascular endothelial growth factor concentrations during military training.

    PubMed

    Suzuki, Go; Tokuno, Shinichi; Nibuya, Masashi; Ishida, Toru; Yamamoto, Tetsuo; Mukai, Yasuo; Mitani, Keiji; Tsumatori, Gentaro; Scott, Daniel; Shimizu, Kunio

    2014-01-01

    Decreased concentrations of plasma brain-derived neurotrophic factor (BDNF) and serum BDNF have been proposed to be a state marker of depression and a biological indicator of loaded psychosocial stress. Stress evaluations of participants in military mission are critically important and appropriate objective biological parameters that evaluate stress are needed. In military circumstances, there are several problems to adopt plasma BDNF concentration as a stress biomarker. First, in addition to psychosocial stress, military missions inevitably involve physical exercise that increases plasma BDNF concentrations. Second, most participants in the mission do not have adequate quality or quantity of sleep, and sleep deprivation has also been reported to increase plasma BDNF concentration. We evaluated plasma BDNF concentrations in 52 participants on a 9-week military mission. The present study revealed that plasma BDNF concentration significantly decreased despite elevated serum enzymes that escaped from muscle and decreased quantity and quality of sleep, as detected by a wearable watch-type sensor. In addition, we observed a significant decrease in plasma vascular endothelial growth factor (VEGF) during the mission. VEGF is also neurotrophic and its expression in the brain has been reported to be up-regulated by antidepressive treatments and down-regulated by stress. This is the first report of decreased plasma VEGF concentrations by stress. We conclude that decreased plasma concentrations of neurotrophins can be candidates for mental stress indicators in actual stressful environments that include physical exercise and limited sleep.

  5. Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite.

    PubMed

    Byerly, Mardi S; Swanson, Roy D; Semsarzadeh, Nina N; McCulloh, Patrick S; Kwon, Kiwook; Aja, Susan; Moran, Timothy H; Wong, G William; Blackshaw, Seth

    2013-06-15

    Disruption of finely coordinated neuropeptide signals in the hypothalamus can result in altered food intake and body weight. We identified neuron-derived neurotrophic factor (NENF) as a novel secreted protein through a large-scale screen aimed at identifying novel secreted hypothalamic proteins that regulate food intake. We observed robust Nenf expression in hypothalamic nuclei known to regulate food intake, and its expression was altered under the diet-induced obese (DIO) condition relative to the fed state. Hypothalamic Nenf mRNA was regulated by brain-derived neurotrophic factor (BDNF) signaling, itself an important regulator of appetite. Delivery of purified recombinant BDNF into the lateral cerebral ventricle decreased hypothalamic Nenf expression, while pharmacological inhibition of trkB signaling increased Nenf mRNA expression. Furthermore, recombinant NENF administered via an intracerebroventricular cannula decreased food intake and body weight and increased hypothalamic Pomc and Mc4r mRNA expression. Importantly, the appetite-suppressing effect of NENF was abrogated in obese mice fed a high-fat diet, demonstrating a diet-dependent modulation of NENF function. We propose the existence of a regulatory circuit involving BDNF, NENF, and melanocortin signaling. Our study validates the power of using an integrated experimental and bioinformatic approach to identify novel CNS-derived proteins with appetite-modulating function and reveals NENF as an important central modulator of food intake.

  6. Neurotrophic Factors (BDNF and GDNF) and the Serotonergic System of the Brain.

    PubMed

    Popova, N K; Ilchibaeva, T V; Naumenko, V S

    2017-03-01

    Neurotrophic factors play a key role in development, differentiation, synaptogenesis, and survival of neurons in the brain as well as in the process of their adaptation to external influences. The serotonergic (5-HT) system is another major factor in the development and neuroplasticity of the brain. In the present review, the results of our own research as well as data provided in the corresponding literature on the interaction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) with the 5-HT-system of the brain are considered. Attention is given to comparison of BDNF and GDNF, the latter belonging to a different family of neurotrophic factors and being mainly considered as a dopaminergic system controller. Data cited in this review show that: (i) BDNF and GDNF interact with the 5-HT-system of the brain through feedback mechanisms engaged in autoregulation of the complex involving 5-HT-system and neurotrophic factors; (ii) GDNF, as well as BDNF, stimulates the growth of 5-HT neurons and affects the expression of key genes of the brain 5-HT-system - those coding tryptophan hydroxylase-2 and 5-HT1A and 5-HT2A receptors. In turn, 5-HT affects the expression of genes that control BDNF and GDNF in brain structures; (iii) the difference between BDNF and GDNF is manifested in different levels and relative distribution of expression of these factors in brain structures (BDNF expression is highest in hippocampus and cortex, GDNF expression in the striatum), in varying reaction of 5-HT2A receptors on BDNF and GDNF administration, and in different effects on certain types of behavior.

  7. The Effect of Repeated Electroacupuncture Analgesia on Neurotrophic and Cytokine Factors in Neuropathic Pain Rats

    PubMed Central

    Wang, Junying; Duanmu, Chenlin; Feng, Xiumei; Yan, Yaxia

    2016-01-01

    Chronic pain is a common disability influencing quality of life. Results of previous studies showed that acupuncture has a cumulative analgesic effect, but the relationship with spinal cytokines neurotrophic factors released by astrocytes remains unknown. The present study was designed to observe the effect of electroacupuncture (EA) treatment on spinal cytokines neurotrophic factors in chronic neuropathic pain rats. The chronic neuropathic pain was established by chronic constrictive injury (CCI). EA treatment was applied at Zusanli (ST36) and Yanglingquan (GB34) (both bilateral) once a day, for 30 min. IL-1β mRNA, TNF-α mRNA, and IL-1 mRNA were detected by quantitative real-time PCR, and the proteins of BDNF, NGF, and NT3/4 were detected by Western blot. The expression levels of cytokines such as IL-1β mRNA, TNF-α mRNA, IL-6 mRNA, and neurotrophic factors such as BDNF, NGF, and NT3/4 in the spinal cord were increased significantly after CCI. The astrocytes released more IL-1β and BDNF after CCI. Repeated EA treatment could suppress the elevated expression of IL-1β mRNA, TNFα mRNA, and BDNF, NGF, and NT3/4 but had no effect on IL-6 mRNA. It is suggested that cytokines and neurotrophic factors which may be closely associated with astrocytes participated in the process of EA relieving chronic pain. PMID:27800006

  8. Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 ...

  9. Chronic hyperoxia alters the expression of neurotrophic factors in the carotid body of neonatal rats.

    PubMed

    Dmitrieff, Elizabeth F; Wilson, Julia T; Dunmire, Kyle B; Bavis, Ryan W

    2011-02-15

    Chronic exposure to hyperoxia alters the postnatal development and innervation of the rat carotid body. We hypothesized that this plasticity is related to changes in the expression of neurotrophic factors or related proteins. Rats were reared in 60% O(2) from 24 to 36h prior to birth until studied at 3d of age (P3). Protein levels for brain-derived neurotrophic factor (BDNF) were significantly reduced (-70%) in the P3 carotid body, while protein levels for its receptor, tyrosine kinase B, and for glial cell line-derived neurotrophic factor (GDNF) were unchanged. Transcript levels in the carotid body were downregulated for the GDNF receptor Ret (-34%) and the neuropeptide Vgf (-67%), upregulated for Cbln1 (+205%), and unchanged for Fgf2; protein levels were not quantified for these genes. Immunohistochemical analysis revealed that Vgf and Cbln1 proteins are expressed within the carotid body glomus cells. These data suggest that BDNF, and perhaps other neurotrophic factors, contribute to abnormal carotid body function following perinatal hyperoxia.

  10. Prospects of Neurotrophic Factors for Parkinson's Disease: Comparison of Protein and Gene Therapy.

    PubMed

    Domanskyi, Andrii; Saarma, Mart; Airavaara, Mikko

    2015-08-01

    Neurotrophic factors (NTFs) hold great potential as therapeutic agents in the treatment of neurodegenerative conditions, including Parkinson's disease (PD), in which the progressive loss of dopamine neurons in the substantia nigra pars compacta causes severe motor symptoms. There is extensive evidence that in preclinical animal models of PD NTFs are both neuroprotective and neurorestorative. In particular, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), cerebral dopamine neurotrophic factor, and mesencephalic astrocyte-derived neurotrophic factor have shown great potential to restore dopamine neurocircuitry. Although some previous clinical trials have demonstrated limited efficacy of GDNF and NRTN, there are several concerns raised with these studies. Moreover, open-label studies with GDNF as well as a study with NRTN showed clinical improvement, particularly in patients with early-stage PD. Indeed, as previous clinical trials with NTFs were associated with several technical problems, there is a great need for further investigations. In this review we discuss the emerging and existing possibilities to use NTFs as neurorestorative agents and the ways to improve their efficacy, and compare gene therapy and recombinant protein therapy approaches for restoring the dopamine circuitry in PD.

  11. Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects wi...

  12. Differential Regulation of Brain-Derived Neurotrophic Factor Transcripts during the Consolidation of Fear Learning

    ERIC Educational Resources Information Center

    Ressler, Kerry J.; Rattiner, Lisa M.; Davis, Michael

    2004-01-01

    Brain-derived neurotrophic factor (BDNF) has been implicated as a molecular mediator of learning and memory. The BDNF gene contains four differentially regulated promoters that generate four distinct mRNA transcripts, each containing a unique noncoding 5[prime]-exon and a common 3[prime]-coding exon. This study describes novel evidence for the…

  13. Chemically extracted acellular allogeneic nerve graft combined with ciliary neurotrophic factor promotes sciatic nerve repair

    PubMed Central

    Zhang, Yanru; Zhang, Hui; Katiella, Kaka; Huang, Wenhua

    2014-01-01

    A chemically extracted acellular allogeneic nerve graft can reduce postoperative immune rejection, similar to an autologous nerve graft, and can guide neural regeneration. However, it remains poorly understood whether a chemically extracted acellular allogeneic nerve graft combined with neurotrophic factors provides a good local environment for neural regeneration. This study investigated the repair of injured rat sciatic nerve using a chemically extracted acellular allogeneic nerve graft combined with ciliary neurotrophic factor. An autologous nerve anastomosis group and a chemical acellular allogeneic nerve bridging group were prepared as controls. At 8 weeks after repair, sciatic functional index, evoked potential amplitude of the soleus muscle, triceps wet weight recovery rate, total number of myelinated nerve fibers and myelin sheath thickness were measured. For these indices, values in the three groups showed the autologous nerve anastomosis group > chemically extracted acellular nerve graft + ciliary neurotrophic factor group > chemical acellular allogeneic nerve bridging group. These results suggest that chemically extracted acellular nerve grafts combined with ciliary neurotrophic factor can repair sciatic nerve defects, and that this repair is inferior to autologous nerve anastomosis, but superior to chemically extracted acellular allogeneic nerve bridging alone. PMID:25221592

  14. Dynamic expression of neurotrophic factor receptors in postnatal spinal motoneurons and in mouse model of ALS.

    PubMed

    Zhang, Jiasheng; Huang, Eric J

    2006-07-01

    Neurotrophic factors support the survival of spinal motoneurons (MNs) and have been considered as strong candidates for treating motoneuron diseases. However, it is unclear if the right combination of neurotrophic factor receptors is present in postnatal spinal MNs. In this study, we show that the level of c-ret expression remains relatively stable in embryonic and postnatal spinal MNs. In contrast, the mRNA and protein of GFRalpha1 and -2 are progressively down-regulated in postnatal life. By 3 and 6 months of age, both receptors are barely detectable in spinal MNs. The down-regulation of GFRalpha1 appears accelerated in transgenic mice expressing mutant SOD1(G93A). Despite the progressive loss of GFRalpha1 and -2, phosphorylation of c-ret shows no detectable reduction on tyrosine residues or on serine 696. In addition to the GFRalpha subunits, expression of TrkB also shows a dynamic change. During embryogenesis, there is twice as much full-length TrkB as the truncated TrkB isoform. However, this ratio is reversed in postnatal spinal cord. Expression of the mutant SOD1(G93A) appears to have no effect on the TrkB receptor ratio. Taken together, our data indicate that the expression of neurotrophic factor receptors, GFRalpha1, -2, and TrkB, is not static, but undergoes dynamic changes in postnatal spinal MNs. These results provide insights into the use of neurotrophic factors as therapeutic agents for ALS.

  15. Neurotrophic factors improve motoneuron survival and function of muscle reinnervated by embryonic neurons.

    PubMed

    Grumbles, Robert M; Sesodia, Sanjay; Wood, Patrick M; Thomas, Christine K

    2009-07-01

    Motoneuron death can occur over several spinal levels with disease or trauma, resulting in muscle denervation. We tested whether cotransplantation of embryonic neurons with 1 or more neurotrophic factors into peripheral nerve improved axon regeneration, muscle fiber area, reinnervation, and function to a greater degree than cell transplantation alone. Sciatic nerves of adult Fischer rats were cut to denervate muscles; 1 week later, embryonic ventral spinal cord cells (days 14-15) were transplanted into the tibial nerve stump as the only source of neurons for muscle reinnervation. Factors that promote motoneuron survival (cardiotrophin 1; fibroblast growth factor 2; glial cell line-derived neurotrophic factor; insulin-like growth factor 1; leukemia inhibitory factor; and hepatocyte growth factor) were added to the transplant individually or in combinations. Inclusion of a single factor with the cells resulted in comparable myelinated axon counts, muscle fiber areas, and evoked electromyographic activity to cells alone 10 weeks after transplantation. Only cell transplantation with glial cell line-derived neurotrophic factor, hepatocyte growth factor, and insulin-like growth factor 1 significantly increased motoneuron survival, myelinated axon counts, muscle reinnervation, and evoked electromyographic activity compared with cells alone. Thus, immediate application of a specific combination of factors to dissociated embryonic neurons improves survival of motoneurons and the long-term function of reinnervated muscle.

  16. Gender and environmental effects on regional brain-derived neurotrophic factor expression after experimental traumatic brain injury.

    PubMed

    Chen, X; Li, Y; Kline, A E; Dixon, C E; Zafonte, R D; Wagner, A K

    2005-01-01

    Alterations in brain-derived neurotrophic factor expression have been reported in multiple brain regions acutely after traumatic brain injury, however neither injury nor post-injury environmental enrichment has been shown to affect hippocampal brain-derived neurotrophic factor gene expression in male rats chronically post-injury. Studies have demonstrated hormone-related neuroprotection for female rats after traumatic brain injury, and estrogen and exercise both influence brain-derived neurotrophic factor levels. Despite recent studies suggesting that exposure post-traumatic brain injury to environmental enrichment improves cognitive recovery in male rats, we have shown that environmental enrichment mediated improvements with spatial learning are gender specific and only positively affect males. Therefore the purpose of this study was to evaluate the effect of gender and environmental enrichment on chronic post-injury cortical and hippocampal brain-derived neurotrophic factor protein expression. Sprague-Dawley male and cycling female rats were placed into environmental enrichment or standard housing after controlled cortical impact or sham surgery. Four weeks post-surgery, hippocampal and frontal cortex brain-derived neurotrophic factor expression were examined using Western blot. Results revealed significant increases in brain-derived neurotrophic factor expression in the frontal cortex ipsilateral to injury for males (P=0.03). Environmental enrichment did not augment this effect. Neither environmental enrichment nor injury significantly affected cortical brain-derived neurotrophic factor expression for females. In the hippocampus ipsilateral to injury brain-derived neurotrophic factor expression for both males and females was half (49% and 51% respectively) of that observed in shams housed in the standard environment. For injured males, there was a trend in this region for environmental enrichment to restore brain-derived neurotrophic factor levels to sham values

  17. Increased synaptic inhibition in dentate gyrus of mice with reduced levels of endogenous brain-derived neurotrophic factor.

    PubMed

    Olofsdotter, K; Lindvall, O; Asztély, F

    2000-01-01

    The aim of this study was to explore the role of endogenous neurotrophins for inhibitory synaptic transmission in the dentate gyrus of adult mice. Heterozygous knockout (+/-) mice or neurotrophin scavenging proteins were used to reduce the levels of endogenous brain-derived neurotrophic factor and neurotrophin-3. Patch-clamp recordings from dentate granule cells in brain slices showed that the frequency, but not the kinetics or amplitude, of miniature inhibitory postsynaptic currents was modulated in brain-derived neurotrophic factor +/- compared to wild-type (+/+) mice. Furthermore, paired-pulse depression of evoked inhibitory synaptic responses was increased in brain-derived neurotrophic factor +/- mice. Similar results were obtained in brain slices from brain-derived neurotrophic factor +/+ mice incubated with tyrosine receptor kinase B-immunoglobulin G, which scavenges endogenous brain-derived neurotrophic factor. The increased inhibitory synaptic activity in brain-derived neurotrophic factor +/- mice was accompanied by decreased excitability of the granule cells. No differences in the frequency, amplitude or kinetics of miniature inhibitory postsynaptic currents were seen between neurotrophin-3 +/- and +/+ mice. From these results we suggest that endogenous brain-derived neurotrophic factor, but not neurotrophin-3, has acute modulatory effects on synaptic inhibition onto dentate granule cells. The site of action seems to be located presynaptically, i.e. brain-derived neurotrophic factor regulates the properties of inhibitory interneurons, leading to increased excitability of dentate granule cells. We propose that through this mechanism, brain-derived neurotrophic factor can change the gating/filtering properties of the dentate gyrus for incoming information from the entorhinal cortex to hippocampus. This will have consequences for the recruitment of hippocampal neural circuitries both under physiological and pathological conditions, such as epileptogenesis.

  18. The roles of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor and nerve growth factor during the final stage of folliculogenesis: a focus on oocyte maturation.

    PubMed

    Linher-Melville, Katja; Li, Julang

    2013-02-01

    Neurotrophic factors were first identified to promote the growth, survival or differentiation of neurons and have also been associated with the early stages of ovarian folliculogenesis. More recently, their effects on the final stage of follicular development, including oocyte maturation and early embryonic development, have been reported. Glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are expressed in numerous peripheral tissues outside of the CNS, most notably the ovary, are now known to stimulate oocyte maturation in various species, also enhancing developmental competence. The mechanisms that underlie their actions in antral follicles, as well as the targets ultimately controlled by these factors, are beginning to emerge. GDNF, BDNF and NGF, alone or in combination, could be added to the media currently utilized for in vitro oocyte maturation, thereby potentially increasing the production and/or quality of early embryos.

  19. Neuroprotective effects of brain-derived neurotrophic factor in seizures during development.

    PubMed

    Tandon, P; Yang, Y; Das, K; Holmes, G L; Stafstrom, C E

    1999-01-01

    Although the immature brain is highly susceptible to seizures, it is more resistant to seizure-induced neuronal loss than the adult brain. The developing brain contains high levels of neurotrophins which are involved in growth, differentiation and survival of neurons. To test the hypothesis that neurotrophins may protect the developing brain from seizure-induced neuronal loss, brain-derived neurotrophic factor up-regulation was blocked by intracerebroventricular infusion of an 18mer antisense oligodeoxynucleotide sequence to brain-derived neurotrophic factor in 19-day-old rats using micro-osmotic pumps. Control rats were infused with sense or missense oligodeoxynucleotide. Status epilepticus was induced by intraperitoneal administration of kainic acid 24 h after the start of oligodeoxynucleotide infusion. Seizure duration was significantly increased in the antisense oligodeoxynucleotide plus kainic acid group compared to groups that received kainic acid alone or kainic acid plus sense or missense oligodeoxynucleotide. There was no difference between groups in the latency to forelimb clonus. A twofold increase in brain-derived neurotrophic factor levels was observed in the hippocampus 20 h following kainic acid-induced seizures. This kainic acid-induced increase was absent in animals receiving infusion of antisense oligodeoxynucleotide to brain-derived neurotrophic factor at time of seizure induction. Hippocampi of rats in this group (antisense oligodeoxynucleotide plus kainic acid) showed a loss of CA1 and CA3 pyramidal cells and hilar interneurons. This neuronal loss was not dependent upon seizure duration since animals injected with diazepam to control seizure activity in the antisense plus kainic acid group also showed similar neuronal loss. Administration of kainic acid or infusion of antisense alone did not produce any cell loss in these regions. Induction of seizures at postnatal day 20, in the presence or absence of antisense oligonucleotide, did not produce

  20. Pro- and anti-addictive neurotrophic factors and cytokines in psychostimulant addiction: mini review.

    PubMed

    Yamada, Kiyofumi; Nabeshima, Toshitaka

    2004-10-01

    Drug addiction is defined as a chronically relapsing disorder that is characterized by compulsive drug taking, inability to limit the intake, and intense drug craving. While the positive reinforcing effects of psychostimulants such as cocaine and amphetamines depend on the mesocorticolimbic dopamine system innervating nucleus accumbens, chronic drug exposure causes stable changes in the structure and function of the brain that may underlie the long-lived behavioral abnormalities in drug addiction. Recent evidence has suggested that various neurotrophic factors and cytokines are involved in the effects of psychomotor stimulants, suggesting that these factors play a role in drug addiction. In this article, a role of neurotrophic factors and cytokines in psychostimulant addiction is discussed.

  1. Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery.

    PubMed

    Lapchak, P A; Miller, P J; Collins, F; Jiao, S

    1997-05-01

    The effects of intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor were tested on low dose (0.05 mg/kg) apomorphine-induced rotations and tyrosine hydroxylase activity in the substantia nigra and striatum of stable 6-hydroxydopamine-lesioned rats. In addition, we determined if 6-hydroxydopamine lesions in the absence or presence of treatment affected neuropeptide (substance P, met-enkephalin, dynorphin) content in the striatum. Glial cell line-derived neurotrophic factor, when administered intranigrally, prevented apomorphine-induced rotational behaviour for 11 weeks following a single injection. In comparison, intraventricularly-administered glial cell line-derived neurotrophic factor produced a transient reduction in rotational behaviour that lasted for two to three weeks following a single injection. We also show that rotational behaviour is reduced following each subsequent intraventricular injection of glial cell line-derived neurotrophic factor given every six weeks, a time-point when baseline rotation deficits were re-established. Intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor significantly reduced weight gain in all 6-hydroxydopamine-lesioned rats in this study. Following behavioural analysis where a confirmed improvement of behaviour was established, tissues were dissected for neurochemical analysis. In lesioned rats with intranigral injections of administered glial cell line-derived neurotrophic factor, significant increases of nigral, but not striatal tyrosine hydroxylase activity were measured. Additionally, 6-hydroxydopamine lesions significantly increased striatal dynorphin (61-139%) and met-enkephalin (81-139%), but not substance P levels. In these rats, intranigrally-administered glial cell line-derived neurotrophic factor injections reversed lesion-induced increases in nigral dynorphin A levels and increased nigral dopamine levels, but did not alter nigral met

  2. Role of brain-derived neurotrophic factor in the aetiology of depression: implications for pharmacological treatment.

    PubMed

    Castrén, Eero; Rantamäki, Tomi

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) is a critical mediator of activity-dependent neuronal plasticity in the cerebral cortex. Deficits in neurotrophic factors have been proposed to underlie mood disorders. However, recent evidence suggests that mood disorders may be produced by abnormalities in the adaptation of neural networks to environmental conditions. Antidepressants may act by enhancing neuronal plasticity, which allows environmental inputs to modify the neuronal networks to better fine tune the individual to the outside world. Recent observations in the visual cortex directly support this idea. According to the network hypothesis of depression, changes in the levels of neurotrophins including BDNF may not directly produce depression or an antidepressant effect, but neurotrophins may act as critical tools in the process whereby environmental conditions guide neuronal networks to better adapt to the environment. This hypothesis suggests that antidepressant drugs should not be used alone but should always be combined with rehabilitation to guide the plastic networks within the brain.

  3. Electroacupuncture-regulated neurotrophic factor mRNA expression in the substantia nigra of Parkinson's disease rats.

    PubMed

    Wang, Shuju; Fang, Jianqiao; Ma, Jun; Wang, Yanchun; Liang, Shaorong; Zhou, Dan; Sun, Guojie

    2013-02-25

    Acupuncture for the treatment of Parkinson's disease has a precise clinical outcome. This study investigated the effect of electroacupuncture at Fengfu (GV16) and Taichong (LR3) acupoints in rat models of Parkinson's disease induced by subcutaneous injection of rotenone into rat neck and back. Reverse transcription-PCR demonstrated that brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression was significantly increased in the substantia nigra of rat models of Parkinson's disease, and that abnormal behavior of rats was significantly improved following electroacupuncture treatment. These results indicated that electroacupuncture treatment upregulated brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression in the substantia nigra of rat models of Parkinson's disease. Thus, electroacupuncture may be useful in the treatment of Parkinson's disease.

  4. Brain-derived and glial cell line-derived neurotrophic factor fusion protein immobilization to laminin

    PubMed Central

    Wang, Baoxin; Yuan, Junjie; Xu, Jiafeng; Chen, Xinwei; Ying, Xinjiang; Dong, Pin

    2017-01-01

    Damage to the recurrent laryngeal nerve often causes hoarseness, dyspnea, dysphagia, and sometimes asphyxia due to vocal cord paralysis which result in a reduction of quality of life. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) play critical roles in peripheral nerve regeneration. However, methods for efficiently delivering these molecules are lacking, which limits their use in clinical applications. The present study reports an effective strategy for targeting BDNF and GDNF to laminin by fusing the N-terminal domains of these molecules with agrin (NtA). More specifically, laminin-binding efficacy was assessed and sustained release assays of the delivery of BDNF or GDNF fused with NtA (LBD-BDNF or LBD-GDNF) to laminin were conducted in vitro. In addition, the bioactivity of LBD-BDNF and LBD-GDNF on laminin in vitro was investigated. LBD-BDNF and LBD-GDNF were each able to specifically bind to laminin and maintain their activity in vitro. Moreover, neurotrophic factors with NtA retained higher concentrations and bioactivity levels compared with those without NtA. The ratio of LBD-BDNF and LBD-GDNF that produced optimal effects was 4:6. BDNF and GDNF fused with NtA were effective in specifically binding to laminin. As laminin is a major component of the extracellular matrix, LBD-BDNF and LBD-GDNF may prove useful in the repair of peripheral nerve injuries. PMID:28123487

  5. The expanding universe of neurotrophic factors: therapeutic potential in aging and age-associated disorders.

    PubMed

    Lanni, C; Stanga, S; Racchi, M; Govoni, S

    2010-01-01

    Multiple molecular, cellular, structural and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively by employing multiple mechanisms in order to maintain the integrity of nerve cell circuits and to facilitate responses to environmental demands. Otherwise, they may succumb to neurodegenerative cascades that result in disorders such as Alzheimer's and Parkinson's diseases. An important role in this balancement is played by neurotrophic factors, which are central to many aspects of nervous system function since they regulate the development, maintenance and survival of neurons and neuron-supporting cells such as glia and oligodendrocytes. A vast amount of evidence indicates that alterations in levels of neurotrophic factors or their receptors can lead to neuronal death and contribute to aging as well as to the pathogenesis of diseases of abnormal trophic support (such as neurodegenerative diseases and depression) and diseases of abnormal excitability (such as epilepsy and central pain sensitization). Cellular and molecular mechanisms by which neurotrophic factors may influence cell survival and excitability are also critically examined to provide novel concepts and targets for the treatment of physiological changes bearing detrimental functional alterations and of different diseases affecting the central nervous system during aging.

  6. Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor.

    PubMed

    Calabrese, Francesca; Guidotti, Gianluigi; Racagni, Giorgio; Riva, Marco A

    2013-12-01

    Aging is a physiological process characterized by a significant reduction of neuronal plasticity that might contribute to the functional defects observed in old subjects. Even if the neurobiological mechanisms that contribute to such impairment remain largely unknown, a role for neurotrophic molecules, such as the neurotrophin brain-derived neurotrophic factor (BDNF), has been postulated. On this basis, the purpose of this study was to provide a detailed investigation of the BDNF system, at transcriptional and translational levels, in the ventral and dorsal hippocampus and in the prefrontal cortex of middle-aged and old rats, compared with in adult animals. The expression of major players in BDNF regulation and response, including the transcription factors, calcium-responsive transcription factor, cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB), and neuronal Per Arnt Sim (PAS) domain protein 4, and the high-affinity receptor tropomyosin receptor kinase B (TrkB), was also analyzed. Our results demonstrate that the BDNF system is affected at different levels in aged rats with global impairment including reduced transcription, impaired protein synthesis and processing, and decreased activation of the TrkB receptors. These modifications might contribute to the cognitive deficits associated with aging and suggest that pharmacological strategies aimed at restoring reduced neurotrophism might be useful to counteract age-related cognitive decline.

  7. NG2 expression in microglial cells affects the expression of neurotrophic and proinflammatory factors by regulating FAK phosphorylation

    PubMed Central

    Zhu, Lie; Su, Qing; Jie, Xiang; Liu, Antang; Wang, Hui; He, Beiping; Jiang, Hua

    2016-01-01

    Neural/glial antigen 2 (NG2), a chondroitin sulfate proteoglycan, is significantly upregulated in a subset of glial cells in the facial motor nucleus (FMN) following CNS injury. NG2 is reported to promote the resulting inflammatory reaction, however, the mechanism by which NG2 mediates these effects is yet to be determined. In this study, we examined the changes in NG2 expressing microglial cells in the FMN in response to facial nerve axotomy (FNA) in mice. Our findings indicated that NG2 expression was progressively induced and upregulated specifically in the ipsilateral facial nucleus following FNA. To further investigate the effects of NG2 expression, in vivo studies in NG2-knockout mice and in vitro studies in rat microglial cells transfected with NG2 shRNAs were performed. Abolition of NG2 expression both in vitro and in vivo resulted in increased expression of neurotrophic factors (nerve growth factor and glial derived neurotrophic factor), decreased expression of inflammatory mediators (tumor necrosis factor-α and interleukin-1β) and decreased apoptosis in the ipsilateral facial nucleus in response to FNA. Furthermore, we demonstrated the role of FAK in these NG2-induced effects. Taken together, our findings suggest that NG2 expression mediates inflammatory reactions and neurodegeneration in microglial cells in response to CNS injury, potentially by regulating FAK phosphorylation. PMID:27306838

  8. Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology

    PubMed Central

    Schmaal, Lianne; Jansen, Rick; Milaneschi, Yuri; Opmeer, Esther M.; Elzinga, Bernet M.; van der Wee, Nic J. A.; Veltman, Dick J.; Penninx, Brenda W. J. H.

    2016-01-01

    Childhood maltreatment (CM) has been associated with altered brain morphology, which may partly be due to a direct impact on neural growth, e.g. through the brain-derived neurotrophic factor (BDNF) pathway. Findings on CM, BDNF and brain volume are inconsistent and have never accounted for the entire BDNF pathway. We examined the effects of CM, BDNF (genotype, gene expression and protein level) and their interactions on hippocampus, amygdala and anterior cingulate cortex (ACC) morphology. Data were collected from patients with depression and/or an anxiety disorder and healthy subjects within the Netherlands Study of Depression and Anxiety (NESDA) (N = 289). CM was assessed using the Childhood Trauma Interview. BDNF Val66Met genotype, gene expression and serum protein levels were determined in blood and T1 MRI scans were acquired at 3T. Regional brain morphology was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed. Amygdala volume was lower in maltreated individuals. This was more pronounced in maltreated met-allele carriers. The expected positive relationship between BDNF gene expression and volume of the amygdala is attenuated in maltreated subjects. Finally, decreased cortical thickness of the ACC was identified in maltreated subjects with the val/val genotype. CM was associated with altered brain morphology, partly in interaction with multiple levels of the BNDF pathway. Our results suggest that CM has different effects on brain morphology in met-carriers and val-homozygotes and that CM may disrupt the neuroprotective effect of BDNF. PMID:27405617

  9. Brain derived neurotrophic factor treatment reduces inflammation and apoptosis in experimental allergic encephalomyelitis.

    PubMed

    Makar, Tapas K; Trisler, David; Sura, Karna T; Sultana, Shireen; Patel, Niraj; Bever, Christopher T

    2008-07-15

    Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) which includes a neurodegenerative component. Brain derived neurotrophic factor (BDNF) is a neuroprotective agent which might be useful in preventing neurodegeneration but its application has been limited because the blood brain barrier restricts its access to the CNS. We have developed a novel delivery system for BDNF using transformed bone marrow stem cells (BMSC) and undertook studies of EAE to determine whether the delivery of BDNF could reduce inflammation and apoptosis. Mice receiving BDNF producing BMSC had reduced clinical impairment compared to control mice receiving BMSC that did not produce BDNF. Pathological examination of brain and spinal cord showed a reduction in inflammatory infiltrating cells in treated compared to control mice. Apoptosis was reduced in brain and spinal cord based on TUNEL and cleaved Caspase-3 staining. Consistent with the known mechanism of action of BDNF on apoptosis, Bcl-2 and Akt were increased in treated mice. Further studies suggested that these increases could be mediated by inhibition of both caspase dependent and caspase independent pathways. These results suggest that the BDNF delivered by the transformed bone marrow stem cells reduced clinical severity, inflammation and apoptosis in this model.

  10. Glial cell line-derived neurotrophic factor gene therapy ameliorates chronic hyperprolactinemia in senile rats.

    PubMed

    Morel, G R; Sosa, Y E; Bellini, M J; Carri, N G; Rodriguez, S S; Bohn, M C; Goya, R G

    2010-05-19

    Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during normal aging is associated in the female rat with chronic hyperprolactinemia. We assessed the effectiveness of glial cell line-derived neurotrophic factor (GDNF) gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. Young (2.5 months) and senile (29 months) rats received a bilateral intrahypothalamic injection (10(10) pfu) of either an adenoviral vector expressing the gene for beta-galactosidase; (Y-betagal and S-betagal, respectively) or a vector expressing rat GDNF (Y-GDNF and S-GDNF, respectively). Transgenic GDNF levels in supernatants of GDNF adenovector-transduced N2a neuronal cell cultures were 25+/-4 ng/ml, as determined by bioassay. In the rats, serum prolactin (PRL) was measured at regular intervals. On day 17 animals were sacrificed and neuronal nuclear antigen (NeuN) and tyrosine hydroxylase (TH) immunoreactive cells counted in the arcuate-periventricular hypothalamic region. The S-GDNF but not the S-betagal rats, showed a significant reduction in body weight. The chronic hyperprolactinemia of the senile females was significantly ameliorated in the S-GDNF rats (P<0.05) but not in the S-betagal rats. Neither age nor GDNF induced significant changes in the number of NeuN and TH neurons. We conclude that transgenic GDNF ameliorates chronic hyperprolactinemia in aging female rats, probably by restoring TIDA neuron function.

  11. Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures.

    PubMed

    Bolton, M M; Pittman, A J; Lo, D C

    2000-05-01

    Brain-derived neurotrophic factor (BDNF) has been postulated to be a key signaling molecule in regulating synaptic strength and overall circuit activity. In this context, we have found that BDNF dramatically increases the frequency of spontaneously initiated action potentials in hippocampal neurons in dissociated culture. Using analysis of unitary synaptic transmission and immunocytochemical methods, we determined that chronic treatment with BDNF potentiates both excitatory and inhibitory transmission, but that it does so via different mechanisms. BDNF strengthens excitation primarily by augmenting the amplitude of AMPA receptor-mediated miniature EPSCs (mEPSCs) but enhances inhibition by increasing the frequency of mIPSC and increasing the size of GABAergic synaptic terminals. In contrast to observations in other systems, BDNF-mediated increases in AMPA-receptor mediated mEPSC amplitudes did not require activity, because blocking action potentials with tetrodotoxin for the entire duration of BDNF treatment had no effect on the magnitude of this enhancement. These forms of synaptic regulations appear to be a selective action of BDNF because intrinsic excitability, synapse number, and neuronal survival are not affected in these cultures. Thus, although BDNF induces a net increase in overall circuit activity, this results from potentiation of both excitatory and inhibitory synaptic drive through distinct and selective physiological mechanisms.

  12. Brain-derived neurotrophic factor mediates the activity-dependent regulation of inhibition in neocortical cultures.

    PubMed

    Rutherford, L C; DeWan, A; Lauer, H M; Turrigiano, G G

    1997-06-15

    The excitability of cortical circuits is modulated by interneurons that release the inhibitory neurotransmitter GABA. In primate and rodent visual cortex, activity deprivation leads to a decrease in the expression of GABA. This suggests that activity is able to adjust the strength of cortical inhibition, but this has not been demonstrated directly. In addition, the nature of the signal linking activity to GABA expression has not been determined. Activity is known to regulate the expression of the neurotrophin brain-derived neurotrophic factor (BDNF), and BDNF has been shown to influence the phenotype of GABAergic interneurons. We use a culture system from postnatal rat visual cortex to test the hypothesis that activity is regulating the strength of cortical inhibition through the regulation of BDNF. Cultures were double-labeled against GABA and the neuronal marker MAP2, and the percentage of neurons that were GABA-positive was determined. Blocking spontaneous activity in these cultures reversibly decreased the number of GABA-positive neurons without affecting neuronal survival. Voltage-clamp analysis of inhibitory currents demonstrated that activity blockade also decreased GABA-mediated inhibition onto pyramidal neurons and raised pyramidal neuron firing rates. All of these effects were prevented by incubation with BDNF during activity blockade, but not by neurotrophin 3 or nerve growth factor. Additionally, blockade of neurotrophin signaling mimicked the effects of activity blockade on GABA expression. These data suggest that activity regulates cortical inhibition through a BDNF-dependent mechanism and that this neurotrophin plays an important role in the control of cortical excitability.

  13. PERIPHERAL NERVE REGENERATION: CELL THERAPY AND NEUROTROPHIC FACTORS

    PubMed Central

    Sebben, Alessandra Deise; Lichtenfels, Martina; da Silva, Jefferson Luis Braga

    2015-01-01

    Peripheral nerve trauma results in functional loss in the innervated organ, and recovery without surgical intervention is rare. Many surgical techniques can be used for nerve repair. Among these, the tubulization technique can be highlighted: this allows regenerative factors to be introduced into the chamber. Cell therapy and tissue engineering have arisen as an alternative for stimulating and aiding peripheral nerve regeneration. Therefore, the aim of this review was to provide a survey and analysis on the results from experimental and clinical studies that used cell therapy and tissue engineering as tools for optimizing the regeneration process. The articles used came from the LILACS, Medline and SciELO scientific databases. Articles on the use of stem cells, Schwann cells, growth factors, collagen, laminin and platelet-rich plasma for peripheral nerve repair were summarized over the course of the review. Based on these studies, it could be concluded that the use of stem cells derived from different sources presents promising results relating to nerve regeneration, because these cells have a capacity for neuronal differentiation, thus demonstrating effective functional results. The use of tubes containing bioactive elements with controlled release also optimizes the nerve repair, thus promoting greater myelination and axonal growth of peripheral nerves. Another promising treatment is the use of platelet-rich plasma, which not only releases growth factors that are important in nerve repair, but also serves as a carrier for exogenous factors, thereby stimulating the proliferation of specific cells for peripheral nerve repair. PMID:27027067

  14. Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.

    PubMed

    Zunino, G; Messina, A; Sgadò, P; Baj, G; Casarosa, S; Bozzi, Y

    2016-06-02

    Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD.

  15. Periocular injection of in situ hydrogels containing Leu-Ile, an inducer for neurotrophic factors, promotes retinal ganglion cell survival after optic nerve injury.

    PubMed

    Nakatani, Masayoshi; Shinohara, Yuko; Takii, Miki; Mori, Hisato; Asai, Nobuharu; Nishimura, Shigeru; Furukawa-Hibi, Yoko; Miyamoto, Yoshiaki; Nitta, Atsumi

    2011-12-01

    Intraocular administration of neurotrophic factors has been shown to delay irreversible degeneration of retinal ganglion cells (RGCs). It would be beneficial for the treatment of optic nerve (ON) injury if such neurotrophic factors could be delivered in a less-invasive manner. The dipeptide leucine-isoleucine (Leu-Ile) appears to induce the production of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), in the brain. We therefore administered Leu-Ile via periocular depot injection in rats and investigated the dipeptide's ability to induce BDNF and GDNF in the retina and to delay RGC loss in an ON injury model. Poloxamer-alginate hydrogels containing Leu-Ile were injected into the subconjunctival space of intact or ON-injured rats. BDNF and GDNF levels in the retina were determined by an enzyme immunoassay. Survival of RGCs was assessed in retinal flatmounts. Activation of extracellular signal-regulated kinases (ERK) and cAMP response element binding protein (CREB) in the retina was examined by Western blotting. At 2 h after injection of fluorescein isothiocyanate-conjugated Leu-Ile, the fluorescence intensities in the retina were 4.3-fold higher than those in the saline control. Treatment with Leu-Ile significantly increased the retinal levels of BDNF at 6 h and GDNF at 6-72 h after injection. Treatment with Leu-Ile significantly increased RGC survival to 14 days after ON injury and enhanced the activation of ERK at 72 h and CREB at 48 h after injection in the ON-injured retina. These results suggest that periocular delivery of Leu-Ile induces BDNF and GDNF production in the retina, which may eventually enhance RGC survival after ON injury.

  16. Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease.

    PubMed

    Kazim, Syed Faraz; Iqbal, Khalid

    2016-07-11

    Alzheimer's disease (AD) is an incurable and debilitating chronic progressive neurodegenerative disorder which is the leading cause of dementia worldwide. AD is a heterogeneous and multifactorial disorder, histopathologically characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of Aβ peptides and abnormally hyperphosphorylated tau protein, respectively. Independent of the various etiopathogenic mechanisms, neurodegeneration is a final common outcome of AD neuropathology. Synaptic loss is a better correlate of cognitive impairment in AD than Aβ or tau pathologies. Thus a highly promising therapeutic strategy for AD is to shift the balance from neurodegeneration to neuroregeneration and synaptic repair. Neurotrophic factors, by virtue of their neurogenic and neurotrophic activities, have potential for the treatment of AD. However, the clinical therapeutic usage of recombinant neurotrophic factors is limited because of the insurmountable hurdles of unfavorable pharmacokinetic properties, poor blood-brain barrier (BBB) permeability, and severe adverse effects. Neurotrophic factor small-molecule mimetics, in this context, represent a potential strategy to overcome these short comings, and have shown promise in preclinical studies. Neurotrophic factor small-molecule mimetics have been the focus of intense research in recent years for AD drug development. Here, we review the relevant literature regarding the therapeutic beneficial effect of neurotrophic factors in AD, and then discuss the recent status of research regarding the neurotrophic factor small-molecule mimetics as therapeutic candidates for AD. Lastly, we summarize the preclinical studies with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021). P021 is a neurogenic and neurotrophic compound which enhances dentate gyrus neurogenesis and memory processes via inhibiting leukemia inhibitory factor (LIF) signaling pathway and increasing

  17. c-Jun Gene-Modified Schwann Cells: Upregulating Multiple Neurotrophic Factors and Promoting Neurite Outgrowth

    PubMed Central

    Huang, Liangliang; Quan, Xin; Liu, Zhongyang; Ma, Teng; Wu, Yazhen; Ge, Jun; Zhu, Shu; Yang, Yafeng; Liu, Liang; Sun, Zhen

    2015-01-01

    Genetically modified Schwann cells (SCs) that overexpress neurotrophic factors (NFs), especially those that overexpress multiple NFs, hold great potential for promoting nerve regeneration. Currently, only one NF can be upregulated in most genetically modified SCs, and simultaneously upregulating multiple NFs in SCs remains challenging. In this study, we found that the overexpression of c-Jun, a component of the AP-1 transcription factor, effectively upregulated the expression and secretion of multiple NFs, including glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, artemin, leukemia inhibitory factor, and nerve growth factor. The c-Jun gene-modified SCs showed a normal morphology in scanning electron microscopy and fluorescent staining analysis. In addition, the c-Jun-modified SCs showed enhanced proliferation and migration abilities compared with vector control cells. We used transwell chambers to establish coculture systems imitating the in vivo conditions in which transplanted SCs might influence native SCs and neurons. We found that the c-Jun-modified SCs enhanced native SC migration and promoted the proliferation of native SCs in the presence of axons. Further analysis revealed that in the c-Jun group, the average length and the total area of neurites divided by the total area of the explant body were μm 1180±25 and 6.4±0.4, respectively, which were significantly greater compared with the other groups. These findings raise the possibility of constructing an optimal therapeutic alternative for nerve repair using c-Jun-modified SCs, which have the potential to promote axonal regeneration and functional recovery by upregulating multiple NFs. In addition, these cells exhibit enhanced migration and proliferation abilities, enhance the biological functions of native SCs, and promote neurite outgrowth. PMID:25588149

  18. Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse.

    PubMed

    Hashikawa, Naoya; Ogawa, Takumi; Sakamoto, Yusuke; Ogawa, Mami; Matsuo, Yumi; Zamami, Yoshito; Hashikawa-Hobara, Narumi

    2015-08-01

    Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15 days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2 weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15 days of stress. NGF mRNA levels were significantly higher 1 week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test.

  19. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats.

    PubMed

    Larsson, E; Nanobashvili, A; Kokaia, Z; Lindvall, O

    1999-11-01

    The levels of brain-derived neurotrophic factor (BDNF) vary between different forebrain areas and show region-specific changes after cerebral ischemia. The present study explores the possibility that the levels of endogenous BDNF determine the susceptibility to ischemic neuronal death. To block BDNF activity the authors used the TrkB-Fc fusion protein, which was infused intraventricularly in rats during 1 week before and 1 week after 5 or 30 minutes of global forebrain ischemia. Ischemic damage was quantified in the striatum and hippocampal formation after 1 week of reperfusion using immunocytochemistry and stereological procedures. After the 30-minute insult, there was a significantly lower number of surviving CA4 pyramidal neurons, neuropeptide Y-immunoreactive dentate hilar neurons, and choline acetyltransferase- and TrkA-positive, cholinergic striatal interneurons in the TrkB-Fc-infused rats as compared to controls. In contrast, the TrkB-Fc treatment did not influence survival of CA1 or CA3 pyramidal neurons or striatal projection neurons. Also, after the mild ischemic insult (5 minutes), neuronal death in the CA1 region was similar in the TrkB-Fc-treated and control groups. These results indicate that endogenous BDNF can protect certain neuronal populations against ischemic damage. It is conceivable, though, that efficient neuroprotection after brain insults is dependent not only on this factor but on the concerted action of a large number of neurotrophic molecules.

  20. Radix Bupleuri ameliorates depression by increasing nerve growth factor and brain-derived neurotrophic factor

    PubMed Central

    Wang, Xia; Feng, Qing; Xiao, Yong; Li, Ping

    2015-01-01

    Background: Chinese herb Radix Bupleuri has been regarded effective to improve treatment of depression, but the molecular mechanism remains unknown. Low levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) increase the likelihood of developing the depression. Therefore, we want to know whether Radix Bupleuri affects the levels of these factors. Methods: A total 160 hemodialysis patients were diagnosed with depression and randomly assigned to two groups: Radix Bupleuri group (received 1 g root power of Radix Bupleuri in a capsule daily Radix Bupleuri) and control group (receive placebo). Results: After three-month follow-up, the patients who received Radix Bupleuri had greater improvement in depression symptoms, anxiety symptoms and general functioning via controls after three-month follow-up (P < 0.05). Serum NGF levels were significantly higher in subjects accepted Radix Bupleuris (178.64 ± 52.18 pg/mL) when compared to a control (103.54 ± 31.23 pg/ml) (P < 0.01). Similarly, serum BDNF levels were significantly higher in subjects accepted Radix Bupleuris (1635.26 ± 121.66 pg/ml) when compared to a control (516.38 ± 44.89 pg/ml) (P < 0.01). The serum levels of NGF and BDNF were negatively related with Montgomery-Asberg Depression Rating Scale (MADRS) and positively related with scores of RAND-36 item Health Survey (RAND-36) (P < 0.01). Conclusion: Thus, Radix Bupleuri ameliorates the patients with depression by increasing serum levels of NGF and BDNF. Radix Bupleuri should be developed a new drug for the therapy of depression. PMID:26309578

  1. The brain-derived neurotrophic factor pathway, life stress, and chronic multi-site musculoskeletal pain

    PubMed Central

    Milaneschi, Yuri; Jansen, Rick; Elzinga, Bernet M; Dekker, Joost; Penninx, Brenda WJH

    2016-01-01

    Introduction Brain-derived neurotrophic factor (BDNF) disturbances and life stress, both independently and in interaction, have been hypothesized to induce chronic pain. We examined whether (a) the BDNF pathway (val66met genotype, gene expression, and serum levels), (b) early and recent life stress, and (c) their interaction are associated with the presence and severity of chronic multi-site musculoskeletal pain. Methods Cross-sectional data are from 1646 subjects of the Netherlands Study of Depression and Anxiety. The presence and severity of chronic multi-site musculoskeletal pain were determined using the Chronic Pain Grade (CPG) questionnaire. The BDNF val66met polymorphism, BDNF gene expression, and BDNF serum levels were measured. Early life stress before the age of 16 was assessed by calculating a childhood trauma index using the Childhood Trauma Interview. Recent life stress was assessed as the number of recent adverse life events using the List of Threatening Events Questionnaire. Results Compared to val66val, BDNF met carriers more often had chronic pain, whereas no differences were found for BDNF gene expression and serum levels. Higher levels of early and recent stress were both associated with the presence and severity of chronic pain (p < 0.001). No interaction effect was found for the BDNF pathway with life stress in the associations with chronic pain presence and severity. Conclusions This study suggests that the BDNF gene marks vulnerability for chronic pain. Although life stress did not alter the impact of BDNF on chronic pain, it seems an independent factor in the onset and persistence of chronic pain. PMID:27145806

  2. Neurotrophic factors and CNS disorders: findings in rodent models of depression and schizophrenia.

    PubMed

    Angelucci, Francesco; Mathé, Aleksander A; Aloe, Luigi

    2004-01-01

    Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system (CNS). Loss of neurons in specific brain regions has been found in depression and schizophrenia, and this chapter summarizes the findings of altered neurotrophins in animal models of those two disorders under baseline condition and following antidepressive and antipsychotic treatments. In a model of depression (Flinders sensitive line/Flinders resistant line; FSL/FRL rats), increased NGF and BDNF concentrations were found in frontal cortex of female, and in occipital cortex of male 'depressed' FSL compared to FRL control rats. Using the same model, the effects of electroconvulsive stimuli (ECS) and chronic lithium treatment on brain NGF, BDNF and glial cell line-derived neurotrophic factors were investigated. ECS and lithium altered the brain concentrations of neurotrophic factors in the hippocampus, frontal cortex, occipital cortex and striatum. ECS mimic the effects of electroconvulsive therapy (ECT) that is an effective treatment for depression and also schizophrenia. Since NGF and BDNF may also be changed in the CNS of animal models of schizophrenia, we investigated whether treatment with antipsychotic drugs (haloperidol, risperidone, and olanzapine) affects the constitutive levels of NGF and BDNF in the CNS. Both typical and atypical antipsychotic drugs altered the regional brain levels of NGF and BDNF. Other studies also demonstrated that these drugs differentially altered neurotrophin mRNAs. Overall, these studies indicate that alteration of brain level of NGF and BDNF could constitute part of the biochemical alterations induced by antipsychotic drugs.

  3. Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders.

    PubMed

    Jana, Arundhati; Modi, Khushbu K; Roy, Avik; Anderson, John A; van Breemen, Richard B; Pahan, Kalipada

    2013-06-01

    This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA - CREB pathway, which may be of benefit for various neurodegenerative disorders.

  4. Stem cell-based delivery of brain-derived neurotrophic factor gene in the rat retina.

    PubMed

    Park, Hae-Young Lopilly; Kim, Jie Hyun; Sun Kim, Hwa; Park, Chan Kee

    2012-08-21

    As an alternative to a viral vector, the application of stem cells to transfer specific genes is under investigation in various organs. Using this strategy may provide more effective method to supply neurotrophic factor to the neurodegenerative diseases caused by neurotrophic factor deprivation. This study investigated the possibility and efficacy of stem cell-based delivery of the brain-derived neurotrophic factor (BDNF) gene to rat retina. Rat BDNF cDNA was transduced into rat bone marrow mesenchymal stem cells (rMSCs) using a retroviral vector. Its incorporation into the experimental rat retina and the expression of BDNF after intravitreal injection or subretinal injection were detected by real-time PCR, western blot analysis, and immunohistochemical staining. For the incorporated rMSCs, retinal-specific marker staining was performed to investigate the changes in morphology and the characteristics of the stem cells. Transduction of the rMSCs by retrovirus was effective, and the transduced rMSCs expressed high levels of the BDNF gene and protein. The subretinal injection of rMSCs produced rMSC migration and incorporation into the rat retina (about 15.7% incorporation rate), and retinal BDNF mRNA and protein expression was increased at 4 weeks after transplantation. When subretinal injection of rMSCs was applied to axotomized rat retina, it significantly increased the expression of BDNF until 4 weeks after transplantation. Some of the transplanted rMSCs exhibited morphological changes, but the retinal-specific marker stain was not sufficient to indicate whether neuronal differentiation had occurred. Using mesenchymal stem cells to deliver the BDNF gene to the retina may provide new treatment for glaucoma.

  5. Analysis of neurotrophic factors in limb and extraocular muscles of mouse model of amyotrophic lateral sclerosis.

    PubMed

    Harandi, Vahid M; Lindquist, Susanne; Kolan, Shrikant Shantilal; Brännström, Thomas; Liu, Jing-Xia

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is currently an incurable fatal motor neuron syndrome characterized by progressive weakness, muscle wasting and death ensuing 3-5 years after diagnosis. Neurotrophic factors (NTFs) are known to be important in both nervous system development and maintenance. However, the attempt to translate the potential of NTFs into the therapeutic options remains limited despite substantial number of approaches, which have been tested clinically. Using quantitative RT-PCR (qRT-PCR) technique, the present study investigated mRNA expression of four different NTFs: brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4) and glial cell line-derived neurotrophic factor (GDNF) in limb muscles and extraocular muscles (EOMs) from SOD1G93A transgenic mice at early and terminal stages of ALS. General morphological examination revealed that muscle fibres were well preserved in both limb muscles and EOMs in early stage ALS mice. However, in terminal ALS mice, most muscle fibres were either atrophied or hypertrophied in limb muscles but unaffected in EOMs. qRT-PCR analysis showed that in early stage ALS mice, NT-4 was significantly down-regulated in limb muscles whereas NT-3 and GDNF were markedly up-regulated in EOMs. In terminal ALS mice, only GDNF was significantly up-regulated in limb muscles. We concluded that the early down-regulation of NT-4 in limb muscles is closely associated with muscle dystrophy and dysfunction at late stage, whereas the early up-regulations of GDNF and NT-3 in EOMs are closely associated with the relatively well-preserved muscle morphology at late stage. Collectively, the data suggested that comparing NTFs expression between limb muscles and EOMs from different stages of ALS animal models is a useful method in revealing the patho-physiology and progression of ALS, and eventually rescuing motor neuron in ALS patients.

  6. [Brain-derived neurotrophic factor gene (BDNF) polymorphism among Moscow citizens].

    PubMed

    2013-12-01

    Recent studies showed that brain-derived neurotrophic factor (BDNF) can participate in pathogenesis of various CNS disorders, being connected with proliferation, differentiation, and survival of neurons. In present study, analysis of occurrence rate was performed for three single nucleotide polymorphisms (SNPs) located in BDNF gene (rs6267 (A/G) allele A-0.265; rs2049046 (A/T) allele A-0.407; rs11030107 (A/G) allele A-0.872) in randomized selection of Moscow citizens. Linkage disequilibrium of rs6165 and rs2049046 loci was shown. Differences in allele frequencies in studied selection and populations of other re- gions were discovered.

  7. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function.

    PubMed

    Teixeira, Antonio Lucio; Barbosa, Izabela Guimarães; Diniz, Breno Satler; Kummer, Arthur

    2010-12-01

    Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the CNS, where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF has become a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have consistently reported altered levels of BDNF in the circulation (i.e., serum or plasma) of patients with major depression, bipolar disorder, Alzheimer's disease, Huntington's disease and Parkinson's disease. Correlations between serum BDNF levels and affective, cognitive and motor symptoms have also been described. BDNF appears to be an unspecific biomarker of neuropsychiatric disorders characterized by neurodegenerative changes.

  8. Brain-derived neurotrophic factor and epilepsy--a missing link?

    PubMed

    Scharfman, Helen E

    2005-01-01

    It has been known for some time that brain-derived neurotrophic factor (BDNF) is critical to normal development of the CNS, and more recently, studies also have documented the ability of BDNF to modify adult CNS structure and function. Therefore, it is no surprise that BDNF has been linked to diseases, such as epilepsy, which may involve abnormal cortical development or altered brain structure and function after maturity. This review evaluates the evidence, particularly from recent studies, that BDNF contributes to the development of temporal lobe epilepsy (TLE).

  9. Possible protective action of neurotrophic factors and natural compounds against common neurodegenerative diseases

    PubMed Central

    Numakawa, Tadahiro

    2014-01-01

    It has been suggested that altered levels/function of brain-derived neurotrophic factor (BDNF) play a role in the pathophysiology of neurodegenerative diseases including Alzheimer's disease. BDNF positively contributes to neural survival and synapse maintenance via stimulating its high affinity receptor TrkB, making upregulation of BDNF and/or activation of BDNF-related intracellular signaling an attractive approach to treating neurodegenerative diseases. In this short review, I briefly introduce small natural compounds such as flavonoids that successfully increase activation of the BDNF system and discuss their beneficial effects against neurodegeneration. PMID:25317165

  10. Neurotrophic factors in Parkinson's disease are regulated by exercise: Evidence-based practice.

    PubMed

    da Silva, Paula Grazielle Chaves; Domingues, Daniel Desidério; de Carvalho, Litia Alves; Allodi, Silvana; Correa, Clynton Lourenço

    2016-04-15

    We carried out a qualitative review of the literature on the influence of forced or voluntary exercise in Parkinson's Disease (PD)-induced animals, to better understand neural mechanisms and the role of neurotrophic factors (NFs) involved in the improvement of motor behavior. A few studies indicated that forced or voluntary exercise may promote neuroprotection, through upregulation of NF expression, against toxicity of drugs that simulate PD. Forced training, such as treadmill exercise and forced-limb use, adopted in most studies, in addition to voluntary exercise on a running wheel are suitable methods for NFs upregulation.

  11. Exposure to Early Life Stress Results in Epigenetic Changes in Neurotrophic Factor Gene Expression in a Parkinsonian Rat Model

    PubMed Central

    Mpofana, Thabisile; Daniels, Willie M. U.; Mabandla, Musa V.

    2016-01-01

    Early life adversity increases the risk of mental disorders later in life. Chronic early life stress may alter neurotrophic factor gene expression including those for brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) that are important in neuronal growth, survival, and maintenance. Maternal separation was used in this study to model early life stress. Following unilateral injection of a mild dose of 6-hydroxydopamine (6-OHDA), we measured corticosterone (CORT) in the blood and striatum of stressed and nonstressed rats; we also measured DNA methylation and BDNF and GDNF gene expression in the striatum using real time PCR. In the presence of stress, we found that there was increased corticosterone concentration in both blood and striatal tissue. Further to this, we found higher DNA methylation and decreased neurotrophic factor gene expression. 6-OHDA lesion increased neurotrophic factor gene expression in both stressed and nonstressed rats but this increase was higher in the nonstressed rats. Our results suggest that exposure to early postnatal stress increases corticosterone concentration which leads to increased DNA methylation. This effect results in decreased BDNF and GDNF gene expression in the striatum leading to decreased protection against subsequent insults later in life. PMID:26881180

  12. Intranasal administration: a potential solution for cross-BBB delivering neurotrophic factors.

    PubMed

    Zhu, Juehua; Jiang, Yongjun; Xu, Gelin; Liu, Xinfeng

    2012-05-01

    Neurotrophic factors (NTFs) are endogenous polypeptides that regulate the growth, survival, differentiation, and functioning of neurons. The neuroprotective effects of NTFs in experimental animals give strong rationale for developing therapies for neurological disorders. However, when NTFs are applied in clinical trials, great expectation leads to equal disappointment. NTFs are large molecular-weighted and hydrophilic proteins, which limits their access to the central nervous system (CNS) after systemic administration, principally due to poor blood-brain barrier (BBB) permeability and unfavorable pharmacokinetic profiles. Although intracerebral infusion may transport NTFs into the CNS, the invasiveness limits its clinical application. Intranasal administration has been under research for decades and presents promising outcomes in preclinical studies for brain delivering of NTFs. After intranasal delivery, NTFs gain direct and quick access into the CNS at concentrations high enough to elicit their biological effects, bypassing the BBB and minimizing systemic exposure. Due to its invasiveness and convenience, intranasal delivery is feasible for NTFs administration. Although direct evidence of nose-to-brain pathway in human is lacking due to ethical problems, the existence of the nose-to-cerebral spinal fluid pathway has been verified in men. Furthermore, there is abundant indirect evidence for the nose-to-brain pathway as determined by the efficacy of intranasally administered neuroproteins, such as insulin, oxytocin, and vasopressin in clinical trials. Based on the solid preclinical research supporting the efficacy of intranasal NTFs, and the successful clinical application of neuroproteins (not NTFs), it is time to evaluate clinical application of NTFs in treating both acute and chronic CNS diseases.

  13. Serum and plasma brain-derived neurotrophic factor (BDNF) in abstinent alcoholics and social drinkers.

    PubMed

    D'Sa, Carrol; Dileone, Ralph J; Anderson, George M; Sinha, Rajita

    2012-05-01

    Although the effects of alcohol on brain-derived neurotrophic factor (BDNF) have been extensively studied in rodents, BDNF levels have rarely been measured in abstinent, alcohol-dependent (AD) individuals. Interpretation of reported group comparisons of serum BDNF levels is difficult due to limited information regarding analytical variance, biological variability, and the relative contribution of platelet and plasma pools to serum BDNF. Analytical variance (intra- and inter-assay coefficients of variation) of the enzyme-linked immunosorbent assay (ELISA) was characterized. Within- and between-subject variability, and group differences in serum and plasma BDNF, was assessed on three separate days in 16, 4-week abstinent AD individuals (7M/9F) and 16 social drinkers (SDs; 8M/8F). Significantly higher mean (±sd) serum BDNF levels were observed for the AD group compared to the SD (p = 0.003). No significant difference in mean baseline plasma BDNF levels was observed between AD and SD groups. The low analytical variance, high day-to-day within-individual stability and the high degree of individuality demonstrates the potential clinical utility of measuring serum BDNF levels. The low correlations that we observed between plasma and serum levels are congruent with their representing separate pools of BDNF. The observation of higher basal serum BDNF in the AD group without a concomitant elevation in plasma BDNF levels indicates that the elevated serum BDNF in AD patients is not due to greater BDNF exposure. Further research is warranted to fully elucidate mechanisms underlying this alteration and determine the utility of serum BDNF as a predictor or surrogate marker of chronic alcohol abuse.

  14. Cabergoline Decreases Alcohol Drinking and Seeking Behaviors Via Glial Cell Line-Derived Neurotrophic Factor

    PubMed Central

    Carnicella, Sebastien; Ahmadiantehrani, Somayeh; He, Dao-Yao; Nielsen, Carsten K.; Bartlett, Selena E.; Janak, Patricia H.; Ron, Dorit

    2010-01-01

    Background Cabergoline is an ergotamine derivative that increases the expression of glial cell line-derived neurotrophic factor (GDNF) in vitro. We recently showed that GDNF in the ventral tegmental area (VTA) reduces the motivation to consume alcohol. We therefore set out to determine whether cabergoline administration decreases alcohol-drinking and -seeking behaviors via GDNF. Methods Reverse transcription polymerase chain reaction (RT-PCR) and Enzyme-Linked ImmunoSorbent Assay (ELISA) were used to measure GDNF levels. Western blot analysis was used for phosphorylation experiments. Operant self-administration in rats and a two-bottle choice procedure in mice were used to assess alcohol-drinking behaviors. Instrumental performance tested during extinction was used to measure alcohol-seeking behavior. The [35S]GTPγS binding assay was used to assess the expression and function of the dopamine D2 receptor (D2R). Results We found that treatment of the dopaminergic-like cell line SH-SY5Y with cabergoline and systemic administration of cabergoline in rats resulted in an increase in GDNF level and in the activation of the GDNF pathway. Cabergoline treatment decreased alcohol-drinking and -seeking behaviors including relapse, and its action to reduce alcohol consumption was localized to the VTA. Finally, the increase in GDNF expression and the decrease in alcohol consumption by cabergoline were abolished in GDNF heterozygous knockout mice. Conclusions Together, these findings suggest that cabergoline-mediated upregulation of the GDNF pathway attenuates alcohol-drinking behaviors and relapse. Alcohol abuse and addiction are devastating and costly problems worldwide. This study puts forward the possibility that cabergoline might be an effective treatment for these disorders. PMID:19232578

  15. Inflammation and activity augment brain-derived neurotrophic factor peripheral release.

    PubMed

    Qiao, L Y; Shen, S; Liu, M; Xia, C; Kay, J C; Zhang, Q L

    2016-03-24

    Brain-derived neurotrophic factor (BDNF) release to nerve terminals in the central nervous system is crucial in synaptic transmission and neuronal plasticity. However, BDNF release peripherally from primary afferent neurons has not been investigated. In the present study, we show that BDNF is synthesized by primary afferent neurons located in the dorsal root ganglia (DRG) in rat, and releases to spinal nerve terminals in response to depolarization or visceral inflammation. In two-compartmented culture that separates DRG neuronal cell bodies and spinal nerve terminals, application of 50mM K(+) to either the nerve terminal or the cell body evokes BDNF release to the terminal compartment. Inflammatory stimulation of the visceral organ (e.g. the urinary bladder) also facilitates an increase in spontaneous BDNF release from the primary afferent neurons to the axonal terminals. In the inflamed viscera, we show that BDNF immunoreactivity is increased in nerve fibers that are immuno-positive to the neuronal marker PGP9.5. Both BDNF and pro-BDNF levels are increased, however, pro-BDNF immunoreactivity is not expressed in PGP9.5-positive nerve-fiber-like structures. Determination of receptor profiles in the inflamed bladder demonstrates that BDNF high affinity receptor TrkB and general receptor p75 expression levels are elevated, with an increased level of TrkB tyrosine phosphorylation/activity. These results suggest a possibility of pro-proliferative effect in the inflamed bladder. Consistently we show that the proliferation marker Ki67 expression levels are enhanced in the inflamed organ. Our results imply that in vivo BDNF release to the peripheral organ is an important event in neurogenic inflammatory state.

  16. Brain-derived neurotrophic factor gene-modified bone marrow mesenchymal stem cells

    PubMed Central

    HAN, ZHONG-MIN; HUANG, HE-MEI; WANG, FEI-FEI

    2015-01-01

    The present study aimed to investigate the effects of human brain-derived neurotrophic factor (hBDNF) on the differentiation of bone marrow mesenchymal stem cells (MSCs) into neuron-like cells. Lentiviral vectors carrying the hBDNF gene were used to modify the bone marrow stromal cells (BMSCs) of Sprague-Dawley (SD) rats. The rat BMSCs were isolated, cultured and identified. A lentivirus bearing hBDNF and enhanced green fluorescent protein (eGFP) genes was subcultured and used to infect the SD rat BMSCs. The expression of eGFP was observed under a fluorescence microscope to determine the infection rate and growth of the transfected cells. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) was used to detect the proliferation rate of cells following transfection. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect the expression levels of hBDNF. Differentiation of neuron-like cells was induced in vitro and the differentiation rate of the induced neural-like cells was compared with that in control groups and analyzed statistically. In the cultured cells, flow cytometry demonstrated positive expression of cluster of differentiation (CD)90 and CD44, and negative expression of CD34 and CD45. The proliferation rate of the rat BMSCs increased following gene transfection. The expression of hBDNF-eGFP was detected in the BMSCs of the experimental group. The differentiation rate of hBDNF-modified cells into neuron-like cells in the experimental group was higher compared with that in empty plasmid and untransfected negative control groups. The difference was statistically significant (P<0.05). Thus, BDNF gene transfection is able to promote the differentiation of BMSCs into neuron-like cells. BDNF may play an important role in the differentiation of MSCs into neuron-like cells. PMID:25574226

  17. Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons.

    PubMed

    Gill, Raminder; Chang, Philip K-Y; Prenosil, George A; Deane, Emily C; McKinney, Rebecca A

    2013-12-01

    Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF-mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury-induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB-Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB-Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two-fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB-Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB-Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury-induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post-traumatic epilepsy. Therefore, our data suggest that blocking the BDNF-TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post-traumatic epilepsy.

  18. Differential expression of human placental neurotrophic factors in preterm and term deliveries.

    PubMed

    Dhobale, Madhavi V; Pisal, Hemlata R; Mehendale, Savita S; Joshi, Sadhana R

    2013-12-01

    Neurotrophic factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are involved in development of the placenta and fetal brain. A series of human and animal studies in our department have shown that micronutrients (folic acid, vitamin B12) and omega 3 fatty acids like DHA are all interlinked in the one carbon cycle. Any alterations in one carbon components will lead to changes in methylation patterns that further affect the gene expression at critical periods of development resulting in complications during pregnancy. This may further contribute to risk for neurodevelopmental disorders in children born preterm. Therefore this study for the first time examines the mRNA levels from preterm and term placentae. A total number of 38 women delivering preterm (<37 weeks gestation) and 37 women delivering at term (=>37 weeks gestation) were recruited. The mRNA levels of BDNF and NGF were analyzed by real time quantitative polymerase chain reaction. Our results indicate that BDNF and NGF mRNA levels were lower in preterm group as compared to term group. There was a positive association of placental BDNF and NGF mRNA levels with cord plasma BDNF and NGF levels. The differential expression of BDNF and NGF gene in preterm placentae may also alter the vascular development in preterm deliveries. Our data suggests that the reduced mRNA levels of BDNF and NGF may possibly be a result of altered epigenetic mechanisms and may have an implication for altered fetal programming in children born preterm.

  19. Preferential Enhancement of Sensory and Motor Axon Regeneration by Combining Extracellular Matrix Components with Neurotrophic Factors

    PubMed Central

    Santos, Daniel; González-Pérez, Francisco; Giudetti, Guido; Micera, Silvestro; Udina, Esther; Del Valle, Jaume; Navarro, Xavier

    2016-01-01

    After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF). Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation. PMID:28036084

  20. Glial cell derived neurotrophic factor induces spermatogonial stem cell marker genes in chicken mesenchymal stem cells.

    PubMed

    Boozarpour, Sohrab; Matin, Maryam M; Momeni-Moghaddam, Madjid; Dehghani, Hesam; Mahdavi-Shahri, Naser; Sisakhtnezhad, Sajjad; Heirani-Tabasi, Asieh; Irfan-Maqsood, Muhammad; Bahrami, Ahmad Reza

    2016-06-01

    Mesenchymal stem cells (MSCs) are known with the potential of multi-lineage differentiation. Advances in differentiation technology have also resulted in the conversion of MSCs to other kinds of stem cells. MSCs are considered as a suitable source of cells for biotechnology purposes because they are abundant, easily accessible and well characterized cells. Nowadays small molecules are introduced as novel and efficient factors to differentiate stem cells. In this work, we examined the potential of glial cell derived neurotrophic factor (GDNF) for differentiating chicken MSCs toward spermatogonial stem cells. MSCs were isolated and characterized from chicken and cultured under treatment with all-trans retinoic acid (RA) or glial cell derived neurotrophic factor. Expression analysis of specific genes after 7days of RA treatment, as examined by RT-PCR, proved positive for some germ cell markers such as CVH, STRA8, PLZF and some genes involved in spermatogonial stem cell maintenance like BCL6b and c-KIT. On the other hand, GDNF could additionally induce expression of POU5F1, and NANOG as well as other genes which were induced after RA treatment. These data illustrated that GDNF is relatively more effective in diverting chicken MSCs towards Spermatogonial stem cell -like cells in chickens and suggests GDNF as a new agent to obtain transgenic poultry, nevertheless, exploitability of these cells should be verified by more experiments.

  1. Exploring Serum Levels of Brain Derived Neurotrophic Factor and Nerve Growth Factor Across Glaucoma Stages

    PubMed Central

    Busanello, Anna; Bonini, Stefano; Quaranta, Luciano; Agnifili, Luca; Manni, Gianluca

    2017-01-01

    Purpose To investigate the serum levels of Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in patients affected by primary open angle glaucoma with a wide spectrum of disease severity compared to healthy controls and to explore their relationship with morphological and functional glaucoma parameters. Materials and Methods 45 patients affected by glaucoma at different stages and 15 age-matched healthy control subjects underwent visual field testing, peripapillary retinal nerve fibre layer thickness measurement using Spectral Domain Optical Coherence Tomography and blood collection for both neurotrophins detection by Enzyme-Linked Immunosorbent Assay. Statistical analysis and association between biostrumental and biochemical data were investigated. Results Serum levels of BDNF in glaucoma patients were significantly lower than those measured in healthy controls (261.2±75.0 pg/ml vs 313.6±79.6 pg/ml, p = 0.03). Subgroups analysis showed that serum levels of BDNF were significantly lower in early (253.8±40.7 pg/ml, p = 0.019) and moderate glaucoma (231.3±54.3 pg/ml, p = 0.04) but not in advanced glaucoma (296.2±103.1 pg/ml, p = 0.06) compared to healthy controls. Serum levels of NGF in glaucoma patients were significantly lower than those measured in the healthy controls (4.1±1 pg/mL vs 5.5±1.2 pg/mL, p = 0.01). Subgroups analysis showed that serum levels of NGF were significantly lower in early (3.5±0.9 pg/mL, p = 0.0008) and moderate glaucoma (3.8±0.7 pg/ml, p<0.0001) but not in advanced glaucoma (5.0±0.7 pg/ml, p = 0.32) compared to healthy controls. BDNF serum levels were not related to age, visual field mean deviation or retinal nerve fibre layer thickness either in glaucoma or in controls while NGF levels were significantly related to visual field mean deviation in the glaucoma group (r2 = 0.26, p = 0.004). Conclusions BDNF and NGF serum levels are reduced in the early and moderate glaucoma stages, suggesting the possibility that

  2. Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity.

    PubMed

    Vaynman, S; Ying, Z; Wu, A; Gomez-Pinilla, F

    2006-01-01

    Synaptic plasticity and behaviors are likely dependent on the capacity of neurons to meet the energy demands imposed by neuronal activity. We used physical activity, a paradigm intrinsically associated with energy consumption/expenditure and cognitive enhancement, to study how energy metabolism interacts with the substrates for neuroplasticity. We found that in an area critical for learning and memory, the hippocampus, exercise modified aspects of energy metabolism by decreasing oxidative stress and increasing the levels of cytochrome c oxidase-II, a specific component of mitochondrial machinery. We infused 1,25-dihydroxyvitamin D3, a modulator of energy metabolism, directly into the hippocampus during 3 days of voluntary wheel running and measured its effects on brain-derived neurotrophic factor-mediated synaptic plasticity. Brain-derived neurotrophic factor is a central player for the effects of exercise on synaptic and cognitive plasticity. We found that 25-dihydroxyvitamin D3 decreased exercise-induced brain-derived neurotrophic factor but had no significant effect on neurotrophin-3 levels, thereby suggesting a level of specificity for brain-derived neurotrophic factor in the hippocampus. 25-Dihydroxyvitamin D3 injection also abolished the effects of exercise on the consummate end-products of brain-derived neurotrophic factor action, i.e. cyclic AMP response element-binding protein and synapsin I, and modulated phosphorylated calmodulin protein kinase II, a signal transduction cascade downstream to brain-derived neurotrophic factor action that is important for learning and memory. We also found that exercise significantly increased the expression of the mitochondrial uncoupling protein 2, an energy-balancing factor concerned with ATP production and free radical management. Our results reveal a fundamental mechanism by which key elements of energy metabolism may modulate the substrates of hippocampal synaptic plasticity.

  3. I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

    PubMed

    Nomura, T; Honmou, O; Harada, K; Houkin, K; Hamada, H; Kocsis, J D

    2005-01-01

    I.V. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

  4. Endogenous ciliary neurotrophic factor modulates anxiety and depressive-like behavior.

    PubMed

    Peruga, Isabella; Hartwig, Silvia; Merkler, Doron; Thöne, Jan; Hovemann, Bernhard; Juckel, Georg; Gold, Ralf; Linker, Ralf A

    2012-04-15

    On a molecular level, depression is characterized by an altered monoaminergic neurotransmission as well as a modulation of cytokines and other mediators in the central nervous system. In particular, neurotrophic factors may influence affective behavior including depression and anxiety. Ciliary neurotrophic factor (CNTF) plays an important role in the regulation of neuronal development, neuroprotection and may also influence cognitive processes. Here we investigate the affective behavior in mice deficient for CNTF (CNTF -/- mice) at young age of 10-20 weeks. CNTF -/- mice displayed an increased anxiety-like behavior with a 30% reduction of the time spent in the bright compartment of the light/dark box as well as a significantly increased startle response. In the learned helplessness paradigm, CNTF -/- mice are more prone to depressive-like behavior. In the hippocampus of 20 weeks old, but not 10 weeks old, CNTF -/- mice, these changes correlated with a loss of parvalbumin immunoreactive GABAergic interneurons and a reduction of serotonin levels as well as 5-HT receptor 1A expression. Modulation of monoaminergic neurotransmitter levels via chronic application of the antidepressants amitriptyline and citalopram did not exert beneficial effects. These data imply that endogenous CNTF plays a pivotal role for the structural maintenance of hippocampal functions and thus has an important impact on the modulation of affective behavior in rodent models of anxiety and depression.

  5. Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

    NASA Astrophysics Data System (ADS)

    Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

    2016-06-01

    The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

  6. Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

    PubMed Central

    Lippoldt, Erika K.; Ongun, Serra; Kusaka, Geoffrey K.; McKemy, David D.

    2016-01-01

    Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors-α3 (GFRα3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFRα3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin–GFRα3 signaling can be targeted to selectively treat cold pain. PMID:27051069

  7. APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation.

    PubMed

    Stanga, Serena; Zanou, Nadège; Audouard, Emilie; Tasiaux, Bernadette; Contino, Sabrina; Vandermeulen, Gaëlle; René, Frédérique; Loeffler, Jean-Philippe; Clotman, Frédéric; Gailly, Philippe; Dewachter, Ilse; Octave, Jean-Noël; Kienlen-Campard, Pascal

    2016-05-01

    Besides its crucial role in the pathogenesis of Alzheimer's disease, the knowledge of amyloid precursor protein (APP) physiologic functions remains surprisingly scarce. Here, we show that APP regulates the transcription of the glial cell line-derived neurotrophic factor (GDNF). APP-dependent regulation of GDNF expression affects muscle strength, muscular trophy, and both neuronal and muscular differentiation fundamental for neuromuscular junction (NMJ) maturation in vivo In a nerve-muscle coculture model set up to modelize NMJ formation in vitro, silencing of muscular APP induces a 30% decrease in secreted GDNF levels and a 40% decrease in the total number of NMJs together with a significant reduction in the density of acetylcholine vesicles at the presynaptic site and in neuronal maturation. These defects are rescued by GDNF expression in muscle cells in the conditions where muscular APP has been previously silenced. Expression of GDNF in muscles of amyloid precursor protein null mice corrected the aberrant synaptic morphology of NMJs. Our findings highlight for the first time that APP-dependent GDNF expression drives the process of NMJ formation, providing new insights into the link between APP gene regulatory network and physiologic functions.-Stanga, S., Zanou, N., Audouard, E., Tasiaux, B., Contino, S., Vandermeulen, G., René, F., Loeffler, J.-P., Clotman, F., Gailly, P., Dewachter, I., Octave, J.-N., Kienlen-Campard, P. APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation.

  8. Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor.

    PubMed

    Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E

    2016-06-27

    The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

  9. Conditional ablation of brain-derived neurotrophic factor-TrkB signaling impairs striatal neuron development.

    PubMed

    Li, Yun; Yui, Daishi; Luikart, Bryan W; McKay, Renée M; Li, Yanjiao; Rubenstein, John L; Parada, Luis F

    2012-09-18

    Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), are associated with the physiology of the striatum and the loss of its normal functioning under pathological conditions. The role of BDNF and its downstream signaling in regulating the development of the striatum has not been fully investigated, however. Here we report that ablation of Bdnf in both the cortex and substantia nigra depletes BDNF in the striatum, and leads to impaired striatal development, severe motor deficits, and postnatal lethality. Furthermore, striatal-specific ablation of TrkB, the gene encoding the high-affinity receptor for BDNF, is sufficient to elicit an array of striatal developmental abnormalities, including decreased anatomical volume, smaller neuronal nucleus size, loss of dendritic spines, reduced enkephalin expression, diminished nigral dopaminergic projections, and severe deficits in striatal dopamine signaling through DARPP32. In addition, TrkB ablation in striatal neurons elicits a non-cell-autonomous reduction of tyrosine hydroxylase protein level in the axonal projections of substantia nigral dopaminergic neurons. Thus, our results establish an essential function for TrkB in regulating the development of striatal neurons.

  10. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease.

    PubMed

    Mariga, Abigail; Mitre, Mariela; Chao, Moses V

    2017-01-01

    Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease.

  11. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease

    PubMed Central

    Mariga, Abigail; Mitre, Mariela; Chao, Moses V.

    2017-01-01

    Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease. PMID:27015693

  12. REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR MESSENGER RNA LEVELS IN AVIAN HYPOTHALAMIC SLICE CULTURES. (R825294)

    EPA Science Inventory

    Mechanisms regulating the expression of brain-derived neurotrophic factor, a member of the neurotrophin family, have been extensively studied in the rat cerebral cortex, hippocampus and cerebellum. In contrast, little is known regarding the regulation of this growth factor in ...

  13. Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease

    PubMed Central

    Borba, Ericksen Mielle; Duarte, Juliana Avila; Bristot, Giovana; Scotton, Ellen; Camozzato, Ana Luiza; Chaves, Márcia Lorena Fagundes

    2016-01-01

    Background/Aims Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). Methods Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant®. Results MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. Discussion The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction. PMID:28101102

  14. The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression.

    PubMed

    Masi, Gabriele; Brovedani, Paola

    2011-11-01

    Depression is a prevalent, highly debilitating mental disorder affecting up to 15% of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50% of patients are poor responders, even to more recently discovered medications. Furthermore, clinical response only occurs following weeks to months of treatment and only chronic treatment is effective, suggesting that actions beyond the rapidly occurring effect of enhancing monoaminergic systems, such as adaptation of these systems, are responsible for the effects of antidepressants. Recent studies indicate that an impairment of synaptic plasticity (neurogenesis, axon branching, dendritogenesis and synaptogenesis) in specific areas of the CNS, particularly the hippocampus, may be a core factor in the pathophysiology of depression. The abnormal neural plasticity may be related to alterations in the levels of neurotrophic factors, namely brain-derived neurotrophic factor (BDNF), which play a central role in plasticity. As BDNF is repressed by stress, epigenetic regulation of the BDNF gene may play an important role in depression. The hippocampus is smaller in depressed patients, although it is unclear whether smaller size is a consequence of depression or a pre-existing, vulnerability marker for depression. Environmental stressors triggering activation of the hypothalamic-pituitary-adrenal axis cause the brain to be exposed to corticosteroids, affecting neurobehavioural functions with a strong downregulation of hippocampal neurogenesis, and are a major risk factor for depression. Antidepressant treatment increases BDNF levels, stimulates neurogenesis and reverses the inhibitory effects of stress, but this effect is evident only after 3-4 weeks of administration, the time course

  15. Additive clinical value of serum brain-derived neurotrophic factor for prediction of chronic heart failure outcome.

    PubMed

    Kadowaki, Shinpei; Shishido, Tetsuro; Honda, Yuki; Narumi, Taro; Otaki, Yoichiro; Kinoshita, Daisuke; Nishiyama, Satoshi; Takahashi, Hiroki; Arimoto, Takanori; Miyamoto, Takuya; Watanabe, Tetsu; Kubota, Isao

    2016-04-01

    The importance of the central nervous system in cardiovascular events has been recognized. Recently, brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is involved in depression mechanisms and also in stress and anxiety. Because BDNF is reported about cardioprotective role, we elucidated whether BDNF is associated with cardiovascular events in patients with chronic heart failure (CHF). We examined serum BDNF levels in 134 patients with CHF and 23 control subjects. The patients were followed to register cardiac events for a median of 426 days. BDNF was significantly lower in CHF patients than in control subjects (25.8 ± 8.4 vs 14.7 ± 8.4, P < 0.0001). Serum BDNF was also lower in patients with cardiac events than in event-free patients (16.1 ± 8.0 vs 12.5 ± 8.5, P < 0.0001). The cutoff value of BDNF was determined by performing receiver operating characteristic curve analysis. Kaplan-Meier analysis demonstrated that patients with low levels of BDNF experienced higher rates of cardiac events than those with high levels of BDNF. Multivariate Cox hazard analysis demonstrated that low BDNF levels (≤12.4 ng/mL) were an independent prognostic factor for cardiac events (hazard ratio 2.932, 95 % confidence interval 1.622-5.301; P = 0.0004). Adding levels of BDNF to the model with BNP levels, age, and eGFR for the prediction of cardiac events yielded significant net reclassification improvement of 0.429 (P < 0.001) and an integrated discrimination improvement of 0.101 (P < 0.001). Low serum BDNF levels were found in patients with CHF, and these levels were found to be independently associated with an increased risk of cardiac events.

  16. Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk, Mechanisms, and Therapy.

    PubMed

    Song, Jing-Hui; Yu, Jin-Tai; Tan, Lan

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) has a neurotrophic support on neuron of central nervous system (CNS) and is a key molecule in the maintenance of synaptic plasticity and memory storage in hippocampus. However, changes of BDNF level and expression have been reported in the CNS as well as blood of Alzheimer's disease (AD) patients in the last decade, which indicates a potential role of BDNF in the pathogenesis of AD. Therefore, this review aims to summarize the latest progress in the field of BDNF and its biological roles in AD pathogenesis. We will discuss the interaction between BDNF and amyloid beta (Aβ) peptide, the effect of BDNF on synaptic repair in AD, and the association between BDNF polymorphism and AD risk. The most important is, enlightening the detailed biological ability and complicated mechanisms of action of BDNF in the context of AD would provide a future BDNF-related remedy for AD, such as increment in the production or release of endogenous BDNF by some drugs or BDNF mimics.

  17. Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation.

    PubMed

    Lambert, W Marcus; Xu, Chong-Feng; Neubert, Thomas A; Chao, Moses V; Garabedian, Michael J; Jeanneteau, Freddy D

    2013-09-01

    Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF- and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism.

  18. Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

    PubMed

    Croll, S D; Suri, C; Compton, D L; Simmons, M V; Yancopoulos, G D; Lindsay, R M; Wiegand, S J; Rudge, J S; Scharfman, H E

    1999-01-01

    Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

  19. Role of neurotrophic factor alterations in the neurodegenerative process in HIV associated neurocognitive disorders.

    PubMed

    Fields, Jerel; Dumaop, Wilmar; Langford, T D; Rockenstein, Edward; Masliah, E

    2014-03-01

    Migration of HIV infected cells into the CNS is associated with a spectrum of neurological disorders, ranging from milder forms of HIV-associated neurocognitive disorders (HAND) to HIV-associated dementia (HAD). These neuro-psychiatric syndromes are related to the neurodegenerative pathology triggered by the release of HIV proteins and cytokine/chemokines from monocytes/macrophages into the CNS -a condition known as HIV encephalitis (HIVE). As a result of more effective combined anti-retroviral therapy patients with HIV are living longer and thus the frequency of HAND has increased considerably, resulting in an overlap between the neurodegenerative pathology associated with HIV and that related to aging. In fact, HIV infection is believed to hasten the aging process. The mechanisms through which HIV and aging lead to neurodegeneration include: abnormal calcium flux, excitotoxicity, signaling abnormalities, oxidative stress and autophagy defects. Moreover, recent studies have shown that defects in the processing and transport of neurotrophic factors such as fibroblast growth factors (FGFs), neural growth factor (NGF) and brain-derived growth factor (BDNF) might also play a role. Recent evidence implicates alterations in neurotrophins in the pathogenesis of neurodegeneration associated with HAND in the context of aging. Here, we report FGF overexpression curtails gp120-induced neurotoxicity in a double transgenic mouse model. Furthermore, our data show disparities in brain neurotrophic factor levels may be exacerbated in HIV patients over 50 years of age. In this review, we discuss the most recent findings on neurotrophins and HAND in the context of developing new therapies to combat HIV infection in the aging population.

  20. Smoking Habits and Neuropeptides: Adiponectin, Brain-derived Neurotrophic Factor, and Leptin Levels

    PubMed Central

    Won, Yong Lim; Ko, Kyung Sun; Roh, Ji won

    2014-01-01

    This study aimed to identify changes in the level of neuropeptides among current smokers, former smokers, and individuals who had never smoked, and how smoking habits affect obesity and metabolic syndrome (MetS). Neuropeptide levels, anthropometric parameters, and metabolic syndrome diagnostic indices were determined among male workers; 117 of these had never smoked, whereas 58 and 198 were former and current smokers, respectively. The total sample comprised 373 male workers. The results obtained from anthropometric measurements showed that current smokers attained significantly lower body weight, body mass index, waist circumference, and abdominal fat thickness values than former smokers and those who had never smoked. Current smokers’ eating habits proved worse than those of non-smokers and individuals who had never smoked. The level of brain-derived neurotrophic factor (BDNF) in the neuropeptides in the case of former smokers was 23.6 ± 9.2 pg/ml, higher than that of current smokers (20.4 ± 6.1) and individuals who had never smoked (22.4 ± 5.8) (F = 6.520, p = 0.002). The level of adiponectin among former smokers was somewhat lower than that of current smokers, whereas leptin levels were higher among former smokers than current smokers; these results were not statistically significant. A relationship was found between adiponectin and triglyceride among non-smokers (odds ratio = 0.660, β value = −0.416, p < 0.01) and smokers (odds ratio = 0.827, β value = −0.190, p < 0.05). Further, waist circumference among non-smokers (odds ratio = 1.622, β value = 0.483, p < 0.001) and smokers (odds ratio = 1.895, β value = 0.639, p < 0.001) was associated with leptin. It was concluded that cigarette smoking leads to an imbalance of energy expenditure and appetite by changing the concentration of neuropeptides such as adiponectin, BDNF, leptin, and hsCRP, and influences food intake, body weight, the body mass index, blood pressure, and abdominal fat, which are

  1. Brain-derived neurotrophic factor: a newly described mediator of angiogenesis.

    PubMed

    Kermani, Pouneh; Hempstead, Barbara

    2007-05-01

    Recent studies indicate that, in addition to its neuropoietic actions, brain derived neurotrophic factor (BDNF) promotes endothelial cell survival and induces neoangiogenesis in ischemic tissues. Unlike many vascular growth factors that act on many vascular beds, BDNF activity is relatively restricted to central arteries, vessels of cardiac and skeletal muscle, and skin. Studies of newly described biologic mediators that act on large-vessel and microvascular beds in these organs will help us to better understand organ-specific vascular development, as well as to develop novel therapeutic strategies to improve the condition of patients with cardiac and peripheral vascular disease. In this review, we summarize dual proangiogenic actions of BDNF, which, through local activation of TrkB receptor, expressed on a subpopulation of endothelial cells and, in addition, by recruitment of bone marrow-derived cells, contribute to neoangiogenesis.

  2. Downregulated Brain-Derived Neurotrophic Factor-Induced Oxidative Stress in the Pathophysiology of Diabetic Retinopathy.

    PubMed

    Behl, Tapan; Kotwani, Anita

    2017-04-01

    Brain-derived neurotrophic factor (BDNF), a member of neurotrophin growth factor family, physiologically mediates induction of neurogenesis and neuronal differentiation, promotes neuronal growth and survival and maintains synaptic plasticity and neuronal interconnections. Unlike the central nervous system, its secretion in the peripheral nervous system occurs in an activity-dependent manner. BDNF improves neuronal mortality, growth, differentiation and maintenance. It also provides neuroprotection against several noxious stimuli, thereby preventing neuronal damage during pathologic conditions. However, in diabetic retinopathy (a neuromicrovascular disorder involving immense neuronal degeneration), BDNF fails to provide enough neuroprotection against oxidative stress-induced retinal neuronal apoptosis. This review describes the prime reasons for the downregulation of BDNF-mediated neuroprotective actions during hyperglycemia, which renders retinal neurons vulnerable to damaging stimuli, leading to diabetic retinopathy.

  3. Pleiotrophin promotes microglia proliferation and secretion of neurotrophic factors by activating extracellular signal-regulated kinase 1/2 pathway.

    PubMed

    Miao, Jiayin; Ding, Minghui; Zhang, Aiwu; Xiao, Zijian; Qi, Weiwei; Luo, Ning; Di, Wei; Tao, Yuqian; Fang, Yannan

    2012-12-01

    Pleiotrophin (PTN) is an effective neuroprotective factor and its expression is strikingly increased in microglia after ischemia/reperfusion injury. However, whether PTN could provide neurotrophic support to neurons by regulating microglia function is not clear. In this study, we demonstrated that the expression of PTN was induced in microglia after oxygen-glucose deprivation/reperfusion. PTN promoted the proliferation of microglia by enhancing the G1 to S phase transition. PTN also stimulated the secretion of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) in microglia, but did not upregulate the expression of proinflammatory factors such as TNF-α, IL-1β and iNOS. Mechanistically, we found that PTN increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in microglia in both concentration-dependent and time-dependent manners. In addition, ERK1/2 inhibitor U0126 abolished the proliferation and G1 to S phase transition of microglia stimulated by PTN, and inhibited the production of BDNF, CNTF and NGF induced by PTN. In conclusion, our results demonstrated that PTN-ERK1/2 pathway plays important role in regulating microglia growth and secretion of neurotrophic factors. These findings provide new insight into the neuroprotective role of PTN and suggest that PTN is a new target for therapeutic intervention of stroke.

  4. Alterations in brain neurotrophic and glial factors following early age chronic methylphenidate and cocaine administration.

    PubMed

    Simchon-Tenenbaum, Yaarit; Weizman, Abraham; Rehavi, Moshe

    2015-04-01

    Attention deficit hyperactivity disorder (ADHD) overdiagnosis and a pharmacological attempt to increase cognitive performance, are the major causes for the frequent (ab)use of psychostimulants in non-ADHD individuals. Methylphenidate is a non-addictive psychostimulant, although its mode of action resembles that of cocaine, a well-known addictive and abused drug. Neuronal- and glial-derived growth factors play a major role in the development, maintenance and survival of neurons in the central nervous system. We hypothesized that methylphenidate and cocaine treatment affect the expression of such growth factors. Beginning on postnatal day (PND) 14, male Sprague Dawley rats were treated chronically with either cocaine or methylphenidate. The rats were examined behaviorally and biochemically at several time points (PND 35, 56, 70 and 90). On PND 56, rats treated with cocaine or methylphenidate from PND 14 through PND 35 exhibited increased hippocampal glial-cell derived neurotrophic factor (GDNF) mRNA levels, after 21 withdrawal days, compared to the saline-treated rats. We found a significant association between cocaine and methylphenidate treatments and age progression in the prefrontal protein expression of brain derived neurotrophic factor (BDNF). Neither treatments affected the behavioral parameters, although acute cocaine administration was associated with increased locomotor activity. It is possible that the increased hippocampal GDNF mRNA levels, may be relevant to the reduced rate of drug seeking behavior in ADHD adolescence that were maintained from childhood on methylphenidate. BDNF protein level increase with age, as well as following stimulant treatments at early age may be relevant to the neurobiology and pharmacotherapy of ADHD.

  5. Treadmill exercise induced functional recovery after peripheral nerve repair is associated with increased levels of neurotrophic factors.

    PubMed

    Park, Jae-Sung; Höke, Ahmet

    2014-01-01

    Benefits of exercise on nerve regeneration and functional recovery have been reported in both central and peripheral nervous system disease models. However, underlying molecular mechanisms of enhanced regeneration and improved functional outcomes are less understood. We used a peripheral nerve regeneration model that has a good correlation between functional outcomes and number of motor axons that regenerate to evaluate the impact of treadmill exercise. In this model, the median nerve was transected and repaired while the ulnar nerve was transected and prevented from regeneration. Daily treadmill exercise resulted in faster recovery of the forelimb grip function as evaluated by grip power and inverted holding test. Daily exercise also resulted in better regeneration as evaluated by recovery of compound motor action potentials, higher number of axons in the median nerve and larger myofiber size in target muscles. Furthermore, these observations correlated with higher levels of neurotrophic factors, glial derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), in serum, nerve and muscle suggesting that increase in muscle derived neurotrophic factors may be responsible for improved regeneration.

  6. Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke.

    PubMed

    Gustafsson, Elin; Andsberg, Gunnar; Darsalia, Vladimer; Mohapel, Paul; Mandel, Ronald J; Kirik, Deniz; Lindvall, Olle; Kokaia, Zaal

    2003-06-01

    To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.

  7. Brain-derived neurotrophic factor regulates cell motility in human colon cancer.

    PubMed

    Huang, Ssu-Ming; Lin, Chingju; Lin, Hsiao-Yun; Chiu, Chien-Ming; Fang, Chia-Wei; Liao, Kuan-Fu; Chen, Dar-Ren; Yeh, Wei-Lan

    2015-06-01

    Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominant-negative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.

  8. Parvalbumin immunoreactivity is enhanced by brain-derived neurotrophic factor in organotypic cultures of rat retina.

    PubMed

    Rickman, D W

    1999-11-15

    The rodent retina undergoes considerable postnatal neurogenesis and phenotypic differentiation, and it is likely that diffusible neurotrophic factors contribute to this development and to the subsequent formation of functional retinal circuitry. Accordingly, perturbation of specific neurotrophin ligand-receptor interactions has provided valuable information as to the fundamental processes underlying this development. In the present studies we have built upon our previous observation that suppression of expression of trk(B), the high-affinity receptor for brain-derived neurotrophic factor (BDNF), in the postnatal rat retina results in the alteration of a specific interneuron in the rod pathway-the parvalbumin (PV)-immunoreactive AII amacrine cell. Here, we isolated retinas from newborn rats and maintained them in organotypic culture for up to 14 days (approximating the time of eye opening, in vivo) in the presence of individual neurotrophins [BDNF or nerve growth factor (NGF)]. We then examined histological sections of cultures for PV immunoreactivity. In control cultures, only sparse PV-immunostained cells were observed. In cultures supplemented with NGF, numerous lightly immunostained somata were present in the inner nuclear layer (INL) at the border of the inner plexiform layer (IPL). Many of these cells had rudimentary dendritic arborizations in the IPL. Cultures supplemented with BDNF displayed numerous well-immunostained somata at the INL/IPL border that gave rise to elaborate dendritic arborizations that approximated the morphology of mature AII amacrine cells in vivo. These observations indicate that neurotrophins have specific effects upon the neurochemical and, perhaps, morphological differentiation of an important interneuron in a specific functional retinal circuit.

  9. Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression.

    PubMed

    Adlard, P A; Cotman, C W

    2004-01-01

    Exercise is increasingly recognized as an intervention that can reduce CNS dysfunctions such as cognitive decline, depression and stress. Previously we have demonstrated that brain-derived neurotrophic factor (BDNF) is increased in the hippocampus following exercise. In this study we tested the hypothesis that exercise can counteract a reduction in hippocampal BDNF protein caused by acute immobilization stress. Since BDNF expression is suppressed by corticosterone (CORT), circulating CORT levels were also monitored. In animals subjected to 2 h immobilization stress, CORT was elevated immediately following, and at 1 h after the cessation of stress, but remained unchanged from baseline up to 24 h post-stress. The stress protocol resulted in a reduction in BDNF protein at 5 and 10 h post-stress that returned to baseline at 24 h. To determine if exercise could prevent this stress-induced reduction in BDNF protein, animals were given voluntary access to running wheels for 3 weeks prior to the stress. Stressed animals, in the absence of exercise, again demonstrated an initial elevation in CORT (at 0 h) and a subsequent decrease in hippocampal BDNF at the 10 h time point. Exercising animals, both non-stressed and stressed, demonstrated circulating CORT and hippocampal BDNF protein levels that were significantly elevated above control values at both time points examined (0 and 10 h post-stress). Thus, the persistently high CORT levels in exercised animals did not affect the induction of BDNF with exercise, and the effect of immobilization stress on BDNF protein was overcome. To examine the role of CORT in the stress-related regulation of BDNF protein, experiments were carried out in adrenalectomized (ADX) animals. BDNF protein was not downregulated as a result of immobilization stress in ADX animals, while there continued to be an exercise-induced upregulation of BDNF. This study demonstrates that CORT modulates stress-related alterations in BDNF protein. Further, exercise

  10. Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates

    EPA Science Inventory

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expressio...

  11. Human umbilical cord blood stem cells and brain-derived neurotrophic factor for optic nerve injury: a biomechanical evaluation

    PubMed Central

    Zhang, Zhong-jun; Li, Ya-jun; Liu, Xiao-guang; Huang, Feng-xiao; Liu, Tie-jun; Jiang, Dong-mei; Lv, Xue-man; Luo, Min

    2015-01-01

    Treatment for optic nerve injury by brain-derived neurotrophic factor or the transplantation of human umbilical cord blood stem cells has gained progress, but analysis by biomechanical indicators is rare. Rabbit models of optic nerve injury were established by a clamp. At 7 days after injury, the vitreous body received a one-time injection of 50 μg brain-derived neurotrophic factor or 1 × 106 human umbilical cord blood stem cells. After 30 days, the maximum load, maximum stress, maximum strain, elastic limit load, elastic limit stress, and elastic limit strain had clearly improved in rabbit models of optical nerve injury after treatment with brain-derived neurotrophic factor or human umbilical cord blood stem cells. The damage to the ultrastructure of the optic nerve had also been reduced. These findings suggest that human umbilical cord blood stem cells and brain-derived neurotrophic factor effectively repair the injured optical nerve, improve biomechanical properties, and contribute to the recovery after injury. PMID:26330839

  12. Dental pulp cells produce neurotrophic factors, interact with trigeminal neurons in vitro, and rescue motoneurons after spinal cord injury.

    PubMed

    Nosrat, I V; Widenfalk, J; Olson, L; Nosrat, C A

    2001-10-01

    Interactions between ingrowing nerve fibers and their target tissues form the basis for functional connectivity with the central nervous system. Studies of the developing dental pulp innervation by nerve fibers from the trigeminal ganglion is an excellent example of nerve-target tissue interactions and will allow specific questions regarding development of the dental pulp nerve system to be addressed. Dental pulp cells (DPC) produce an array of neurotrophic factors during development, suggesting that these proteins might be involved in supporting trigeminal nerve fibers that innervate the dental pulp. We have established an in vitro culture system to study the interactions between the dental pulp cells and trigeminal neurons. We show that dental pulp cells produce several neurotrophic factors in culture. When DPC are cocultured with trigeminal neurons, they promote survival and a specific and elaborate neurite outgrowth pattern from trigeminal neurons, whereas skin fibroblasts do not provide a similar support. In addition, we show that dental pulp tissue becomes innervated when transplanted ectopically into the anterior chamber of the eye in rats, and upregulates the catecholaminergic nerve fiber density of the irises. Interestingly, grafting the dental pulp tissue into hemisected spinal cord increases the number of surviving motoneurons, indicating a functional bioactivity of the dental pulp-derived neurotrophic factors in vivo by rescuing motoneurons. Based on these findings, we propose that dental pulp-derived neurotrophic factors play an important role in orchestrating the dental pulp innervation.

  13. Brain-Derived Neurotrophic Factor and the Development of Structural Neuronal Connectivity

    PubMed Central

    Cohen-Cory, Susana; Kidane, Adhanet H.; Shirkey, Nicole J.; Marshak, Sonya

    2010-01-01

    During development, neural networks are established in a highly organized manner which persists throughout life. Neurotrophins play crucial roles in the developing nervous system. Among the neurotrophins, brain-derived neurotrophic factor (BDNF) is highly conserved in gene structure and function during vertebrate evolution, and serves an important role during brain development and in synaptic plasticity. BDNF participates in the formation of appropriate synaptic connections in the brain, and disruptions in this process contribute to disorders of cognitive function. In this review, we first briefly highlight current knowledge on the expression, regulation, and secretion of BDNF. Further, we provide an overview of the possible actions of BDNF in the development of neural circuits, with an emphasis on presynaptic actions of BDNF during the structural development of central neurons. PMID:20186709

  14. Activity-dependent expression of brain-derived neurotrophic factor in dendrites: facts and open questions.

    PubMed

    Tongiorgi, Enrico

    2008-08-01

    Long-lasting synaptic changes in transmission and morphology at the basis of memory storage, require delivery of newly synthesized proteins to affected synapses. Although many of these proteins are generated in the cell body, several key molecules for plasticity can be delivered in the form of silent mRNAs at synapses in extra somatic compartments where they are locally translated. One of such mRNAs encodes brain-derived neurotrophic factor (BDNF), a key molecule in neuronal development, learning and memory. A single BDNF protein is produced from several splice variants having a different 5' untranslated region. These mRNA variants have a different subcellular localization (soma, proximal or distal dendritic compartment) and may represent a spatial code for a local control of BDNF availability. This review will highlight current knowledge on the mechanisms of spatial and temporal regulation of activity-dependent BDNF mRNA localization in dendrites in relation with synaptic plasticity.

  15. [BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF): NEUROBIOLOGY AND MARKER VALUE IN NEUROPSYCHIATRY].

    PubMed

    Levada, O A; Cherednichenko, N V

    2015-01-01

    In this review current publications about neurobiology and marker value of brain derived neurotrophic factor (BDNF) in neuropsychiatry are analyzed. It is shown that BDNF is an important member of the family of neurotrophins which widely represented in various structures of the CNS. In prenatal period BDNF is involved in all stages of neuronal networks formation, and in the postnatal period its main role is maintaining the normal brain architectonics, involvement in the processes of neurogenesis and realization of neuroprotective functions. BDNF plays an important role in learning and memory organization, food and motor behavior. BDNF brain expression decreases with age, as well as in degenerative and vascular dementias, affective, anxiety, and behavioral disorders. The reducing of BDNF serum, level reflects the decreasing of its cerebral expression and could be used as a neurobiological marker of these pathological processes but the rising of its concentration could indicate the therapy effectiveness.

  16. Serum concentrations of brain-derived neurotrophic factor in patients with gender identity disorder.

    PubMed

    Fontanari, Anna-Martha V; Andreazza, Tahiana; Costa, Ângelo B; Salvador, Jaqueline; Koff, Walter J; Aguiar, Bianca; Ferrari, Pamela; Massuda, Raffael; Pedrini, Mariana; Silveira, Esalba; Belmonte-de-Abreu, Paulo S; Gama, Clarissa S; Kauer-Sant'Anna, Marcia; Kapczinski, Flavio; Lobato, Maria Ines R

    2013-10-01

    Gender Identity Disorder (GID) is characterized by a strong and persistent cross-gender identification that affects different aspects of behavior. Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF-signaling is thought to contribute to the pathogenesis of psychiatric disordersand is related to traumatic life events. To examine serum BDNF levels, we compared one group of DSM-IV GID patients (n = 45) and one healthy control group (n = 66). Serum BDNF levels were significantly decreased in GID patients (p = 0.013). This data support the hypothesis that the reduction found in serum BDNF levels in GID patients may be related to the psychological abuse that transsexuals are exposed during their life.

  17. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments.

    PubMed

    Cunha, Carla; Angelucci, Andrea; D'Antoni, Angela; Dobrossy, Mate D; Dunnett, Stephen B; Berardi, Nicoletta; Brambilla, Riccardo

    2009-03-01

    In this study we analyzed the effect on behavior of a chronic exposure to brain-derived neurotrophic factor (BDNF), by analysing a mouse line overexpressing BDNF under the alphaCaMKII promoter, which drives the transgene expression exclusively to principal neurons of the forebrain. BDNF transgenic mice and their WT littermates were examined with a battery of behavioral tests, in order to evaluate motor coordination, learning, short and long-term memory formation. Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.

  18. The brain derived neurotrophic factor and influences of stress in depression.

    PubMed

    Kimpton, Jessica

    2012-09-01

    Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is widely expressed throughout the central nervous system (CNS). BDNF is involved in proliferation, differentiation, survival and death of neuronal and non-neuronal cells in the developing and adult CNS. The BDNF hypothesis of depression postulates that a reduction in BDNF is directly involved in the pathophysiology of depression, whilst anti-depressant mediated restoration of BDNF is responsible for the alleviation of the depressive state. This hypothesis is drawn from several studies implicating BDNF in depression and has received considerable support, which will be reviewed in this paper. This review will also discuss the implications of the functional Val66Met polymorphism of the gene encoding BDNF, which may reduce BDNF expression particularly when exposed to stress and thus may play a critical role in the pathogenesis of depression.

  19. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments.

    PubMed

    Castrén, Eero; Kojima, Masami

    2017-01-01

    Levels of brain-derived neurotrophic factor (BDNF) are reduced in the brain and serum of depressed patients and at least the reduction in serum levels is reversible upon successful treatment. These data, together with a wealth of reports using different animal models with depression-like behavior or manipulation of expression of BDNF or its receptor TrkB have implicated BDNF in the pathophysiology of depression as well as in the mechanism of action of antidepressant treatments. Recent findings have shown that posttranslational processing of BDNF gene product can yield different molecular entities that differently influence signaling through BNDF receptor TrkB and the pan-neurotrophin receptor p75(NTR). We will here review these data and discuss new insights into the possible pathophysiological roles of those new BDNF subtypes as well as recent findings on the role of BDNF mediated neuronal plasticity in mood disorders and their treatments.

  20. Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus.

    PubMed

    Mou, Zongyang; Hyde, Thomas M; Lipska, Barbara K; Martinowich, Keri; Wei, Peter; Ong, Chiew-Jen; Hunter, Lindsay A; Palaguachi, Gladys I; Morgun, Eva; Teng, Rujia; Lai, Chen; Condarco, Tania A; Demidowich, Andrew P; Krause, Amanda J; Marshall, Leslie J; Haack, Karin; Voruganti, V Saroja; Cole, Shelley A; Butte, Nancy F; Comuzzie, Anthony G; Nalls, Michael A; Zonderman, Alan B; Singleton, Andrew B; Evans, Michele K; Martin, Bronwen; Maudsley, Stuart; Tsao, Jack W; Kleinman, Joel E; Yanovski, Jack A; Han, Joan C

    2015-11-10

    Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

  1. Brain-derived neurotrophic factor does not improve recovery after cardiac arrest in rats.

    PubMed

    Callaway, Clifton W; Ramos, Ramiro; Logue, Eric S; Betz, Amy E; Wheeler, Matthew; Repine, Melissa J

    2008-11-07

    Increased brain-derived neurotrophic factor (BDNF) levels and extracellular-signal regulated kinase (ERK) signaling are associated with reduced brain injury after cerebral ischemia. In particular, mild hypothermia after cardiac arrest increases BDNF and ERK signaling. This study tested whether intracerebroventricular infusions (0.025 microg/h x 3 days) of BDNF also improved recovery of rats resuscitated from cardiac arrest and maintained at 37 degrees C. BDNF infusions initiated at the time of cardiac arrest did not alter survival, neurological recovery, or histological injury. Separate experiments confirmed that BDNF infusions increased tissue levels of BDNF. However, these infusions did not increase ERK activation in hippocampus. These data suggest that increased BDNF levels are not sufficient to explain the beneficial effects of mild hypothermia after cardiac arrest, and that exogenous BDNF administration does not increase extracellular ERK signaling.

  2. Aerobic Exercise Does Not Predict Brain Derived Neurotrophic Factor And Cortisol Alterations in Depressed Patients.

    PubMed

    Lamego, Murilo Khede; de Souza Moura, Antonio Marcos; Paes, Flávia; Ferreira Rocha, Nuno Barbosa; de Sá Filho, Alberto Souza; Lattari, Eduardo; Rimes, Ridson; Manochio, João; Budde, Henning; Wegner, Mirko; Mura, Gioia; Arias-Carrión, Oscar; Yuan, Ti-Fei; Nardi, Antonio Egidio; Machado, Sergio

    2015-01-01

    The pathophysiology of depression is related to neurobiological changes that occur in the monoamine system, hypothalamic-pituitary-adrenal axis, neurogenesis system and the neuroimmune system. In recent years, there has been a growing interest in the research of the effects of exercise on brain function, with a special focus on its effects on brain-derived neurotrophic factor (BDNF), cortisol and other biomarkers. Thus, the aim of this study is to present a review investigating the acute and chronic effects of aerobic exercise on BDNF and cortisol levels in individuals with depression. It was not possible to establish an interaction between aerobic exercise and concentration of BDNF and cortisol, which may actually be the result of the divergence of methods, such as type of exercises, duration of the sessions, and prescribed intensity and frequency of sessions.

  3. Rapid and Sensitive Detection of Brain-Derived Neurotrophic Factor with a Plasmonic Chip

    NASA Astrophysics Data System (ADS)

    Tawa, Keiko; Satoh, Mari; Uegaki, Koichi; Hara, Tomoko; Kojima, Masami; Kumanogoh, Haruko; Aota, Hiroyuki; Yokota, Yoshiki; Nakaoki, Takahiko; Umetsu, Mitsuo; Nakazawa, Hikaru; Kumagai, Izumi

    2013-06-01

    Plasmonic chips, which are grating replicas coated with thin metal layers and overlayers such as ZnO, were applied in immunosensors to improve their detection sensitivity. Fluorescence from labeled antibodies bound to plasmonic chips can be enhanced on the basis of a grating-coupled surface plasmon resonance (GC-SPR) field. In this study, as one of the representative candidate protein markers for brain disorders, the brain-derived neurotrophic factor (BDNF) was quantitatively measured by sandwich assay on a plasmonic chip and detected on our plasmonic chip in the concentration of 5-7 ng/mL within 40 min. Furthermore, BDNF was detected in the blood sera from three types of mice: wild-type mice and two types of mutant mice. This technique is promising as a new clinical diagnosis tool for brain disorders based on scientific evidence such as blood test results.

  4. Brain derived neurotrophic factor release from layer-by-layer coated agarose nerve guidance scaffolds.

    PubMed

    Lynam, Daniel A; Shahriari, Dena; Wolf, Kayla J; Angart, Phillip A; Koffler, Jacob; Tuszynski, Mark H; Chan, Christina; Walton, Patrick; Sakamoto, Jeffrey

    2015-05-01

    Agarose nerve guidance scaffolds (NGS) seeded with cells expressing brain derived neurotrophic factor (BDNF) have demonstrated robust nerve regeneration in the rat central nervous system. The purpose of this work was to explore whether agarose NGS coated with hydrogen-bonded layer-by-layer (HLbL) could provide an acellular method of delivering prolonged and consistent dosages of active BDNF. Our results show that HLbL-coated agarose NGS could release BDNF over 10days in consistent dosages averaging 80.5±12.5(SD)ng/mL. Moreover, the BDNF released from HLbL was confirmed active by in vitro cell proliferation assays. To our knowledge, this is the first report demonstrating that HLbL assembled onto a hydrogel can provide consistent, prolonged release of active BDNF in clinically relevant dosages.

  5. Effect of selegiline on neural stem cells differentiation: a possible role for neurotrophic factors

    PubMed Central

    Hassanzadeh, Kambiz; Nikzaban, Mehrnoush; Moloudi, Mohammad Raman; Izadpanah, Esmael

    2015-01-01

    Objective(s): The stimulation of neural stem cells (NSCs) differentiation into neurons has attracted great attention in management of neurodegenerative disease and traumatic brain injury. It has been reported that selegiline could enhance the morphologic differentiation of embryonic stem cells. Therefore this study aimed to investigate the effects of selegiline on NSCs differentiation with focus on the role of neurotrophic factor gene expression. Materials and Methods: The NSCs were isolated from lateral ventricle of C57 mice brain. The cells were exposed to selegiline in nano to micromolar concentrations for 24 hr or 72 hr. In order to assay the effect of selegiline on NSCs differentiation into neurons, astrocytes and oligodendrocytes, immunocytochemical techniques were utilized. Samples were exposed to specific antibodies against neurons (β tubulin), astrocytes (GFAP) and oligodendrocytes (OSP). The expression of BDNF, NGF and NT3 genes was investigated using Real-Time PCR. Results: Our findings revealed that selegiline increased NSCs differentiation into neurons at 10-7 and 10-8 M and decreased the differentiation into astrocytes at 10-9, while oligodendrocyte did not significantly change in any of the used concentrations. In addition data analyses showed that selegiline increased BDNF, NGF and NT3 gene expression at 24 hr, but did not change them in the other time of exposure (72 hr) except 10-7 M concentration of selegiline, which increased NT3 expression. Conclusion: Our results indicate selegiline induced the differentiation of NSCs into neurons and in this context the role of neurotrophic factors is important and should be considered. PMID:26221478

  6. Reduced serum concentrations of nerve growth factor, but not brain-derived neurotrophic factor, in chronic cannabis abusers.

    PubMed

    Angelucci, Francesco; Ricci, Valerio; Spalletta, Gianfranco; Pomponi, Massimiliano; Tonioni, Federico; Caltagirone, Carlo; Bria, Pietro

    2008-12-01

    Chronic cannabis use produces effects within the central nervous system (CNS) which include deficits in learning and attention tasks and decreased brain volume. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are proteins that serve as survival factors for CNS neurons. Deficits in the production and utilization of these proteins can lead to CNS dysfunctions including those associated with cannabis abuse. In this study we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF serum levels in two groups of subjects: cannabis-dependent patients and healthy subjects. We found that NGF serum levels were significantly reduced in cannabis abusers as compared to healthy subjects. These findings indicate that NGF may have a role in the central action of cannabis and potentially in the neurotoxicity induced by this drug. These data also suggest that chronic cannabis consumption may be a risk factor for developing psychosis among drug users.

  7. Effects of brain-derived neurotrophic factor on local inflammation in experimental stroke of rat.

    PubMed

    Jiang, Yongjun; Wei, Ning; Zhu, Juehua; Lu, Tingting; Chen, Zhaoyao; Xu, Gelin; Liu, Xinfeng

    2010-01-01

    This study was aimed to investigate whether brain-derived neurotrophic factor (BDNF) can modulate local cerebral inflammation in ischemic stroke. Rats were subjected to ischemia by occluding the right middle cerebral artery (MCAO) for 2 hours. Rats were randomized as control, BDNF, and antibody groups. The local inflammation was evaluated on cellular, cytokine, and transcription factor levels with immunofluorescence, enzyme-linked immunosorbent assay, real-time qPCR, and electrophoretic mobility shift assay, respectively. Exogenous BDNF significantly improved motor-sensory, sensorimotor function, and vestibulomotor function, while BDNF did not decrease the infarct volume. Exogenous BDNF increased the number of both activated and phagocytotic microglia in brain. BDNF upregulated interleukin10 and its mRNA expression, while downregulated tumor necrosis factor α and its mRNA expression. BDNF also increased DNA-binding activity of nuclear factor-kappa B. BDNF antibody, which blocked the activity of endogenous BDNF, showed the opposite effect of exogenous BDNF. Our data indicated that BDNF may modulate local inflammation in ischemic brain tissues on the cellular, cytokine, and transcription factor levels.

  8. Effect of Brain-Derived Neurotrophic Factor Haploinsufficiency on Stress-Induced Remodeling of Hippocampal Neurons

    PubMed Central

    Magariños, A.M.; Li, C.J.; Toth, J. Gal; Bath, K.G.; Jing, D.; Lee, F.S.; McEwen, B.S.

    2010-01-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. PMID:20095008

  9. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons.

    PubMed

    Magariños, A M; Li, C J; Gal Toth, J; Bath, K G; Jing, D; Lee, F S; McEwen, B S

    2011-03-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF(±) ) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF(±) mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF(±) mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling.

  10. Neurotrophic factors for spinal cord repair: Which, where, how and when to apply, and for what period of time?

    PubMed

    Harvey, Alan R; Lovett, Sarah J; Majda, Bernadette T; Yoon, Jun H; Wheeler, Lachlan P G; Hodgetts, Stuart I

    2015-09-04

    A variety of neurotrophic factors have been used in attempts to improve morphological and behavioural outcomes after experimental spinal cord injury (SCI). Here we review many of these factors, their cellular targets, and their therapeutic impact on spinal cord repair in different, primarily rodent, models of SCI. A majority of studies report favourable outcomes but results are by no means consistent, thus a major aim of this review is to consider how best to apply neurotrophic factors after SCI to optimize their therapeutic potential. In addition to which factors are chosen, many variables need be considered when delivering trophic support, including where and when to apply a given factor or factors, how such factors are administered, at what dose, and for how long. Overall, the majority of studies have applied neurotrophic support in or close to the spinal cord lesion site, in the acute or sub-acute phase (0-14 days post-injury). Far fewer chronic SCI studies have been undertaken. In addition, comparatively fewer studies have administered neurotrophic factors directly to the cell bodies of injured neurons; yet in other instructive rodent models of CNS injury, for example optic nerve crush or transection, therapies are targeted directly at the injured neurons themselves, the retinal ganglion cells. The mode of delivery of neurotrophic factors is also an important variable, whether delivered by acute injection of recombinant proteins, sub-acute or chronic delivery using osmotic minipumps, cell-mediated delivery, delivery using polymer release vehicles or supporting bridges of some sort, or the use of gene therapy to modify neurons, glial cells or precursor/stem cells. Neurotrophic factors are often used in combination with cell or tissue grafts and/or other pharmacotherapeutic agents. Finally, the dose and time-course of delivery of trophic support should ideally be tailored to suit specific biological requirements, whether they relate to neuronal survival, axonal

  11. Ovarian brain-derived neurotrophic factor (BDNF) promotes the development of oocytes into preimplantation embryos

    PubMed Central

    Kawamura, Kazuhiro; Kawamura, Nanami; Mulders, Sabine M.; Gelpke, Maarten D. Sollewijn; Hsueh, Aaron J. W.

    2005-01-01

    Optimal development of fertilized eggs into preimplantation embryos is essential for reproduction. Although mammalian oocytes ovulated after luteinizing hormone (LH) stimulation can be fertilized and promoted into early embryos in vitro, little is known about ovarian factors important for the conditioning of eggs for early embryo development. Because LH interacts only with ovarian somatic cells, its potential regulation of oocyte functions is presumably mediated by local paracrine factors. We performed DNA microarray analyses of ovarian transcripts and identified brain-derived neurotrophic factor (BDNF) secreted by granulosa and cumulus cells as an ovarian factor stimulated by the preovulatory LH surge. Ovarian BDNF acts on TrkB receptors expressed exclusively in oocytes to enhance first polar body extrusion of oocytes and to promote the in vitro development of zygotes into preimplantation embryos. Furthermore, in vivo treatment with a Trk receptor inhibitor suppressed first polar body extrusion and the progression of zygotes into blastocysts. Thus, ovarian BDNF is important to nuclear and cytoplasmic maturation of the oocyte, which is essential for successful oocyte development into preimplantation embryos. Treatment with BDNF could condition the cultured oocytes for optimal progression into the totipotent blastocysts. PMID:15967989

  12. Growth and turning properties of adult glial cell-derived neurotrophic factor coreceptor α1 nonpeptidergic sensory neurons.

    PubMed

    Guo, GuiFang; Singh, Vandana; Zochodne, Douglas W

    2014-09-01

    An overlapping population of adult primary sensory neurons that innervate the skin express the glial cell-derived neurotrophic factor coreceptor α1 (GFRα1), the lectin IB4, and the "regenerative brake" phosphatase and tensin homolog deleted on chromosome 10. Using an adapted turning and growth assay, we analyzed the growth cone behavior of adult immunoselected GFRα1 sensory neurons. These neurons had less robust baseline growth and reluctant responsiveness to individual growth factors but responded to synergistic types of input from glial cell-derived neurotrophic factor, hepatocyte growth factor, a phosphatase and tensin homolog deleted on chromosome 10 inhibitor, or a downstream Rho kinase inhibitor. Hepatocyte growth factor and the phosphatase and tensin homolog deleted on chromosome 10 inhibitor were associated with growth cone turning. A gradient of protein extracted from skin samples, a primary target of GFRα1 axons, replicated the impact of synergistic support. Within the skin, glial cell-derived neurotrophic factor was expressed within epidermal axons, indicating an autocrine role accompanying local hepatocyte growth factor synthesis. Taken together, our findings identify unique growth properties and plasticity of a distinct population of epidermal axons that are relevant to neurologic repair and skin reinnervation.

  13. Ciliary neurotrophic factor-treated astrocyte-conditioned medium increases the intracellular free calcium concentration in rat cortical neurons

    PubMed Central

    SUN, MEIQUN; LIU, HONGLI; MIN, SHENGPING; WANG, HONGTAO; WANG, XIAOJING

    2016-01-01

    Ciliary neurotrophic factor (CNTF) is involved in the activation of astrocytes. A previous study showed that CNTF-treated astrocyte-conditioned medium (CNTF-ACM) contributed to the increase of the calcium current and the elevation of corresponding ion channels in cortical neurons. On this basis, it is reasonable to assume that CNTF-ACM may increase the intracellular free calcium concentration ([Ca2+]i) in neurons. In the present study, the effects of CNTF-ACM on [Ca2+]i in rat cortical neurons were determined, and on this basis, the aim was to investigate the potential active ingredients in ACM that are responsible for this biological process. As expected, the data indicated that CNTF-ACM resulted in a clear elevation of [Ca2+]i in neurons. Additionally, the fibroblast growth factor-2 (FGF-2) contained in the CNTF-ACM was found to participate in the upregulation of [Ca2+]i. Taken together, CNTF induces the production of active factors (at least including FGF-2) released from astrocytes, which finally potentiate the increase of [Ca2+]i in cortical neurons. PMID:27073624

  14. [Brain-derived neurotrophic factor: from nerve growth factor to modulator of brain plasticity in cognitive processes and psychiatric diseases].

    PubMed

    Laske, C; Eschweiler, G W

    2006-05-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and plays an important role in neuronal survival and plasticity in the CNS. The proform of BDNF (pro-BDNF) is secreted and cleaved extracellularly by the serine protease plasmin to mature BDNF, which potentiates synaptic plasticity and long-term potentiation. Recent findings in animal models suggest an involvement of BDNF and its genetic functional single nucleotide polymorphism in the pathogenesis of different psychiatric diseases including depression, mania, schizophrenia, eating disorders, dementia, and Huntington's disease. In the brain and serum, BDNF is modulated by different factors. It is downregulated by stress and upregulated by learning processes, several antidepressive treatments, physical activity, and dietary restriction. Measurement of BDNF serum concentrations may be of diagnostic value. Additionally, the influence of different strategies for BDNF allocation seems to be relevant for the treatment and prevention of the above psychiatric disorders.

  15. Brain-derived neurotrophic factor as a drug target for CNS disorders.

    PubMed

    Pezet, Sophie; Malcangio, Marzia

    2004-10-01

    Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of trophic factors. BDNF is widely and abundantly expressed in the CNS and is available to some peripheral nervous system neurons that uptake the neurotrophin produced by peripheral tissues. BDNF promotes survival and differentiation of certain neuronal populations during development. In adulthood, BDNF can modulate neuronal synaptic strength and has been implicated in hippocampal mechanisms of learning and memory and spinal mechanisms for pain. Several CNS disorders are associated with a decrease in trophic support. As BDNF and its high affinity receptor are abundant throughout the whole CNS, and BDNF is a potent neuroprotective agent, this trophic factor is a good candidate for therapeutic treatment of some of CNS disorders. This review aims to correlate the features of some CNS disorders (Parkinson's disease, Alzheimer's disease, depression, epilepsy and chronic pain) to changes in BDNF expression in the brain. The cellular and molecular mechanism by which BDNF might be a therapeutic strategy are critically examined.

  16. Quantitative analysis of cerebrospinal fluid brain derived neurotrophic factor in the patients with multiple sclerosis.

    PubMed

    Mashayekhi, Farhad; Salehi, Zivar; Jamalzadeh, Hamid Reza

    2012-01-01

    Multiple sclerosis (MS) is the most common cause ofnontraumatic neurological disability in Europe and North America. Growth factor expression could participate in the repair process of the demyelinating disease. Among growth factors, brain derived neurotrophic factors (BDNF) has been demonstrated to play an important role in neuronal and axonal survival. In the central nervous system (CNS), neurons are the main source of BDNF. Another potential source are activated astrocytes, which are present in inflamed areas in the CNS as shown in MS. In this study, total protein concentration (TPC) and BDNF levels in the cerebrospinal fluid (CSF) samples from the patients with MS (n = 48) and control subjects (n = 53) were measured using a Bio-Rad protein assay and enzyme linked immunosorbent assay (ELISA). No significant change in the CSF TPC of patients with MS was seen as compared to normal CSF. The presence of BDNF in the CSF samples was shown by Western blot. Using ELISA, it was shown that the level of BDNF in the MS CSF is higher than in normal CSF. It is concluded that BDNF is a constant component of human CSF. Moreover, it could be implicated in the pathophysiology of MS.

  17. Edaravone enhances brain-derived neurotrophic factor production in the ischemic mouse brain.

    PubMed

    Okuyama, Satoshi; Morita, Mayu; Sawamoto, Atsushi; Terugo, Tsukasa; Nakajima, Mitsunari; Furukawa, Yoshiko

    2015-04-02

    Edaravone, a clinical drug used to treat strokes, protects against neuronal cell death and memory loss in the ischemic brains of animal models through its antioxidant activity. In the present study, we subcutaneously administrated edaravone to mice (3 mg/kg/day) for three days immediately after bilateral common carotid artery occlusion, and revealed through an immunohistochemical analysis that edaravone (1) accelerated increases in the production of brain-derived neurotrophic factor (BDNF) in the hippocampus; (2) increased the number of doublecortin-positive neuronal precursor cells in the dentate gyrus subgranular zone; and (3) suppressed the ischemia-induced inactivation of calcium-calmodulin-dependent protein kinase II in the hippocampus. We also revealed through a Western blotting analysis that edaravone (4) induced the phosphorylation of cAMP response element-binding (CREB), a transcription factor that regulates BDNF gene expression; and (5) induced the phosphorylation of extracellular signal-regulated kinases 1/2, an upstream signal factor of CREB. These results suggest that the neuroprotective effects of edaravone following brain ischemia were mediated not only by the elimination of oxidative stress, but also by the induction of BDNF production.

  18. Adjuvant neurotrophic factors in peripheral nerve repair with chondroitin sulfate proteoglycan-reduced acellular nerve allografts

    PubMed Central

    Boyer, Richard B.; Sexton, Kevin W.; Rodriguez-Feo, Charles L.; Nookala, Ratnam; Pollins, Alonda C.; Cardwell, Nancy L.; Tisdale, Keonna Y.; Nanney, Lillian B.; Shack, R. Bruce; Thayer, Wesley P.

    2014-01-01

    Background Acellular nerve allografts are now standard tools in peripheral nerve repair due to decreased donor site morbidity and operative time savings. Preparation of nerve allografts involves several steps of decellularization and modification of extracellular matrix to remove chondroitin sulfate proteoglycans (CSPGs), which have been shown to inhibit neurite outgrowth through a poorly understood mechanism involving RhoA and ECM-integrin interactions. Chondroitinase ABC (ChABC) is an enzyme that degrades CSPG molecules and has been shown to promote neurite outgrowth following injury of the central and peripheral nervous systems. Variable results following chondroitinase ABC treatment make it difficult to predict the effects of this drug in human nerve allografts, especially in the presence of native extracellular signaling molecules. Several studies have shown cross-talk between neurotrophic factor and CSPG signaling pathways, but their interaction remains poorly understood. In this study, we examined the adjuvant effects of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on neurite outgrowth post-injury in CSPG-reduced substrates and acellular nerve allografts. Materials and Methods E12 chicken DRG explants were cultured in medium containing ChABC, ChABC + NGF, ChABC + GDNF or control media. Explants were imaged at 3 d and neurite outgrowths measured. The rat sciatic nerve injury model involved a 1-cm sciatic nerve gap that was microsurgically repaired with ChABC pre-treated acellular nerve allografts. Prior to implantation, nerve allografts were incubated in NGF, GDNF or sterile water. Nerve histology was evaluated at 5d and 8wk post-injury. Results The addition of GDNF in vitro produced significant increase in sensory neurite length at 3 d compared to ChABC alone (P < 0.01), while NGF was not significantly different from control. In vivo adjuvant NGF produced increases in total myelinated axon count (P < 0.005) and motor axon

  19. Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons.

    PubMed

    Satriotomo, I; Nichols, N L; Dale, E A; Emery, A T; Dahlberg, J M; Mitchell, G S

    2016-05-13

    Repetitive acute intermittent hypoxia (rAIH) increases growth/trophic factor expression in respiratory motor neurons, thereby eliciting spinal respiratory motor plasticity and/or neuroprotection. Here we demonstrate that rAIH effects are not unique to respiratory motor neurons, but are also expressed in non-respiratory, spinal alpha motor neurons and upper motor neurons of the motor cortex. In specific, we used immunohistochemistry and immunofluorescence to assess growth/trophic factor protein expression in spinal sections from rats exposed to AIH three times per week for 10weeks (3×wAIH). 3×wAIH increased brain-derived neurotrophic factor (BDNF), its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and phosphorylated TrkB (pTrkB) immunoreactivity in putative alpha motor neurons of spinal cervical 7 (C7) and lumbar 3 (L3) segments, as well as in upper motor neurons of the primary motor cortex (M1). 3×wAIH also increased immunoreactivity of vascular endothelial growth factor A (VEGFA), the high-affinity VEGFA receptor (VEGFR-2) and an important VEGF gene regulator, hypoxia-inducible factor-1α (HIF-1α). Thus, rAIH effects on growth/trophic factors are characteristic of non-respiratory as well as respiratory motor neurons. rAIH may be a useful tool in the treatment of disorders causing paralysis, such as spinal injury and motor neuron disease, as a pretreatment to enhance motor neuron survival during disease, or as preconditioning for cell-transplant therapies.

  20. Peripheral brain-derived neurotrophic factor is related to cardiovascular risk factors in active and inactive elderly men

    PubMed Central

    Zembron-Lacny, A.; Dziubek, W.; Rynkiewicz, M.; Morawin, B.; Woźniewski, M.

    2016-01-01

    Regular exercise plays an important preventive and therapeutic role in heart and vascular diseases, and beneficially affects brain function. In blood, the effects of exercise appear to be very complex and could include protection of vascular endothelial cells via neurotrophic factors and decreased oxidative stress. The purpose of this study was to identify the age-related changes in peripheral brain-derived neurotrophic factor (BDNF) and its relationship to oxidative damage and conventional cardiovascular disease (CVD) biomarkers, such as atherogenic index, C-reactive protein (hsCRP) and oxidized LDL (oxLDL), in active and inactive men. Seventeen elderly males (61-80 years) and 17 young males (20-24 years) participated in this study. According to the 6-min Åstrand-Rhyming bike test, the subjects were classified into active and inactive groups. The young and elderly active men had a significantly better lipoprotein profile and antioxidant status, as well as reduced oxidative damage and inflammatory state. The active young and elderly men had significantly higher plasma BDNF levels compared to their inactive peers. BDNF was correlated with VO2max (r=0.765, P<0.001). In addition, we observed a significant inverse correlation of BDNF with atherogenic index (TC/HDL), hsCRP and oxLDL. The findings demonstrate that a high level of cardiorespiratory fitness reflected in VO2max was associated with a higher level of circulating BDNF, which in turn was related to common CVD risk factors and oxidative damage markers in young and elderly men. PMID:27332774

  1. [Hematopoietic growth factor EPO has neuro-protective and neuro-trophic effects--review].

    PubMed

    Zhou, Zhuo-Yan; Yang, Mo; Fok, Tai-Fai

    2005-04-01

    Erythropoietin (EPO) is an acidic glycoprotein that was first detected as a hematopoietic factor and its synthesis is triggered in response to cellular hypoxia-sensing. EPO binds to type I cytokine receptors, which associate with the non-receptor tyrosine kinase Jak2, and thereby activate Stat 5a/5b, Ras/MAPK, and PI3-K/Akt signaling pathways. The recent discovery shows that there is a specific EPO/EPO-receptor system in the central nervous system (CNS), independently of the haematopoietic system. Hypoxia and anemia can up-regulate EPO/EPOR expressions in the CNS. Further studies demonstrate that EPO has substantial neuro-protective effects and acts as a neurotrophic factor on central cholinergic neurons, influencing their differentiation and regeneration. EPO also exerts neuro-protective activities in different models of brain damage in vivo and in vitro, such as hypoxia, cerebral ischaemia and sub-arachnoid haemorrhage. EPO may also be involved in synaptic plasticity via the inhibition or stimulation of various neurotransmitters. Therefore, human recombinant EPO that activate its receptors in the central nervous system might be utilized in the future clinical practice involving neuroprotection and brain repair.

  2. Plasma brain-derived neurotrophic factor levels in patients suffering from post-traumatic stress disorder.

    PubMed

    Su, Shanshan; Xiao, Zeping; Lin, Zhiguang; Qiu, Yongming; Jin, Yichao; Wang, Zhen

    2015-09-30

    A number of studies have been done to investigate the role of brain-derived neurotrophic factor (BDNF) in patients with post-traumatic stress disorder (PTSD). In this study we aimed to test the relationship between plasma BDNF levels and PTSD. We solicited 65 subjects having recently experienced road traffic accidents (RTA) conforming to screening criteria. They were given follow-up examinations after one month, three months, and six months. PTSD was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-R-TR, American Psychiatric Association, 2000) using the Mini International Neuropsychiatric Interview (MINI). All participants were divided into two groups: a group with PTSD and a group without PTSD. There were no significant differences in plasma BDNF levels between the two groups at either the 48h or six-month examination. Within the PTSD group, no significant differences were found in plasma BDNF levels between the two examinations. BDNF levels in those without PTSD showed a higher trend over time after trauma. Higher BDNF levels may be an important protective factor for the prevention of traumatized subjects from developing PTSD.

  3. Imipramine induces brain-derived neurotrophic factor mRNA expression in cultured astrocytes.

    PubMed

    Takano, Katsura; Yamasaki, Hiroshi; Kawabe, Kenji; Moriyama, Mitsuaki; Nakamura, Yoichi

    2012-01-01

    Depression is one of the most prevalent and livelihood-threatening forms of mental illnesses and the neural circuitry underlying depression remains incompletely understood. Recent studies suggest that the neuronal plasticity involved with brain-derived neurotrophic factor (BDNF) plays an important role in the recovery from depression. Some antidepressants are reported to induce BDNF expression in vivo; however, the mechanisms have been considered solely in neurons and not fully elucidated. In the present study, we evaluated the effects of imipramine, a classic tricyclic antidepressant drug, on BDNF expression in cultured rat brain astrocytes. Imipramine dose-dependently increased BDNF mRNA expression in astrocytes. The imipramine-induced BDNF increase was suppressed with inhibitors for protein kinase A (PKA) or MEK/ERK. Moreover, imipramine exposure activated transcription factor cAMP response element binding protein (CREB) in a dose-dependent manner. These results suggested that imipramine induced BDNF expression through CREB activation via PKA and/or ERK pathways. Imipramine treatment in depression might exert antidepressant action through BDNF production from astrocytes, and glial BDNF expression might be a target of developing novel antidepressants.

  4. Brain-derived neurotrophic factor promotes central nervous system myelination via a direct effect upon oligodendrocytes.

    PubMed

    Xiao, Junhua; Wong, Agnes W; Willingham, Melanie M; van den Buuse, Maarten; Kilpatrick, Trevor J; Murray, Simon S

    2010-01-01

    The extracellular factors that are responsible for inducing myelination in the central nervous system (CNS) remain elusive. We investigated whether brain-derived neurotrophic factor (BDNF) is implicated, by first confirming that BDNF heterozygous mice exhibit delayed CNS myelination during early postnatal development. We next established that the influence of BDNF upon myelination was direct, by acting on oligodendrocytes, using co-cultures of dorsal root ganglia neurons and oligodendrocyte precursor cells. Importantly, we found that BDNF retains its capacity to enhance myelination of neurons or by oligodendrocytes derived from p75NTR knockout mice, indicating the expression of p75NTR is not necessary for BDNF-induced myelination. Conversely, we observed that phosphorylation of TrkB correlated with myelination, and that inhibiting TrkB signalling also inhibited the promyelinating effect of BDNF, suggesting that BDNF enhances CNS myelination via activating oligodendroglial TrkB-FL receptors. Together, our data reveal a previously unknown role for BDNF in potentiating the normal development of CNS myelination, via signalling within oligodendrocytes.

  5. Novel systems for tailored neurotrophic factor release based on hydrogel and resorbable glass hollow fibers.

    PubMed

    Novajra, G; Tonda-Turo, C; Vitale-Brovarone, C; Ciardelli, G; Geuna, S; Raimondo, S

    2014-03-01

    A novel system for the release of neurotrophic factor into a nerve guidance channel (NGC) based on resorbable phosphate glass hollow fibers (50P2O5-30CaO-9Na2O-3SiO2-3MgO-2.5K2O-2.5TiO2 mol%) in combination with a genipin-crosslinked agar/gelatin hydrogel (A/G_GP) is proposed. No negative effect on the growth of neonatal olfactory bulb ensheathing cell line (NOBEC) as well as on the expression of pro- and anti-apoptotic proteins was measured in vitro in the presence of fiber dissolution products in the culture medium. For the release studies, fluorescein isothiocyanate-dextran (FD-20), taken as growth factor model molecule, was solubilized in different media and introduced into the fiber lumen exploiting the capillary action. The fibers were filled with i) FD-20/phosphate buffered saline (PBS) solution, ii) FD-20/hydrogel solution before gelation and iii) hydrogel before gelation, subsequently lyophilized and then filled with the FD-20/PBS solution. The different strategies used for the loading of the FD-20 into the fibers resulted in different release kinetics. A slower release was observed with the use of A/G_GP hydrogel. At last, poly(ε-caprolactone) (PCL) nerve guides containing the hollow fibers and the hydrogel have been fabricated.

  6. Brain-derived neurotrophic factor increase during treatment in severe mental illness inpatients

    PubMed Central

    Nuernberg, G L; Aguiar, B; Bristot, G; Fleck, M P; Rocha, N S

    2016-01-01

    Meta-analytical evidence suggests that brain-derived neurotrophic factor (BDNF) is altered in various psychiatric disorders. However, meta-analyses may be hampered by the heterogeneity of BDNF assays, lack of BDNF standard values and heterogeneity among the populations included in the studies. To address these issues, our study aimed to test, in a ‘true-to-life' setting, the hypothesis that the serum BDNF level is nonspecifically reduced in acute severe mental illness (SMI) patients and increases during inpatient treatment. Consecutive samples of 236 inpatients with SMI and 100 healthy controls were recruited. SMI includes schizophrenia and severe mood disorders, and is characterized in the sample by the presence of at least 2 years of psychiatric treatment and disability. Generalized estimating equations were used to analyze BDNF serum levels at admission and upon discharge controlled by confounding factors. BDNF levels increased significantly between admission and discharge in SMI patients. BDNF levels showed significant reductions compared with controls both at admission and upon discharge. In addition, BDNF levels showed no difference among SMI patient diagnostic subgroups (unipolar depression, bipolar depression, schizophrenia and manic episode). The increase but non-restoration of BDNF levels, even with the general acute improvement of clinical scores, may reflect the progression of the disorder characteristically seen in these patients. BDNF levels could be considered as a marker for the presence of a nonspecific psychiatric disorder and possibly a transdiagnostic and nonspecific marker of disease activity. PMID:27959329

  7. Dipeptide Mimetic of the Brain-derived Neurotrophic Factor Prevents Impairments of Neurogenesis in Stressed Mice.

    PubMed

    Gudasheva, T A; Povarnina, P Yu; Seredenin, S B

    2017-02-01

    Brain-derived neurotrophic factor (BDNF) plays the central role in the mechanisms of regulation of neurogenesis and neuroplasticity. Impairment of these mechanisms is considered as one of the main etiological factors of depression. Dimeric dipeptide mimetic of BDNF loop 4 bis-(N-monosuccinyl-l-seryl-l-lysine) hexamethylenediamide (GSB-106) was synthesized at the V. V. Zakusov Research Institute of Pharmacology. In vivo experiments revealed significant antidepressant properties of GSB-106 in doses of 0.1-10 mg/kg (intraperitoneally and orally). Effects of GSB-106 on hippocampal neurogenesis were studied in mice subjected to chronic predator stress. Proliferative activity in the subgranular zone of the dental gyrus was assessed immunohistochemically by Ki-67 expression (a marker of dividing cells). It was found that GSB-106 (10 mg/kg, intraperitoneally, 5 days) completely prevents neurogenesis disturbances in stressed mice. These findings suggest that GSB-106 is a promising candidate for the development of antidepressant agents with BDNF-like mechanism of action.

  8. Val66Met polymorphism of brain-derived neurotrophic factor is associated with idiopathic dystonia.

    PubMed

    Sako, Wataru; Murakami, Nagahisa; Izumi, Yuishin; Kaji, Ryuji

    2015-03-01

    The Val66Met (G196A; rs6265) single nucleotide polymorphism of brain-derived neurotrophic factor (BDNF) affects morphology and neuronal activity, and is expected to be associated with central nervous system disorders. However, it remains controversial whether Val66Met polymorphism is a risk factor for idiopathic dystonia. We aimed to clarify the impact of BDNF polymorphism on idiopathic dystonia. A literature search of PubMed was carried out. A random-effects model was employed for the meta-analysis. A pooled odds ratio (OR) was calculated along with 95% confidence intervals (CI) to reflect the risk of idiopathic dystonia in each genotype (GG, AG, AA) or minor allele. The proportion of variation due to heterogeneity was computed and expressed as I(2). Five case-control studies, comprising a total sample size of 1804 subjects (784 idiopathic dystonia patients, 1020 normal controls), were included in this meta-analysis. AA genotype was significantly more frequent in patients with idiopathic dystonia (OR=1.47, 95% CI 1.09-1.99, p=0.01, four studies, n=1716). This finding was derived from homogeneous studies (p=0.97, I(2)=0%). Our meta-analysis has revealed a significant overall effect of the AA genotype on the development of idiopathic dystonia.

  9. Are the changes in the peripheral brain-derived neurotrophic factor levels due to platelet activation?

    PubMed Central

    Serra-Millàs, Montserrat

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in central nervous system development, neurogenesis and neuronal plasticity. BDNF is also expressed in several non-neuronal tissues, and it could play an important role in other processes, such as cancer, angiogenesis, etc. Platelets are the major source of peripheral BDNF. However, platelets also contain high amounts of serotonin; they express specific surface receptors during activation, and a multitude of pro-inflammatory and immunomodulatory bioactive compounds are secreted from the granules. Until recently, there was insufficient knowledge regarding the relationship between BDNF and platelets. Recent studies showed that BDNF is present in two distinct pools in platelets, in α-granules and in the cytoplasm, and only the BDNF in the granules is secreted following stimulation, representing 30% of the total BDNF in platelets. BDNF has an important role in the pathophysiology of depression. Low levels of serum BDNF have been described in patients with major depressive disorder, and BDNF levels increased with chronic antidepressant treatment. Interestingly, there is an association between depression and platelet function. This review analyzed studies that evaluated the relationship between BDNF and platelet activation and the effect of treatments on both parameters. Only a few studies consider this possible confounding factor, and it could be very important in diseases such as depression, which show changes in both parameters. PMID:27014600

  10. The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking

    PubMed Central

    Darcq, Emmanuel; Morisot, Nadege; Phamluong, Khanhky; Warnault, Vincent; Jeanblanc, Jerome; Longo, Frank M.; Massa, Stephen M.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) keeps alcohol intake in moderation. For example, activation of the BDNF receptor tropomyosin receptor kinase B (TrkB) in the DLS reduces intake in rats that consume moderate amounts of alcohol. Here, we tested whether long-term excessive consumption of alcohol produces neuroadaptations in BDNF signaling in the rat DLS. We found that BDNF was no longer able to gate alcohol self-administration after a history of repeated cycles of binge alcohol drinking and withdrawal. We then elucidated the possible neuroadaptations that could block the ability of BDNF to keep consumption of alcohol in moderation. We report that intermittent access to 20% alcohol in a two-bottle choice paradigm that models excessive alcohol drinking produces a mobilization of DLS p75 neurotrophin receptor (p75NTR), whose activities oppose those of the Trk receptors, including TrkB. These neuroadaptations were not observed in the DLS of rats exposed to continuous access to 10% alcohol or in rats consuming sucrose. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of the p75NTR gene in the DLS, as well as intra-DLS infusion or systemic administration of the p75NTR modulator, LM11A-31, significantly reduced binge drinking of alcohol. Together, our results suggest that excessive alcohol consumption produces a change in BDNF signaling in the DLS, which is mediated by the recruitment of p75NTR. Our data also imply that modulators of p75NTR signaling could be developed as medications for alcohol abuse disorders. SIGNIFICANCE STATEMENT Neuroadaptations gate or drive excessive, compulsive alcohol drinking. We previously showed that brain-derived neurotrophic factor and its receptor, TrkB, in the dorsolateral striatum (DLS), are part of an endogenous system that keeps alcohol drinking in moderation. Here, we show that a history of excessive alcohol intake produces neuroadaptations in the DLS that preclude BDNF

  11. Altered Expression of NF- κ B and SP1 after Exposure to Advanced Glycation End-Products and Effects of Neurotrophic Factors in AGEs Exposed Rat Retinas.

    PubMed

    Bikbova, Guzel; Oshitari, Toshiyuki; Baba, Takayuki; Yamamoto, Shuichi

    2015-01-01

    To determine the effect of advanced glycation end-products (AGEs) on neurite regeneration, and also to determine the regenerative effects of different neurotrophic factors (NTFs) on rat retinal explants, the retinas of SD rats were cultured in three-dimensional collagen gels and incubated in 6 types of media: (1) serum-free control culture media; (2) 100 μg/mL AGEs-BSA media; (3) AGEs-BSA + 100 ng/mL neurotrophin-4 (NT-4) media; (4) AGEs-BSA + 100 ng/mL hepatocyte growth factor media; (5) AGEs-BSA + 100 ng/mL glial cell line-derived neurotrophic factor media; or (6) AGEs-BSA + 100 µM tauroursodeoxycholic acid media. After 7 days, the number of regenerating neurites was counted. The explants were immunostained for nuclear factor-κB (NF-κB) and specificity protein 1 (SP1). Statistical analyses were performed by one-way ANOVA. In retinas incubated with AGEs, the numbers of neurites were fewer than in control. All of the NTFs increased the number of neurites, and the increase was more significant in the NT-4 group. The number of NF-κB and SP1 immunopositive cells was higher in retinas exposed to AGEs than in control. All of the NTFs decreased the number of NF-κB immunopositive cells but did not significantly affect SP1 expression. These results demonstrate the potential of the NTFs as axoprotectants in AGEs exposed retinal neurons.

  12. Cervical dorsal rhizotomy increases brain-derived neurotrophic factor and neurotrophin-3 expression in the ventral spinal cord.

    PubMed

    Johnson, R A; Okragly, A J; Haak-Frendscho, M; Mitchell, G S

    2000-05-15

    Although neurotrophic factors have been implicated in several forms of neuroplasticity, little is known concerning their potential role in spinal plasticity. Cervical dorsal rhizotomy (CDR) enhances serotonin terminal density near (spinal) phrenic motoneurons and serotonin-dependent long-term facilitation of phrenic motor output (Kinkead et al., 1998). We tested the hypothesis that selected neurotrophic factors change in a manner consistent with an involvement in this model of spinal plasticity. Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophic factor (GDNF), and transforming growth factor-beta(1) (TGF-beta(1)) concentrations were measured (ELISA) in three regions of interest to respiratory control: (1) ventral cervical spinal segments associated with the phrenic motor nucleus (C3-C6), (2) ventral thoracic spinal segments associated with inspiratory intercostal motor output (T3-T6) and (3) the diaphragm. Tissues were harvested from rats 7 d after bilateral CDR and compared with sham-operated and unoperated control rats. CDR increased BDNF (110%; p = 0.002) and NT-3 (100%; p = 0.002) in the cervical and NT-3 in the thoracic spinal cord (98%; p = 0.009). GDNF and TGF-beta(1) were not altered by CDR in any tissue. Immunohistochemistry localized BDNF and NT-3 to motoneurons and interneurons of the ventral spinal cord. These studies provide novel, suggestive evidence that BDNF and NT-3, possibly through their trophic effects on serotonergic neurons and/or motoneurons, may underlie serotonin-dependent plasticity in (spinal) respiratory motor control after CDR.

  13. Dendrobium alkaloids prevent Aβ25–35-induced neuronal and synaptic loss via promoting neurotrophic factors expression in mice

    PubMed Central

    Nie, Jing; Tian, Yong; Zhang, Yu; Lu, Yan-Liu; Li, Li-Sheng

    2016-01-01

    Background Neuronal and synaptic loss is the most important risk factor for cognitive impairment. Inhibiting neuronal apoptosis and preventing synaptic loss are promising therapeutic approaches for Alzheimer’s disease (AD). In this study, we investigate the protective effects of Dendrobium alkaloids (DNLA), a Chinese medicinal herb extract, on β-amyloid peptide segment 25–35 (Aβ25-35)-induced neuron and synaptic loss in mice. Method Aβ25–35(10 µg) was injected into the bilateral ventricles of male mice followed by an oral administration of DNLA (40 mg/kg) for 19 days. The Morris water maze was used for evaluating the ability of spatial learning and memory function of mice. The morphological changes were examined via H&E staining and Nissl staining. TUNEL staining was used to check the neuronal apoptosis. The ultrastructure changes of neurons were observed under electron microscope. Western blot was used to evaluate the protein expression levels of ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex. Results DNLA significantly attenuated Aβ25–35-induced spatial learning and memory impairments in mice. DNLA prevented Aβ25–35-induced neuronal loss in the hippocampus and cortex, increased the number of Nissl bodies, improved the ultrastructural injury of neurons and increased the number of synapses in neurons. Furthermore, DNLA increased the protein expression of neurotrophic factors BDNF, CNTF and GDNF in the hippocampus and cortex. Conclusions DNLA can prevent neuronal apoptosis and synaptic loss. This effect is mediated at least in part via increasing the expression of BDNF, GDNF and CNTF in the hippocampus and cortex; improving Aβ-induced spatial learning and memory impairment in mice. PMID:27994964

  14. Central expression and anorectic effect of brain-derived neurotrophic factor are regulated by circulating estradiol levels.

    PubMed

    Zhu, Zheng; Liu, Xian; Senthil Kumar, Shiva Priya Dharshan; Zhang, Jing; Shi, Haifei

    2013-03-01

    Estrogens potently suppress food intake. Compelling evidence suggests that estradiol, the primary form of estrogens, reduces food intake by facilitating other anorectic signals. Brain-derived neurotrophic factor (BDNF), like estradiol, appears to suppress food intake by affecting meal size. We hypothesized that estradiol modulates Bdnf expression and the anorectic effect of BDNF. The first goal was to determine whether Bdnf expression was regulated by endogenous estradiol of cycling rats and by cyclic estradiol treatment using ovariectomized rats. Bdnf expression within the ventromedial nucleus of hypothalamus (VMH) was temporally elevated at estrus following the estradiol peak, which coincided with the decline in feeding at this phase of the ovarian cycle. Additionally, food intake and body weight were increased following ovariectomy with a parallel decrease in Bdnf expression in the VMH. All of these alterations were reversed by cyclic estradiol treatment, suggesting that Bdnf expression within the VMH was regulated in an estradiol-dependent manner. The second goal was to determine whether estradiol modulates the anorectic effect of BDNF. Sham-operated estrous rats and ovariectomized rats cyclically treated with estradiol responded to a lower dose of central administration of BDNF to decrease food intake than male rats and oil-treated ovariectomized rats, implying that endogenous estradiol or cyclic estradiol replacement increased the sensitivity to anorectic effect of BDNF. These data indicate that Bdnf expression within the VMH and the anorectic effect of BDNF varied depending on plasma estradiol levels, suggesting that estradiol may regulate BDNF signaling to regulate feeding.

  15. Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons.

    PubMed

    Cui, Qi; Yip, Henry K; Zhao, Robert C H; So, Kwok-Fai; Harvey, Alan R

    2003-01-01

    In vitro, cyclic AMP (cAMP) elevation alters neuronal responsiveness to diffusible growth factors and myelin-associated inhibitory molecules. Here we used an established in vivo model of adult central nervous system injury to investigate the effects of elevated cAMP on neuronal survival and axonal regeneration. We studied the effects of intraocular injections of neurotrophic factors and/or a cAMP analogue (CPT-cAMP) on the regeneration of axotomized rat retinal ganglion cell (RGC) axons into peripheral nerve autografts. Elevation of cAMP alone did not significantly increase RGC survival or the number of regenerating RGCs. Ciliary neurotrophic factor increased RGC viability and axonal regrowth, the latter effect substantially enhanced by coapplication with CPT-cAMP. Under these conditions over 60% of surviving RGCs regenerated their axons. Neurotrophin-4/5 injections also increased RGC viability, but there was reduced long-distance axonal regrowth into grafts, an effect partially ameliorated by cAMP elevation. Thus, cAMP can act cooperatively with appropriate neurotrophic factors to promote axonal regeneration in the injured adult mammalian central nervous system.

  16. From molecular to nanotechnology strategies for delivery of neurotrophins: emphasis on brain-derived neurotrophic factor (BDNF).

    PubMed

    Géral, Claire; Angelova, Angelina; Lesieur, Sylviane

    2013-02-08

    Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted.

  17. From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF)

    PubMed Central

    Géral, Claire; Angelova, Angelina; Lesieur, Sylviane

    2013-01-01

    Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted. PMID:24300402

  18. Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons.

    PubMed

    Burkhalter, Julia; Fiumelli, Hubert; Allaman, Igor; Chatton, Jean-Yves; Martin, Jean-Luc

    2003-09-10

    Brain-derived neurotrophic factor (BDNF) promotes the biochemical and morphological differentiation of selective populations of neurons during development. In this study we examined the energy requirements associated with the effects of BDNF on neuronal differentiation. Because glucose is the preferred energy substrate in the brain, the effect of BDNF on glucose utilization was investigated in developing cortical neurons via biochemical and imaging studies. Results revealed that BDNF increases glucose utilization and the expression of the neuronal glucose transporter GLUT3. Stimulation of glucose utilization by BDNF was shown to result from the activation of Na+/K+-ATPase via an increase in Na+ influx that is mediated, at least in part, by the stimulation of Na+-dependent amino acid transport. The increased Na+-dependent amino acid uptake by BDNF is followed by an enhancement of overall protein synthesis associated with the differentiation of cortical neurons. Together, these data demonstrate the ability of BDNF to stimulate glucose utilization in response to an enhanced energy demand resulting from increases in amino acid uptake and protein synthesis associated with the promotion of neuronal differentiation by BDNF.

  19. Transgenic Brain-Derived Neurotrophic Factor Modulates a Developing Cerebellar Inhibitory Synapse

    PubMed Central

    Bao, Shaowen; Chen, Lu; Qiao, Xiaoxi; Thompson, Richard F.

    1999-01-01

    Brain-derived neurotrophic factor (BDNF) has been shown to promote synapse formation and maturation in neurons of many brain regions, including inhibitory synapses. In the cerebellum, the Golgi cell-granule cell GABAergic synaptic responses undergo developmental transition from slow-decaying to fast-decaying kinetics, which parallels a developmental increase of GABAA receptor α6 subunit expression in the cerebellar granule cells. In culture, BDNF accelerates the expression of GABAA receptor α6 subunit expression in granule cells. Here we examined synaptic GABAA response kinetics in BDNF transgenic mice. The mutant mouse, which carries a BDNF transgene driven by a β-actin promoter, overexpresses BDNF (two- to fivefold increase compared with wild types) in all brain regions. Recordings of the spontaneous GABAA responses indicate that the decay time constant of the GABAergic responses decreases during early postnatal development; this transition is accelerated in the BDNF transgenic mouse. The amplitude of the spontaneous GABAA responses was also larger in the transgenic mouse than in the wild-type mouse. However, the frequency of the spontaneous GABAA responses were not different between the two groups. Our results suggest that BDNF may modulate GABAergic synapse maturation in the cerebellum. PMID:10492009

  20. Anatomical evidence for transsynaptic influences of estrogen on brain-derived neurotrophic factor expression.

    PubMed

    Blurton-Jones, M; Kuan, P N; Tuszynski, M H

    2004-01-12

    Several studies have demonstrated that estrogen modulates brain-derived neurotrophic factor (BDNF) mRNA and protein within the adult hippocampus and cortex. However, mechanisms underlying this regulation are unknown. Although an estrogen response element (ERE)-like sequence has been identified within the BDNF gene, such a classical mechanism of estrogen-induced transcriptional activation requires the colocalized expression of estrogen receptors within cells that produce BDNF. Developmental studies have demonstrated such a relationship, but to date no studies have examined colocalization of estrogen receptors and BDNF within the adult brain. By utilizing double-label immunohistochemistry for BDNF, estrogen receptor-alpha (ER-alpha), and estrogen receptor-beta (ER-beta), we found only sparse colocalization between ER-alpha and BDNF in the hypothalamus, amygdala, prelimbic cortex, and ventral hippocampus. Furthermore, ER-beta and BDNF do not colocalize in any brain region. Given the recent finding that cortical ER-beta is almost exclusively localized to parvalbumin-immunoreactive GABAergic neurons, we performed BDNF/parvalbumin double labeling and discovered that axons from cortical ER-beta-expressing inhibitory neurons terminate on BDNF-immunoreactive pyramidal cells. Collectively, these findings support a potential transsynaptic relationship between estrogen state and cortical BDNF: By directly modulating GABAergic interneurons, estrogen may indirectly influence the activity and expression of BDNF-producing cortical neurons.

  1. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke.

    PubMed

    Clarkson, Andrew N; Overman, Justine J; Zhong, Sheng; Mueller, Rudolf; Lynch, Gary; Carmichael, S Thomas

    2011-03-09

    Stroke is the leading cause of adult disability. Recovery after stroke shares similar molecular and cellular properties with learning and memory. A main component of learning-induced plasticity involves signaling through AMPA receptors (AMPARs). We systematically tested the role of AMPAR function in motor recovery in a mouse model of focal stroke. AMPAR function controls functional recovery beginning 5 d after the stroke. Positive allosteric modulators of AMPARs enhance recovery of limb control when administered after a delay from the stroke. Conversely, AMPAR antagonists impair motor recovery. The contributions of AMPARs to recovery are mediated by release of brain-derived neurotrophic factor (BDNF) in periinfarct cortex, as blocking local BDNF function in periinfarct cortex blocks AMPAR-mediated recovery and prevents the normal pattern of motor recovery. In contrast to a delayed AMPAR role in motor recovery, early administration of AMPAR agonists after stroke increases stroke damage. These findings indicate that the role of glutamate signaling through the AMPAR changes over time in stroke: early potentiation of AMPAR signaling worsens stroke damage, whereas later potentiation of the same signaling system improves functional recovery.

  2. Overexpression of brain-derived neurotrophic factor in the hippocampus protects against post-stroke depression.

    PubMed

    Chen, Hao-Hao; Zhang, Ning; Li, Wei-Yun; Fang, Ma-Rong; Zhang, Hui; Fang, Yuan-Shu; Ding, Ming-Xing; Fu, Xiao-Yan

    2015-09-01

    Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor (BDNF). In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of post-stroke depression. The middle cerebral artery was occluded to produce a model of focal cerebral ischemia. These rats were then subjected to isolation-housing combined with chronic unpredictable mild stress to generate a model of post-stroke depression. A BDNF gene lentiviral vector was injected into the hippocampus. At 7 days after injection, western blot assay and real-time quantitative PCR revealed that BDNF expression in the hippocampus was increased in depressive rats injected with BDNF lentivirus compared with depressive rats injected with control vector. Furthermore, sucrose solution consumption was higher, and horizontal and vertical movement scores were increased in the open field test in these rats as well. These findings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors.

  3. The Effects of Acute Exercise on Memory and Brain-Derived Neurotrophic Factor (BDNF).

    PubMed

    Etnier, Jennifer L; Wideman, Laurie; Labban, Jeffrey D; Piepmeier, Aaron T; Pendleton, Daniel M; Dvorak, Kelly K; Becofsky, Katie

    2016-08-01

    Acute exercise benefits cognition, and some evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in this effect. The purpose of this study was to explore the dose-response relationship between exercise intensity, memory, and BDNF. Young adults completed 3 exercise sessions at different intensities relative to ventilator threshold (Vt) (VO2max, Vt - 20%, Vt + 20%). For each session, participants exercised for approximately 30 min. Following exercise, they performed the Rey Auditory Verbal Learning Test (RAVLT) to assess short-term memory, learning, and long-term memory recall. Twenty-four hours later, they completed the RAVLT recognition trial, which provided another measure of long-term memory. Blood was drawn before exercise, immediately postexercise, and after the 30-min recall test. Results indicated that long-term memory as assessed after the 24-hr delay differed as a function of exercise intensity with the largest benefits observed following maximal intensity exercise. BDNF data showed a significant increase in response to exercise; however, there were no differences relative to exercise intensity and there were no significant associations between BDNF and memory. Future research is warranted so that we can better understand how to use exercise to benefit cognitive performance.

  4. Brain-derived Neurotrophic Factor Promotes the Migration of Olfactory Ensheathing Cells Through TRPC Channels.

    PubMed

    Wang, Ying; Teng, Hong-Lin; Gao, Yuan; Zhang, Fan; Ding, Yu-Qiang; Huang, Zhi-Hui

    2016-12-01

    Olfactory ensheathing cells (OECs) are a unique type of glial cells with axonal growth-promoting properties in the olfactory system. Organized migration of OECs is essential for neural regeneration and olfactory development. However, the molecular mechanism of OEC migration remains unclear. In the present study, we examined the effects of brain-derived neurotrophic factor (BDNF) on OEC migration. Initially, the "scratch" migration assay, the inverted coverslip and Boyden chamber migration assays showed that BDNF could promote the migration of primary cultured OECs. Furthermore, BDNF gradient attracted the migration of OECs in single-cell migration assays. Mechanistically, TrkB receptor expressed in OECs mediated BDNF-induced OEC migration, and BDNF triggered calcium signals in OECs. Finally, transient receptor potential cation channels (TRPCs) highly expressed in OECs were responsible for BDNF-induced calcium signals, and required for BDNF-induced OEC migration. Taken together, these results demonstrate that BDNF promotes the migration of cultured OECs and an unexpected finding is that TRPCs are required for BDNF-induced OEC migration. GLIA 2016;64:2154-2165.

  5. Synergetic effects of ciliary neurotrophic factor and olfactory ensheathing cells on optic nerve reparation (complete translation)

    PubMed Central

    Yin, Dan-ping; Chen, Qing-ying; Liu, Lin

    2016-01-01

    At present, there is no effective treatment for the repair of the optic nerve after injury, or improvement of its microenvironment for regeneration. Intravitreally injected ciliary neurotrophic factor (CNTF) and olfactory ensheathing cells (OECs) promote the long-distance regrowth of severed optic nerve fibers after intracranial injury. Here, we examined the efficacy of these techniques alone and in combination, in a rat model of optic nerve injury. We injected condensed OEC suspension at the site of injury, or CNTF into the vitreous body, or both simultaneously. Retrograde tracing techniques showed that 4 weeks postoperatively, the number of surviving retinal ganglion cells and their axonal density in the optic nerve were greater in rats subjected to OEC injection only than in those receiving CNTF injection only. Furthermore, combined OEC + CNTF injection achieved better results than either monotherapy. These findings confirm that OECs are better than CNTF at protecting injured neurons in the eye, but that combined OEC and CNTF therapy is notably more effective than either treatment alone. PMID:27482233

  6. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor

    PubMed Central

    Szuhany, Kristin L.; Bugatti, Matteo; Otto, Michael W.

    2014-01-01

    Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1,111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges’ g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges’ g = 0.58, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges’ g = 0.28, p = 0.005). When analyzing results across paradigms, sex significantly moderated the effect of exercise on BDNF levels, such that studies with more women showed less BDNF change resulting from exercise. Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans, but indicates that the magnitude of these effects may be lower in females relative to males. PMID:25455510

  7. Methamphetamine self-administration attenuates hippocampal serotonergic deficits: Role of brain derived neurotrophic factor

    PubMed Central

    McFadden, Lisa M.; Vieira-Brock, Paula L.; Hanson, Glen R.; Fleckenstein, Annette E.

    2014-01-01

    Preclinical studies suggest that prior treatment with escalating doses of methamphetamine (METH) attenuates the persistent deficits in hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter (SERT) function resulting from a subsequent “binge” METH exposure. Previous work also demonstrates that brain derived neurotrophic factor (BDNF) exposure increases SERT function. The current study investigated changes in hippocampal BDNF protein and SERT function in rats exposed to saline or METH self-administration prior to a binge exposure to METH or saline. Results revealed that METH self-administration increased hippocampal mature BDNF (mBDNF) immunoreactivity compared to saline-treated rats as assessed 24 h after the start of the last session. Further, mBDNF immunoreactivity was increased and SERT function was not altered at this timepoint in rats that self-administered METH prior to the binge METH exposure. These results suggest that prior exposure to contingent METH increases hippocampal mBDNF, and this may contribute to attenuated deficits in SERT function. PMID:24650575

  8. Resveratrol improves postnatal hippocampal neurogenesis and brain derived neurotrophic factor in prenatally stressed rats.

    PubMed

    Madhyastha, Sampath; Sekhar, Sudhanshu; Rao, Gayathri

    2013-11-01

    Prenatal stress induced neuronal dysfunction is multifactorial, including suppressed neurogenesis in developing brain. Resveratrol is known to exert its neuroprotective potential by enhancing neurogenesis. But the efficacy of resveratrol against prenatal stress was not addressed in detail. Hence in the present study we evaluated the neuroprotective action of resveratrol on prenatal stress-induced impaired neurogenesis. Pregnant rats were subjected to restraint stress during early or late gestational period. Another sets of rats received resveratrol during entire gestational period along with early or late gestational stress. The study parameters included neuronal assay of doublecortin positive neurons (DCX +ve) and brain derived neurotrophic factor (BDNF) estimations in 40th postnatal day rat brain. Both early and late gestational stress resulted in significant decrease in generation of new born neurons and BDNF expression in hippocampus. The decrease in number of DCX +ve neurons and hippocampal BDNF expression was more profound in the offspring who received late gestational stress compared to early gestational stress. Resveratrol treatment has improved the expression of DCX +ve neurons and BDNF expression. These data suggest the neuroprotective efficacy of resveratrol against prenatal stress induced impaired neurogenesis.

  9. Genetic variation in brain-derived neurotrophic factor and human fear conditioning.

    PubMed

    Hajcak, G; Castille, C; Olvet, D M; Dunning, J P; Roohi, J; Hatchwell, E

    2009-02-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in hippocampal-dependent learning processes, and carriers of the Met allele of the Val66Met BDNF genotype are characterized by reduced hippocampal structure and function. Recent nonhuman animal work suggests that BDNF is also crucial for amygdala-dependent associative learning. The present study sought to examine fear conditioning as a function of the BDNF polymorphism. Fifty-seven participants were genotyped for the BDNF polymorphism and took part in a differential-conditioning paradigm. Participants were shocked following a particular conditioned stimulus (CS+) and were also presented with stimuli that ranged in perceptual similarity to the CS+ (20, 40 or 60% smaller or larger than the CS+). The eye blink component of the startle response was measured to quantify fear conditioning; post-task shock likelihood ratings for each stimulus were also obtained. All participants reported that shock likelihood varied with perceptual similarity to the CS+ and showed potentiated startle in response to CS +/- 20% stimuli. However, only the Val/Val group had potentiated startle responses to the CS+. Met allele carrying individuals were characterized by deficient fear conditioning--evidenced by an attenuated startle response to CS+ stimuli. Variation in the BDNF genotype appears related to abnormal fear conditioning, consistent with nonhuman animal work on the importance of BDNF in amygdala-dependent associative learning. The relation between genetic variation in BDNF and amygdala-dependent associative learning deficits is discussed in terms of potential mechanisms of risk for psychopathology.

  10. Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor.

    PubMed

    Carbone, D L; Handa, R J

    2013-06-03

    The neurotrophin, brain-derived neurotrophic factor (BDNF), is recognized as a key component in the regulation of CNS ontogeny, homeostasis and adult neuroplasticity. The importance of BDNF in CNS development and function is well documented by numerous reports from animal studies linking abnormal BDNF signaling to metabolic disturbances and anxiety or depressive-like behavior. Despite the diverse roles for BDNF in nearly all aspects of CNS physiology, the regulation of BDNF expression, as well as our understanding of the signaling mechanisms associated with this neurotrophin, remains incomplete. However, links between sex hormones such as estradiol and testosterone, as well as endogenous and synthetic glucocorticoids (GCs), have emerged as important mediators of BDNF expression and function. Examples of such regulation include brain region-specific induction of Bdnf mRNA in response to estradiol. Additional studies have also documented regulation of the expression of the high-affinity BDNF receptor Tropomyosin-Related Kinase B by estradiol, thus implicating sex steroids not only in the regulation of BDNF expression, but also in mechanisms of signaling associated with it. In addition to gonadal steroids, further evidence also suggests functional interaction between BDNF and GCs, such as in the regulation of corticotrophin-releasing hormone and other important neuropeptides. In this review, we provide an overview of the roles played by selected sex or stress hormones in the regulation of BDNF expression and signaling in the CNS.

  11. Brain-derived neurotrophic factor and the course of experimental cerebral malaria.

    PubMed

    Linares, María; Marín-García, Patricia; Pérez-Benavente, Susana; Sánchez-Nogueiro, Jesús; Puyet, Antonio; Bautista, José M; Diez, Amalia

    2013-01-15

    The role of neurotrophic factors on the integrity of the central nervous system (CNS) during cerebral malaria (CM) infection remains obscure, but the long-standing neurocognitive sequelae often observed in rescued children can be attributed in part to the modulation of neuronal survival and synaptic plasticity. To discriminate the contribution of key responses in the time-sequence of the pathogenic events that trigger the development of neurocognitive malaria syndrome we defined four stages (I-IV) of the neurological progression of CM in C57BL/6 mice infected with Plasmodium berghei ANKA. Upregulation of ICAM-1, VCAM-1, e-selectin and p-selectin expression was detected in all cerebral regions before parasitized red blood cells (pRBC) accumulation. As the severity of symptoms increased, BDNF mRNA progressively diminished in several brain regions, earliest in the thalamus-hypothalamus, cerebellum, brainstem and cortex, and correlated with a four-stage disease sequence. Immunohistochemical confocal microscopy revealed changes in the BDNF distribution pattern, suggesting altered axonal transport. During CM progression, molecular markers of neurological infection and inflammation in the parasite and the host, respectively, were accompanied by a switch in the brain constitutive proteasome to the immunoproteasome, which could impede normal protein turnover. In parallel with BDNF downregulation, NCAM expression also diminished with increased CM severity. Together, these data suggest that changes in BDNF availability could be involved in the pathogenesis of CM.

  12. Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation.

    PubMed

    Guo, Wei; Robbins, Meredith T; Wei, Feng; Zou, Shiping; Dubner, Ronald; Ren, Ke

    2006-01-04

    In the adult mammalian brain, brain-derived neurotrophic factor (BDNF) is critically involved in long-term synaptic plasticity. Here, we show that supraspinal BDNF-tyrosine kinase receptor B (TrkB) signaling contributes to pain facilitation. We show that BDNF-containing neurons in the periaqueductal gray (PAG), the central structure for pain modulation, project to and release BDNF in the rostral ventromedial medulla (RVM), a relay between the PAG and spinal cord. BDNF in PAG and TrkB phosphorylation in RVM neurons are upregulated after inflammation. Intra-RVM sequestration of BDNF and knockdown of TrkB by RNA interference attenuate inflammatory pain. Microinjection of BDNF (10-100 fmol) into the RVM facilitates nociception, which is dependent on NMDA receptors (NMDARs). In vitro studies with RVM slices show that BDNF induces tyrosine phosphorylation of the NMDAR NR2A subunit in RVM via a signal transduction cascade involving IP(3), PKC, and Src. The supraspinal BDNF-TrkB signaling represents a previously unknown mechanism underlying the development of persistent pain. Our findings also caution that application of BDNF for recovery from CNS disorders could lead to undesirable central pain.

  13. Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development.

    PubMed

    Suzuki, Shingo; Kiyosue, Kazuyuki; Hazama, Shunsuke; Ogura, Akihiko; Kashihara, Megumi; Hara, Tomoko; Koshimizu, Hisatsugu; Kojima, Masami

    2007-06-13

    Brain-derived neurotrophic factor (BDNF) exerts multiple biological functions in the CNS. Although BDNF can control transcription and protein synthesis, it still remains open to question whether BDNF regulates lipid biosynthesis. Here we show that BDNF elicits cholesterol biosynthesis in cultured cortical and hippocampal neurons. Importantly, BDNF elicited cholesterol synthesis in neurons, but not in glial cells. Quantitative reverse transcriptase-PCR revealed that BDNF stimulated the transcription of enzymes in the cholesterol biosynthetic pathway. BDNF-induced cholesterol increases were blocked by specific inhibitors of cholesterol synthesis, mevastatin and zaragozic acid, suggesting that BDNF stimulates de novo synthesis of cholesterol rather than the incorporation of extracellular cholesterol. Because cholesterol is a major component of lipid rafts, we investigated whether BDNF would increase the cholesterol content in lipid rafts or nonraft membrane domains. Interestingly, the BDNF-mediated increase in cholesterol occurred in rafts, but not in nonrafts, suggesting that BDNF promotes the development of neuronal lipid rafts. Consistent with this notion, BDNF raised the level of the lipid raft marker protein caveolin-2 in rafts. Remarkably, BDNF increased the levels of presynaptic proteins in lipid rafts, but not in nonrafts. An electrophysiological study revealed that BDNF-dependent cholesterol biosynthesis plays an important role for the development of a readily releasable pool of synaptic vesicles. Together, these results suggest a novel role for BDNF in cholesterol metabolism and synapse development.

  14. The role of dorsal root ganglia activation and brain-derived neurotrophic factor in multiple sclerosis.

    PubMed

    Zhu, Wenjun; Frost, Emma E; Begum, Farhana; Vora, Parvez; Au, Kelvin; Gong, Yuewen; MacNeil, Brian; Pillai, Prakash; Namaka, Mike

    2012-08-01

    Multiple sclerosis (MS) is characterized by focal destruction of the white matter of the brain and spinal cord. The exact mechanisms underlying the pathophysiology of the disease are unknown. Many studies have shown that MS is predominantly an autoimmune disease with an inflammatory phase followed by a demyelinating phase. Recent studies alongside current treatment strategies, including glatiramer acetate, have revealed a potential role for brain-derived neurotrophic factor (BDNF) in MS. However, the exact role of BDNF is not fully understood. We used the experimental autoimmune encephalomyelitis (EAE) model of MS in adolescent female Lewis rats to identify the role of BDNF in disease progression. Dorsal root ganglia (DRG) and spinal cords were harvested for protein and gene expression analysis every 3 days post-disease induction (pdi) up to 15 days. We show significant increases in BDNF protein and gene expression in the DRG of EAE animals at 12 dpi, which correlates with peak neurological disability. BDNF protein expression in the spinal cord was significantly increased at 12 dpi, and maintained at 15 dpi. However, there was no significant change in mRNA levels. We show evidence for the anterograde transport of BDNF protein from the DRG to the dorsal horn of the spinal cord via the dorsal roots. Increased levels of BDNF within the DRG and spinal cord in EAE may facilitate myelin repair and neuroprotection in the CNS. The anterograde transport of DRG-derived BDNF to the spinal cord may have potential implications in facilitating central myelin repair and neuroprotection.

  15. Brain-derived neurotrophic factor and glucocorticoids: reciprocal influence on the central nervous system.

    PubMed

    Numakawa, T; Adachi, N; Richards, M; Chiba, S; Kunugi, H

    2013-06-03

    Brain-derived neurotrophic factor (BDNF) has multiple roles in the central nervous system (CNS), including maintaining cell survival and regulation of synaptic function. In CNS neurons, BDNF triggers activation of phospholipase Cγ (PLCγ), mitogen-activated protein/extracellular signal-regulated kinase (MAPK/ERK), and phosphoinositide 3-kinase (PI3K)/Akt pathways, influencing neuronal cells beneficially through these intracellular signaling cascades. There is evidence to suggest that decreased BDNF expression or function is related to the pathophysiology of brain diseases including psychiatric disorders. Additionally, glucocorticoids, which are critical stress hormones, also influence neuronal function in the CNS, and are putatively involved in the onset of depression when levels are abnormally high. In animal models of depression, changes in glucocorticoid levels, expression of glucocorticoid receptor (GR), and alterations in BDNF signaling are observed. Interestingly, several studies using in vivo and in vitro systems suggest that glucocorticoids interact with BDNF to ultimately affect CNS function. In the present review, we provide an overview of recent evidence concerning the interaction between BDNF and glucocorticoids.

  16. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor.

    PubMed

    Parkhurst, Christopher N; Yang, Guang; Ninan, Ipe; Savas, Jeffrey N; Yates, John R; Lafaille, Juan J; Hempstead, Barbara L; Littman, Dan R; Gan, Wen-Biao

    2013-12-19

    Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling.

  17. Pro-region engineering for improved yeast display and secretion of brain derived neurotrophic factor.

    PubMed

    Burns, Michael L; Malott, Thomas M; Metcalf, Kevin J; Puguh, Arthya; Chan, Jonah R; Shusta, Eric V

    2016-03-01

    Brain derived neurotrophic factor (BDNF) is a promising therapeutic candidate for a variety of neurological diseases. However, it is difficult to produce as a recombinant protein. In its native mammalian context, BDNF is first produced as a pro-protein with subsequent proteolytic removal of the pro-region to yield mature BDNF protein. Therefore, in an attempt to improve yeast as a host for heterologous BDNF production, the BDNF pro-region was first evaluated for its effects on BDNF surface display and secretion. Addition of the wild-type pro-region to yeast BDNF production constructs improved BDNF folding both as a surface-displayed and secreted protein in terms of binding its natural receptors TrkB and p75, but titers remained low. Looking to further enhance the chaperone-like functions provided by the pro-region, two rounds of directed evolution were performed, yielding mutated pro-regions that further improved the display and secretion properties of BDNF. Subsequent optimization of the protease recognition site was used to control whether the produced protein was in pro- or mature BDNF forms. Taken together, we have demonstrated an effective strategy for improving BDNF compatibility with yeast protein engineering and secretion platforms.

  18. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress

    PubMed Central

    Jiang, De-guo; Jin, Shi-li; Li, Gong-ying; Li, Qing-qing; Li, Zhi-ruo; Ma, Hong-xia; Zhuo, Chuan-jun; Jiang, Rong-huan; Ye, Min-jie

    2016-01-01

    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-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A 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 mRNA expression levels were higher in the 5-HT1A and the 5-HT2A 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 mRNA expression levels were lower in the 5-HT1A and 5-HT2A 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. PMID:27857753

  19. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness.

    PubMed

    Khalin, Igor; Alyautdin, Renad; Kocherga, Ganna; Bakar, Muhamad Abu

    2015-01-01

    Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood-retinal barrier and blood-cochlear barrier, which have a comparable structure to the blood-brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration.

  20. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease

    PubMed Central

    Jiao, S-S; Shen, L-L; Zhu, C; Bu, X-L; Liu, Y-H; Liu, C-H; Yao, X-Q; Zhang, L-L; Zhou, H-D; Walker, D G; Tan, J; Götz, J; Zhou, X-F; Wang, Y-J

    2016-01-01

    Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy. PMID:27701410

  1. Involvement of brain-derived neurotrophic factor (BDNF) in MP4-induced autoimmune encephalomyelitis.

    PubMed

    Javeri, Sita; Rodi, Michael; Tary-Lehmann, Magdalena; Lehmann, Paul V; Addicks, Klaus; Kuerten, Stefanie

    2010-11-01

    The role of brain-derived neurotrophic factor (BDNF) in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still unclear. Here we investigate the clinical course, CNS histopathology and peripheral antigen-specific immunity in MP4-induced EAE of BDNF (-/+) mice. We demonstrate that these mice displayed less severe disease compared to BDNF (+/+) mice, reflected by decreased inflammation and demyelination. In correspondence to diminished frequencies of T and B cells in CNS infiltrates, the peripheral MP4-specific T(H)1/T(H)17 response was attenuated in BDNF (-/+), but not in wild-type animals. In contrast, immunization with ovalbumin triggered similar frequencies of IFN-γ- and IL-17-secreting T cells in both groups. The cytokine secretion and proliferative activity upon mitogen stimulation did not reveal any global defect of T cell function in BDNF (-/+) mice. By influencing the antigen-specific immune response in autoimmune encephalomyelitis, BDNF may support and maintain the disease in ways that go beyond its alleged neuroprotective role.

  2. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease.

    PubMed

    Jiao, S-S; Shen, L-L; Zhu, C; Bu, X-L; Liu, Y-H; Liu, C-H; Yao, X-Q; Zhang, L-L; Zhou, H-D; Walker, D G; Tan, J; Götz, J; Zhou, X-F; Wang, Y-J

    2016-10-04

    Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.

  3. Abundant Production of Brain-Derived Neurotrophic Factor by Adult Visceral Epithelia

    PubMed Central

    Lommatzsch, Marek; Braun, Armin; Mannsfeldt, Anne; Botchkarev, Vladimir A.; Botchkareva, Natalia V.; Paus, Ralf; Fischer, Axel; Lewin, Gary R.; Renz, Harald

    1999-01-01

    Brain-derived neurotrophic factor (BDNF) plays a crucial role for the survival of visceral sensory neurons during development. However, the physiological sources and the function of BDNF in the adult viscera are poorly described. We have investigated the cellular sources and the potential role of BDNF in adult murine viscera. We found markedly different amounts of BDNF protein in different organs. Surprisingly, BDNF levels in the urinary bladder, lung, and colon were higher than those found in the brain or skin. In situ hybridization experiments revealed that BDNF mRNA was made by visceral epithelial cells, several types of smooth muscle, and neurons of the myenteric plexus. Epithelia that expressed BDNF lacked both the high- and low-affinity receptors for BDNF, trkB and p75NTR. In contrast, both receptors were present on neurons of the peripheral nervous system. Studies with BDNF−/−mice demonstrated that epithelial and smooth muscle cells developed normally in the absence of BDNF. These data provide evidence that visceral epithelia are a major source, but not a target, of BDNF in the adult viscera. The abundance of BDNF protein in certain internal organs suggests that this neurotrophin may regulate the function of adult visceral sensory and motor neurons. PMID:10514401

  4. Peripheral Brain Derived Neurotrophic Factor Precursor Regulates Pain as an Inflammatory Mediator

    PubMed Central

    Luo, Cong; Zhong, Xiao-Lin; Zhou, Fiona H.; Li, Jia-yi; Zhou, Pei; Xu, Jun-Mei; Song, Bo; Li, Chang-Qi; Zhou, Xin-Fu; Dai, Ru-Ping

    2016-01-01

    The precursor of brain derived neurotrophic factor (proBDNF), the unprocessed BDNF gene product, binds to its receptors and exerts the opposing biologic functions of mature BDNF. proBDNF is expressed in the peripheral tissues but the functions of peripheral proBDNF remain elusive. Here we showed that proBDNF and its predominant receptor, p75 pan-neurotrophin receptor were upregulated in the nerve fibers and inflammatory cells in the local tissue in inflammatory pain. Neutralization of proBDNF by polyclonal antibody attenuated pain in different models of inflammatory pain. Unilateral intra-plantar supplementation of proBDNF by injecting exogenous proBDNF or ectopic overexpression resulted in pain hypersensitivity and induced spinal phosphorylated extracellular signal-regulated kinase activation. Exogenous proBDNF injection induced the infiltration of inflammatory cells and the activation of proinflammatory cytokines, suggesting that inflammatory reaction contributed to the pro-algesic effect of proBDNF. Finally, we generated monoclonal anti-proBDNF antibody that could biologically block proBDNF. Administration of monoclonal Ab-proBDNF attenuated various types of inflammatory pain and surgical pain. Thus, peripheral proBDNF is a potential pain mediator and anti-proBDNF pretreatment may alleviate the development of inflammatory pain. PMID:27251195

  5. Brain-derived neurotrophic factor Val66Met polymorphism, human memory, and synaptic neuroplasticity.

    PubMed

    Lamb, Yvette N; McKay, Nicole S; Thompson, Christopher S; Hamm, Jeffrey P; Waldie, Karen E; Kirk, Ian J

    2015-01-01

    Some people have much better memory than others, and there is compelling evidence that a considerable proportion of this variation in memory ability is genetically inherited. A form of synaptic plasticity known as long-term potentiation (LTP) is the principal candidate mechanism underlying memory formation in neural circuits, and it might be expected, therefore, that a genetic influence on the degree of LTP might in turn influence memory abilities. Of the genetic variations thought to significantly influence mnemonic ability in humans, the most likely to have its effect via LTP is a single nucleotide polymorphism affecting brain-derived neurotrophic factor [BDNF (Val66Met)]. However, although it is likely that BDNF influences memory via a modulation of acute plasticity (i.e., LTP), BDNF also has considerable influence on structural development of neural systems. Thus, the influence of BDNF (Val66Met) on mnemonic performance via influences of brain structure as well as function must also be considered. In this brief review, we will describe the phenomenon of LTP and its study in non-human animals. We will discuss the relatively recent attempts to translate this work to studies in humans. We will describe how this has enabled investigation of the effect of the BDNF polymorphism on LTP, on brain structure, and on memory performance.

  6. Serum brain-derived neurotrophic factor levels were reduced during methamphetamine early withdrawal.

    PubMed

    Chen, Pao-Huan; Huang, Ming-Chi; Lai, Ying-Ching; Chen, Po-Yu; Liu, Hsing-Cheng

    2014-05-01

    Methamphetamine (METH) abuse is an increasing public health problem worldwide. Many of the METH-induced physical and mental problems are associated with the neurotoxic effects of METH. Animal studies have shown that brain-derived neurotrophic factor (BDNF) decreased after repeated amphetamine administration and increased at 30 and 90 days from psychostimulant withdrawal, suggesting that there might be a psychostimulant-induced neuroprotective dysfunction followed by a neuroadaptive process in the brain. However, current research on the role of BDNF in human METH addiction is limited, particularly during early withdrawal. The aim of this study was to assess the serum BDNF levels in METH abusers during the early withdrawal stage. Two groups of subjects were enrolled: (1) 59 DSM-IV METH abusers confirmed by board-certified psychiatrists during the first 3 weeks of withdrawal; (2) 59 age- and sex-matched healthy controls. We found that serum BDNF levels were significantly and constantly lower in the METH abusers during early withdrawal than those of the healthy controls. This indicates that METH abusers might have severe BDNF dysfunction and an impaired neuroprotective function after repetitive METH misuse.

  7. The Effect of Brain-Derived Neurotrophic Factor on Periodontal Furcation Defects

    PubMed Central

    Jimbo, Ryo; Tovar, Nick; Janal, Malvin N.; Mousa, Ramy; Marin, Charles; Yoo, Daniel; Teixeira, Hellen S.; Anchieta, Rodolfo B.; Bonfante, Estevam A.; Konishi, Akihiro; Takeda, Katsuhiro; Kurihara, Hidemi; Coelho, Paulo G.

    2014-01-01

    This study aimed to observe the regenerative effect of brain-derived neurotrophic factor (BDNF) in a non-human primate furcation defect model. Class II furcation defects were created in the first and second molars of 8 non-human primates to simulate a clinical situation. The defect was filled with either, Group A: BDNF (500 µg/ml) in high-molecular weight-hyaluronic acid (HMW-HA), Group B: BDNF (50 µg/ml) in HMW-HA, Group C: HMW-HA acid only, Group D: empty defect, or Group E: BDNF (500 µg/ml) in saline. The healing status for all groups was observed at different time-points with micro computed tomography. The animals were euthanized after 11 weeks, and the tooth-bone specimens were subjected to histologic processing. The results showed that all groups seemed to successfully regenerate the alveolar buccal bone, however, only Group A regenerated the entire periodontal tissue, i.e., alveolar bone, cementum and periodontal ligament. It is suggested that the use of BDNF in combination with a scaffold such as the hyaluronic acid in periodontal furcation defects may be an effective treatment option. PMID:24454754

  8. Low-level laser therapy promotes dendrite growth via upregulating brain-derived neurotrophic factor expression

    NASA Astrophysics Data System (ADS)

    Meng, Chengbo; He, Zhiyong; Xing, Da

    2014-09-01

    Downregulation of brain-derived neurotrophic factor (BDNF) in the hippocampus occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival and dendrite growth, BDNF upregulation may contribute to rescue dendrite atrophy and cell loss in AD. Low-level laser therapy (LLLT) has been demonstrated to regulate neuronal function both in vitro and in vivo. In the present study, we found that LLLT rescued neurons loss and dendritic atrophy via the increase of both BDNF mRNA and protein expression. In addition, dendrite growth was improved after LLLT, characterized by upregulation of PSD95 expression, and the increase in length, branching, and spine density of dendrites in hippocampal neurons. Together, these studies suggest that upregulation of BDNF with LLLT can ameliorate Aβ-induced neurons loss and dendritic atrophy, thus identifying a novel pathway by which LLLT protects against Aβ-induced neurotoxicity. Our research may provide a feasible therapeutic approach to control the progression of Alzheimer's disease.

  9. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

    PubMed Central

    Khalin, Igor; Alyautdin, Renad; Kocherga, Ganna; Bakar, Muhamad Abu

    2015-01-01

    Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood–retinal barrier and blood–cochlear barrier, which have a comparable structure to the blood–brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration. PMID:25995632

  10. Brain-derived neurotrophic factor into adult neocortex strengthens a taste aversion memory.

    PubMed

    Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F; Escobar, Martha L

    2016-01-15

    Nowadays, it is known that brain derived neurotrophic-factor (BDNF) is a protein critically involved in regulating long-term memory related mechanisms. Previous studies from our group in the insular cortex (IC), a brain structure of the temporal lobe implicated in acquisition, consolidation and retention of conditioned taste aversion (CTA), demonstrated that BDNF is essential for CTA consolidation. Recent studies show that BDNF-TrkB signaling is able to mediate the enhancement of memory. However, whether BDNF into neocortex is able to enhance aversive memories remains unexplored. In the present work, we administrated BDNF in a concentration capable of inducing in vivo neocortical LTP, into the IC immediately after CTA acquisition in two different conditions: a "strong-CTA" induced by 0.2M lithium chloride i.p. as unconditioned stimulus, and a "weak-CTA" induced by 0.1M lithium chloride i.p. Our results show that infusion of BDNF into the IC converts a weak CTA into a strong one, in a TrkB receptor-dependent manner. The present data suggest that BDNF into the adult insular cortex is sufficient to increase an aversive memory-trace.

  11. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

    PubMed

    Haile, C N; Murrough, J W; Iosifescu, D V; Chang, L C; Al Jurdi, R K; Foulkes, A; Iqbal, S; Mahoney, J J; De La Garza, R; Charney, D S; Newton, T F; Mathew, S J

    2014-02-01

    Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

  12. Directed evolution of brain-derived neurotrophic factor for improved folding and expression in Saccharomyces cerevisiae.

    PubMed

    Burns, Michael L; Malott, Thomas M; Metcalf, Kevin J; Hackel, Benjamin J; Chan, Jonah R; Shusta, Eric V

    2014-09-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in nervous system function and has therapeutic potential. Microbial production of BDNF has resulted in a low-fidelity protein product, often in the form of large, insoluble aggregates incapable of binding to cognate TrkB or p75 receptors. In this study, employing Saccharomyces cerevisiae display and secretion systems, it was found that BDNF was poorly expressed and partially inactive on the yeast surface and that BDNF was secreted at low levels in the form of disulfide-bonded aggregates. Thus, for the purpose of increasing the compatibility of yeast as an expression host for BDNF, directed-evolution approaches were employed to improve BDNF folding and expression levels. Yeast surface display was combined with two rounds of directed evolution employing random mutagenesis and shuffling to identify BDNF mutants that had 5-fold improvements in expression, 4-fold increases in specific TrkB binding activity, and restored p75 binding activity, both as displayed proteins and as secreted proteins. Secreted BDNF mutants were found largely in the form of soluble homodimers that could stimulate TrkB phosphorylation in transfected PC12 cells. Site-directed mutagenesis studies indicated that a particularly important mutational class involved the introduction of cysteines proximal to the native cysteines that participate in the BDNF cysteine knot architecture. Taken together, these findings show that yeast is now a viable alternative for both the production and the engineering of BDNF.

  13. TrkB-Mediated Neuroprotective and Antihypoxic Properties of Brain-Derived Neurotrophic Factor.

    PubMed

    Vedunova, Maria V; Mishchenko, Tatiana A; Mitroshina, Elena V; Mukhina, Irina V

    2015-01-01

    The neuroprotective and antihypoxic effects of brain-derived neurotrophic factor (BDNF) on dissociated hippocampal cultures in a hypoxia model were investigated. These experiments demonstrate that 10 minutes of normobaric hypoxia increased the number of dead cells in primary culture, whereas a preventive application of BDNF increased the number of viable cells. Spontaneous bioelectrical and calcium activity in neural networks was analyzed using multielectrode arrays and functional intravital calcium imaging. The results indicate that BDNF affects the functional parameters of neuronal networks in dissociated hippocampal cultures over the 7-day posthypoxic period. In addition, the effects of k252a, an antagonist of tropomyosin-related kinase B (TrkB), on functional bioelectrical activity during and after acute hypoxia were investigated. It was shown that the protective effects of BDNF are associated with binding to the TrkB receptor. Finally, intravital fluorescent mRNA probes were used to study the role of NF-κB1 in the protective effects of BDNF. Our experiments revealed that BDNF application stimulates NF-κB1 mRNA synthesis in primary dissociated hippocampal cells under normal conditions but not in hypoxic state.

  14. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons.

    PubMed

    Murphy, D D; Cole, N B; Segal, M

    1998-09-15

    Dendritic spines are of major importance in information processing and memory formation in central neurons. Estradiol has been shown to induce an increase of dendritic spine density on hippocampal neurons in vivo and in vitro. The neurotrophin brain-derived neurotrophic factor (BDNF) recently has been implicated in neuronal maturation, plasticity, and regulation of GABAergic interneurons. We now demonstrate that estradiol down-regulates BDNF in cultured hippocampal neurons to 40% of control values within 24 hr of exposure. This, in turn, decreases inhibition and increases excitatory tone in pyramidal neurons, leading to a 2-fold increase in dendritic spine density. Exogenous BDNF blocks the effects of estradiol on spine formation, and BDNF depletion with a selective antisense oligonucleotide mimics the effects of estradiol. Addition of BDNF antibodies also increases spine density, and diazepam, which facilitates GABAergic neurotransmission, blocks estradiol-induced spine formation. These observations demonstrate a functional link between estradiol, BDNF as a potent regulator of GABAergic interneurons, and activity-dependent formation of dendritic spines in hippocampal neurons.

  15. Brain-derived neurotrophic factor promoter methylation and cortical thickness in recurrent major depressive disorder.

    PubMed

    Na, Kyoung-Sae; Won, Eunsoo; Kang, June; Chang, Hun Soo; Yoon, Ho-Kyoung; Tae, Woo Suk; Kim, Yong-Ku; Lee, Min-Soo; Joe, Sook-Haeng; Kim, Hyun; Ham, Byung-Joo

    2016-02-15

    Recent studies have reported that methylation of the brain-derived neurotrophic factor (BDNF) gene promoter is associated with major depressive disorder (MDD). This study aimed to investigate the association between cortical thickness and methylation of BDNF promoters as well as serum BDNF levels in MDD. The participants consisted of 65 patients with recurrent MDD and 65 age- and gender-matched healthy controls. Methylation of BDNF promoters and cortical thickness were compared between the groups. The right medial orbitofrontal, right lingual, right lateral occipital, left lateral orbitofrontal, left pars triangularis, and left lingual cortices were thinner in patients with MDD than in healthy controls. Among the MDD group, right pericalcarine, right medical orbitofrontal, right rostral middle frontal, right postcentral, right inferior temporal, right cuneus, right precuneus, left frontal pole, left superior frontal, left superior temporal, left rostral middle frontal and left lingual cortices had inverse correlations with methylation of BDNF promoters. Higher levels of BDNF promoter methylation may be closely associated with the reduced cortical thickness among patients with MDD. Serum BDNF levels were significantly lower in MDD, and showed an inverse relationship with BDNF methylation only in healthy controls. Particularly the prefrontal and occipital cortices seem to indicate key regions in which BDNF methylation has a significant effect on structure.

  16. Acute exercise ameliorates reduced brain-derived neurotrophic factor in patients with panic disorder.

    PubMed

    Ströhle, Andreas; Stoy, Meline; Graetz, Barbara; Scheel, Michael; Wittmann, André; Gallinat, Jürgen; Lang, Undine E; Dimeo, Fernando; Hellweg, Rainer

    2010-04-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in depression and anxiety. Antidepressants and exercise increase BDNF expression, and both have an antidepressant and anxiolytic activity. To further characterize the association of anxiety, BDNF and exercise, we studied panic disorder patients (n=12) and individually matched healthy control subjects (n=12) in a standardized exercise paradigm. Serum samples for BDNF analyses were taken before and after 30min of exercise (70 VO(2max)) or quiet rest. The two conditions were separated by 1 week and the order was randomized. Non-parametric statistical analyses were performed. There was a negative correlation of BDNF concentrations and subjective arousal at baseline (r=-0.42, p=0.006). Compared to healthy control subjects, patients with panic disorder had significantly reduced BDNF concentrations at baseline and 30min of exercise significantly increased BDNF concentrations only in these patients. Our results suggest that acute exercise ameliorates reduced BDNF concentrations in panic disorder patients and raise the question whether this is also found after long-term exercise training and if it is related to the therapeutic outcome.

  17. Zinc-triggered induction of tissue plasminogen activator by brain-derived neurotrophic factor and metalloproteinases.

    PubMed

    Hwang, Ih-Yeon; Sun, Eun-Sun; An, Ji Hak; Im, Hana; Lee, Sun-Ho; Lee, Joo-Yong; Han, Pyung-Lim; Koh, Jae-Young; Kim, Yang-Hee

    2011-09-01

    Tissue plasminogen activator (tPA) is necessary for hippocampal long-term potentiation. Synaptically released zinc also contributes to long-term potentiation, especially in the hippocampal CA3 region. Using cortical cultures, we examined whether zinc increased the concentration and/or activity of tPA. Two hours after a 10-min exposure to 300 μM zinc, expression of tPA and its substrate, plasminogen, were significantly increased, as was the proteolytic activity of tPA. In contrast, increasing extracellular or intracellular calcium levels did not affect the expression or secretion of tPA. Changing zinc influx or chelating intracellular zinc also failed to alter tPA/plasminogen induction by zinc, indicating that zinc acts extracellularly. Zinc-mediated extracellular activation of matrix metalloproteinase (MMP) underlies the up-regulation of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase (Trk) signaling. Consistent with these findings, co-treatment with a neutralizing antibody against BDNF or specific inhibitors of MMPs or Trk largely reversed tPA/plasminogen induction by zinc. Treatment of cortical cultures with p-aminophenylmercuric acetate, an MMP activator, MMP-2, or BDNF alone induced tPA/plasminogen expression. BDNF mRNA and protein expression was also increased by zinc and mediated by MMPs. Thus, an extracellular zinc-dependent, MMP- and BDNF-mediated synaptic mechanism may regulate the levels and activity of tPA.

  18. Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype.

    PubMed

    Guiard, Bruno P; David, Denis J P; Deltheil, Thierry; Chenu, Franck; Le Maître, Erwan; Renoir, Thibault; Leroux-Nicollet, Isabelle; Sokoloff, Pierre; Lanfumey, Laurence; Hamon, Michel; Andrews, Anne M; Hen, René; Gardier, Alain M

    2008-02-01

    Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/- heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/- mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/- mice. A significant decrease in [3H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3H]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT1A autoreceptors were not desensitized in BDNF +/- mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus.

  19. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress.

    PubMed

    Jiang, De-Guo; Jin, Shi-Li; Li, Gong-Ying; Li, Qing-Qing; Li, Zhi-Ruo; Ma, Hong-Xia; Zhuo, Chuan-Jun; Jiang, Rong-Huan; Ye, Min-Jie

    2016-09-01

    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-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A 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 mRNA expression levels were higher in the 5-HT1A and the 5-HT2A 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 mRNA expression levels were lower in the 5-HT1A and 5-HT2A 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.

  20. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor.

    PubMed

    Szuhany, Kristin L; Bugatti, Matteo; Otto, Michael W

    2015-01-01

    Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). When analyzing results across paradigms, sex significantly moderated the effect of exercise on BDNF levels, such that studies with more women showed less BDNF change resulting from exercise. Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans, but indicates that the magnitude of these effects may be lower in females relative to males.

  1. Effect of Training Exercise on Urinary Brain-derived Neurotrophic Factor Levels and Cognitive Performances in Overweight and Obese Subjects: A Pilot Study.

    PubMed

    Russo, Angelo; Buratta, Livia; Pippi, Roberto; Aiello, Cristina; Ranucci, Claudia; Reginato, Elisa; Santangelo, Valerio; DeFeo, Pierpaolo; Mazzeschi, Claudia

    2016-11-21

    Exercise-mediated, brain-derived neurotrophic factor induction benefits health and cognitive functions. The multifaceted interplay between physical activity, urinary brain-derived neurotrophic factor levels and cognitive functioning has been largely neglected in previous literature. In this pilot study, two bouts of training exercise (65% and 70% of heart rate reserve) influenced urinary brain-derived neurotrophic factor levels and cognitive performances in 12 overweight and obese participants. Percent heart rate reserve, expenditure energy, brain-derived neurotrophic factor urinary levels and cognitive performances were measured before and after the exercise. No significant variations in energy expenditure were observed, while differences of heart rate reserve between two groups were maintained. Both bouts of training exercise induced a similar reduction in urinary brain-derived neurotrophic factor levels. Only visuo-spatial working memory capacity at 65% of heart rate reserve showed a significant increase. These findings indicate a consistent effect of training exercise on urinary brain-derived neurotrophic factor levels and cognitive factors in overweight and obese participants.

  2. The effect of regular Taekwondo exercise on Brain-derived neurotrophic factor and Stroop test in undergraduate student

    PubMed Central

    Kim, Youngil

    2015-01-01

    [Purpose] The purpose of this study was to investigate the effect of Taekwondo exercise on Brain-derived neurotrophic factor and the Stroop test in undergraduate students. [Methods] Fourteen male subjects participated in this study. They were separated into a Control group (N = 7) and an Exercise group (N = 7). Subjects participated in Taekwondo exercise training for 8 weeks. They underwent to Taekwondo exercise training for 85 minutes per day, 5 times a week at RPE of 11~15. The taekwondo exercise training comprised an aerobic exercise (20min) mode and a dynamic exercise (65min) mode. All data were analyzed by repeated measures two-way ANOVA. [Results] There were no significant differences in the physical characteristics of the subjects. Although weight and BMI showed a tendency to decreased in the exercise group (EG). Also, neurotrophic factors (BDNF, NGF, IGF-1) were not significantly different after 8 weeks in the two groups. However, BDNF and IGF-1 showed a tendency to increase in the exercise group (EG). Finally, the Stroop test (word, color) results were significantly different(p < .05) in the exercise group (EG). [Conclusion] These finding suggest that 8 weeks of regular Taekwondo exercise training may increase cognitive functions (Stroop test). However the training did not statistically affect neurotrophic factors (BDNF, NGF, IGF-1) in undergraduate students. PMID:26244125

  3. Human umbilical cord blood-derived stem cells and brain-derived neurotrophic factor protect injured optic nerve: viscoelasticity characterization

    PubMed Central

    Lv, Xue-man; Liu, Yan; Wu, Fei; Yuan, Yi; Luo, Min

    2016-01-01

    The optic nerve is a viscoelastic solid-like biomaterial. Its normal stress relaxation and creep properties enable the nerve to resist constant strain and protect it from injury. We hypothesized that stress relaxation and creep properties of the optic nerve change after injury. More-over, human brain-derived neurotrophic factor or umbilical cord blood-derived stem cells may restore these changes to normal. To validate this hypothesis, a rabbit model of optic nerve injury was established using a clamp approach. At 7 days after injury, the vitreous body re-ceived a one-time injection of 50 μg human brain-derived neurotrophic factor or 1 × 106 human umbilical cord blood-derived stem cells. At 30 days after injury, stress relaxation and creep properties of the optic nerve that received treatment had recovered greatly, with patho-logical changes in the injured optic nerve also noticeably improved. These results suggest that human brain-derived neurotrophic factor or umbilical cord blood-derived stem cell intervention promotes viscoelasticity recovery of injured optic nerves, and thereby contributes to nerve recovery. PMID:27212930

  4. Human umbilical cord blood-derived stem cells and brain-derived neurotrophic factor protect injured optic nerve: viscoelasticity characterization.

    PubMed

    Lv, Xue-Man; Liu, Yan; Wu, Fei; Yuan, Yi; Luo, Min

    2016-04-01

    The optic nerve is a viscoelastic solid-like biomaterial. Its normal stress relaxation and creep properties enable the nerve to resist constant strain and protect it from injury. We hypothesized that stress relaxation and creep properties of the optic nerve change after injury. More-over, human brain-derived neurotrophic factor or umbilical cord blood-derived stem cells may restore these changes to normal. To validate this hypothesis, a rabbit model of optic nerve injury was established using a clamp approach. At 7 days after injury, the vitreous body re-ceived a one-time injection of 50 μg human brain-derived neurotrophic factor or 1 × 10(6) human umbilical cord blood-derived stem cells. At 30 days after injury, stress relaxation and creep properties of the optic nerve that received treatment had recovered greatly, with patho-logical changes in the injured optic nerve also noticeably improved. These results suggest that human brain-derived neurotrophic factor or umbilical cord blood-derived stem cell intervention promotes viscoelasticity recovery of injured optic nerves, and thereby contributes to nerve recovery.

  5. A novel cysteine-rich neurotrophic factor in Aplysia facilitates growth, MAPK activation, and long-term synaptic facilitation.

    PubMed

    Pu, Lu; Kopec, Ashley M; Boyle, Heather D; Carew, Thomas J

    2014-04-01

    Neurotrophins are critically involved in developmental processes such as neuronal cell survival, growth, and differentiation, as well as in adult synaptic plasticity contributing to learning and memory. Our previous studies examining neurotrophins and memory formation in Aplysia showed that a TrkB ligand is required for MAPK activation, long-term synaptic facilitation (LTF), and long-term memory (LTM) for sensitization. These studies indicate that neurotrophin-like molecules in Aplysia can act as key elements in a functionally conserved TrkB signaling pathway. Here we report that we have cloned and characterized a novel neurotrophic factor, Aplysia cysteine-rich neurotrophic factor (apCRNF), which shares classical structural and functional characteristics with mammalian neurotrophins. We show that apCRNF (1) is highly enriched in the CNS, (2) enhances neurite elongation and branching, (3) interacts with mammalian TrkB and p75(NTR), (4) is released from Aplysia CNS in an activity-dependent fashion, (5) facilitates MAPK activation in a tyrosine kinase dependent manner in response to sensitizing stimuli, and (6) facilitates the induction of LTF. These results show that apCRNF is a native neurotrophic factor in Aplysia that can engage the molecular and synaptic mechanisms underlying memory formation.

  6. Effects of aerobic exercise training on peripheral brain-derived neurotrophic factor and eotaxin-1 levels in obese young men.

    PubMed

    Cho, Su Youn; Roh, Hee Tae

    2016-04-01

    [Purpose] The aim of the present study was to investigate the effects of aerobic exercise training on the levels of peripheral brain-derived neurotrophic factor and eotaxin-1 in obese young men. [Subjects and Methods] The subjects included sixteen obese young men with a body mass index greater than 25 kg/m(2). They were randomly divided between control and exercise groups (n = 8 in each group). The exercise group performed treadmill exercise for 40 min, 3 times a week for 8 weeks at the intensity of 70% heart rate reserve. Blood collection was performed to examine the levels of serum glucose, plasma malonaldehyde, serum brain-derived neurotrophic factor, and plasma eotaxin-1 before and after the intervention (aerobic exercise training). [Results] Following the intervention, serum BDNF levels were significantly higher, while serum glucose, plasma MDA, and plasma eotaxin-1 levels were significantly lower than those prior to the intervention in the exercise group. [Conclusion] Aerobic exercise training can induce neurogenesis in obese individuals by increasing the levels of brain-derived neurotrophic factor and reducing the levels of eotaxin-1. Alleviation of oxidative stress is possibly responsible for such changes.

  7. Antidepressant effect of electroacupuncture regulates signal targeting in the brain and increases brain-derived neurotrophic factor levels

    PubMed Central

    Duan, Dong-mei; Tu, Ya; Liu, Ping; Jiao, Shuang

    2016-01-01

    Electroacupuncture improves depressive behavior faster and with fewer adverse effects than antidepressant medication. However, the antidepressant mechanism of electroacupuncture remains poorly understood. Here, we established a rat model of chronic unpredicted mild stress, and then treated these rats with electroacupuncture at Yintang (EX-HN3) and Baihui (DU20) with sparse waves at 2 Hz and 0.6 mA for 30 minutes, once a day. We found increased horizontal and vertical activity, and decreased immobility time, at 2 and 4 weeks after treatment. Moreover, levels of neurotransmitters (5-hydroxytryptamine, glutamate, and γ-aminobutyric acid) and protein levels of brain-derived neurotrophic factor and brain-derived neurotrophic factor-related proteins (TrkB, protein kinase A, and phosphorylation of cyclic adenosine monophosphate response element binding protein) were increased in the hippocampus. Similarly, protein kinase A and TrkB mRNA levels were increased, and calcium-calmodulin-dependent protein kinase II levels decreased. These findings suggest that electroacupuncture increases phosphorylation of cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor levels by regulating multiple targets in the cyclic adenosine monophosphate response element binding protein signaling pathway, thereby promoting nerve regeneration, and exerting an antidepressive effect. PMID:27904490

  8. TRPC3 regulates release of brain-derived neurotrophic factor from human airway smooth muscle.

    PubMed

    Vohra, Pawan K; Thompson, Michael A; Sathish, Venkatachalem; Kiel, Alexander; Jerde, Calvin; Pabelick, Christina M; Singh, Brij B; Prakash, Y S

    2013-12-01

    Exogenous brain-derived neurotrophic factor (BDNF) enhances Ca(2+) signaling and cell proliferation in human airway smooth muscle (ASM), especially with inflammation. Human ASM also expresses BDNF, raising the potential for autocrine/paracrine effects. The mechanisms by which ASM BDNF secretion occurs are not known. Transient receptor potential channels (TRPCs) regulate a variety of intracellular processes including store-operated Ca(2+) entry (SOCE; including in ASM) and secretion of factors such as cytokines. In human ASM, we tested the hypothesis that TRPC3 regulates BDNF secretion. At baseline, intracellular BDNF was present, and BDNF secretion was detectable by enzyme linked immunosorbent assay (ELISA) of cell supernatants or by real-time fluorescence imaging of cells transfected with GFP-BDNF vector. Exposure to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) (20ng/ml, 48h) or a mixture of allergens (ovalbumin, house dust mite, Alternaria, and Aspergillus extracts) significantly enhanced BDNF secretion and increased TRPC3 expression. TRPC3 knockdown (siRNA or inhibitor Pyr3; 10μM) blunted BDNF secretion, and prevented inflammation effects. Chelation of extracellular Ca(2+) (EGTA; 1mM) or intracellular Ca(2+) (BAPTA; 5μM) significantly reduced secreted BDNF, as did the knockdown of SOCE proteins STIM1 and Orai1 or plasma membrane caveolin-1. Functionally, secreted BDNF had autocrine effects suggested by phosphorylation of high-affinity tropomyosin-related kinase TrkB receptor, prevented by chelating extracellular BDNF with chimeric TrkB-Fc. These data emphasize the role of TRPC3 and Ca(2+) influx in the regulation of BDNF secretion by human ASM and the enhancing effects of inflammation. Given the BDNF effects on Ca(2+) and cell proliferation, BDNF secretion may contribute to altered airway structure and function in diseases such as asthma.

  9. Brain-derived neurotrophic factor promotes neurite growth and survival of antennal lobe neurons in brain from the silk moth, Bombyx mori in vitro.

    PubMed

    Kim, Jin Hee; Sung, Dong Kyung; Park, Chan Woo; Park, Hun Hee; Park, Cheolin; Jeon, Soung-Hoo; Kang, Pil Don; Kwon, O-Yu; Lee, Bong Hee

    2005-03-01

    This study was conducted to investigate effects of brain-derived neurotrophic factor on the neurite growth and the survival rate of antennal lobe neurons in vitro, and secretion of brain-derived neurotrophic factor-like neuropeptide from brain into hemolymph in the silk moth, Bombyx mori. In primary culture of antennal lobe neurons with brain-derived neurotrophic factor, it promoted both a neurite extension of putative antennal lobe projection neurons and an outgrowth of branches from principal neurites of putative antennal interneurons with significance (p<0.05). Brain-derived neurotrophic factor also increased significantly a survival rate of antennal lobe neurons (p<0.05). Results from immunolabeling of brain and retrocerebral complex, and ELISA assay of hemolymph showed that brain-derived neurotrophic factor-like neuropeptide was synthesized by both median and lateral neurosecretory cells of brain, then transported to corpora allata for storage, and finally secreted into hemolymph for action. These results will provide valuable information for differentiation of invertebrate brain neurons with brain-derived neurotrophic factor.

  10. Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims.

    PubMed

    Pandey, Ghanshyam N; Ren, Xinguo; Rizavi, Hooriyah S; Conley, Robert R; Roberts, Rosalinda C; Dwivedi, Yogesh

    2008-12-01

    Teenage suicide is a major public health concern, but its neurobiology is not very well understood. Stress and major mental disorders are major risk factors for suicidal behaviour, and it has been shown that brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) are not only regulated by stress but are also altered in these illnesses. We therefore examined if BDNF/TrkB signalling is altered in the post-mortem brain of teenage suicide victims. Protein and mRNA expression of BDNF and of TrkB receptors were determined in the prefrontal cortex (PFC), Brodmann's Area 9 (BA 9), and hippocampus obtained from 29 teenage suicide victims and 25 matched normal control subjects. Protein expression was determined using the Western blot technique; mRNA levels by a quantitative RT-PCR technique. The protein expression of BDNF was significantly decreased in the PFC of teenage suicide victims compared with normal control subjects, whereas no change was observed in the hippocampus. Protein expression of TrkB full-length receptors was significantly decreased in both PFC and hippocampus of teenage suicide victims without any significant changes in the truncated form of TrkB receptors. mRNA expression of both BDNF and TrkB was significantly decreased in the PFC and hippocampus of teenage suicide victims compared with normal control subjects. These studies indicate a down-regulation of both BDNF and its receptor TrkB in the PFC and hippocampus of teenage suicide victims, which suggests that stress and altered BDNF may represent a major vulnerability factor in teenage suicidal behaviour.

  11. Cerebrolysin, a mixture of neurotrophic factors induces marked neuroprotection in spinal cord injury following intoxication of engineered nanoparticles from metals.

    PubMed

    Menon, Preeti Kumaran; Muresanu, Dafin Fior; Sharma, Aruna; Mössler, Herbert; Sharma, Hari Shanker

    2012-02-01

    Spinal cord injury (SCI) is the world's most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; cerebrolysin that is a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins

  12. Computerized cognitive training and brain derived neurotrophic factor during bed rest: mechanisms to protect individual during acute stress

    PubMed Central

    Passaro, Angelina; Soavi, Cecilia; Sanz, Juana M.; Morieri, Mario L.; Dalla Nora, Edoardo; Kavcic, Voyko; Narici, Marco V.; Reggiani, Carlo; Biolo, Gianni; Zuliani, Giovanni; Lazzer, Stefano; Pišot, Rado

    2017-01-01

    Acute stress, as bed rest, was shown to increase plasma level of the neurotrophin brain-derived neurotrophic factor (BDNF) in older, but not in young adults. This increase might represent a protective mechanism towards acute insults in aging subjects. Since computerized cognitive training (CCT) is known to protect brain, herein we evaluated the effect of CCT during bed rest on BDNF, muscle mass, neuromuscular function and metabolic parameters. The subjects that underwent CCT did not show an increase of BDNF after bed rest, and showed an anti-insular modification pattern in metabolism. Neuromuscular function parameters, already shown to beneficiate from CCT, negatively correlated with BDNF in research participants undergoing CCT, while positively correlated in the control group. In conclusion, BDNF increase can be interpreted as a standardized protective mechanism taking place whenever an insult occurs; it gives low, but consistent preservation of neuromuscular function. CCT, acting as an external protective mechanism, seems to modify this standardized response, avoiding BDNF increase or possibly modifying its time course. Our results suggest the possibility of differential neuroprotective mechanisms among ill and healthy individuals, and the importance of timing in determining the effects of protective mechanisms. PMID:28161695

  13. Ameliorating effect of hypothalamic brain-derived neurotrophic factor against impaired glucose metabolism after cerebral ischemic stress in mice.

    PubMed

    Harada, Shinichi; Fujita-Hamabe, Wakako; Tokuyama, Shogo

    2012-01-01

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has potent neuroprotective effects against brain injury. We recently reported that glucose intolerance/hyperglycemia could be induced by ischemic stress (i.e., post-ischemic glucose intolerance) following ischemic neuronal damage. Therefore, the aim of this study was to determine the effects of BDNF on the development of post-ischemic glucose intolerance and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. On day 1, the expression levels of BDNF were significantly decreased in the cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor, a BDNF receptor, decreased in the hypothalamus and liver and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of BDNF (50 ng/mouse) suppressed the development of post-ischemic glucose intolerance on day 1 and neuronal damage on day 3 after MCAO. In the liver and skeletal muscle, the expression levels of insulin receptors decreased, while gluconeogenic enzyme levels increased on day 1 after MCAO. These changes completely recovered to normal levels in the presence of BDNF. These results indicate that regulation of post-ischemic glucose intolerance by BDNF may suppress ischemic neuronal damage.

  14. The Effect of Exercise Training on Resting Concentrations of Peripheral Brain-Derived Neurotrophic Factor (BDNF): A Meta-Analysis

    PubMed Central

    Dinoff, Adam; Herrmann, Nathan; Swardfager, Walter; Liu, Celina S.; Sherman, Chelsea; Chan, Sarah; Lanctôt, Krista L.

    2016-01-01

    Background The mechanisms through which physical activity supports healthy brain function remain to be elucidated. One hypothesis suggests that increased brain-derived neurotrophic factor (BDNF) mediates some cognitive and mood benefits. This meta-analysis sought to determine the effect of exercise training on resting concentrations of BDNF in peripheral blood. Methods MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer-reviewed reports of peripheral blood BDNF concentrations before and after exercise interventions ≥ 2 weeks. Risk of bias was assessed using standardized criteria. Standardized mean differences (SMDs) were generated from random effects models. Risk of publication bias was assessed using funnel plots and Egger’s test. Potential sources of heterogeneity were explored in subgroup analyses. Results In 29 studies that met inclusion criteria, resting concentrations of peripheral blood BDNF were higher after intervention (SMD = 0.39, 95% CI: 0.17–0.60, p < 0.001). Subgroup analyses suggested a significant effect in aerobic (SMD = 0.66, 95% CI: 0.33–0.99, p < 0.001) but not resistance training (SMD = 0.07, 95% CI: -0.15–0.30, p = 0.52) interventions. No significant difference in effect was observed between males and females, nor in serum vs plasma. Conclusion Aerobic but not resistance training interventions increased resting BDNF concentrations in peripheral blood. PMID:27658238

  15. Association of brain-derived neurotrophic factor and nerve growth factor gene polymorphisms with susceptibility to migraine

    PubMed Central

    Coskun, Salih; Varol, Sefer; Ozdemir, Hasan H; Agacayak, Elif; Aydın, Birsen; Kapan, Oktay; Camkurt, Mehmet Akif; Tunc, Saban; Cevik, Mehmet Ugur

    2016-01-01

    Migraine is one of the most common neurological diseases worldwide. Migraine pathophysiology is very complex. Genetic factors play a major role in migraine. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), play an important role in central nervous system functioning, development, and modulation of pain. This study investigates whether polymorphisms in the BDNF and NGF genes are associated with migraine disease in a Turkish case–control population. Overall, 576 subjects were investigated (288 patients with migraine and 288 healthy controls) for the following polymorphisms: rs6265(G/A), rs8192466(C/T), rs925946(G/T), rs2049046(A/T), and rs12273363(T/C) in the BDNF gene, and rs6330(C/T), rs11466112(C/T), rs11102930(C/A), and rs4839435(G/A) in the NGF gene using 5′-exonuclease allelic discrimination assays. We found no differences in frequency of the analyzed eight polymorphisms between migraine and control groups. However, the frequency of minor A alleles of rs6265 in BDNF gene was borderline significant in the patients compared with the healthy controls (P=0.049; odds ratios [ORs] [95% confidence intervals {CIs}] =0.723 [0.523–0.999]). Moreover, when the migraine patients were divided into two subgroups, migraine with aura (MA) and migraine without aura (MO), the minor TT genotype of rs6330 in NGF was significantly higher in MA patients than in MO patients (P=0.036) or healthy controls (P=0.026), and this disappeared after correction for multiple testing. Also, the rs6330*T minor allele was more common in the MA group than in the MO group or controls (P=0.011, ORs [95% CIs] =1.626 [1.117–2.365] or P=0.007, ORs [95% CIs] =1.610 [1.140–2.274], respectively). In conclusion, this is the first clinical study to evaluate the association between BDNF and NGF polymorphisms in migraine patients compared with health controls. Our findings suggest that the NGF rs6330*T minor allele might be nominated as a risk

  16. Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain.

    PubMed

    Trang, Tuan; Beggs, Simon; Salter, Michael W

    2011-02-01

    One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia expresses several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia-neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia-neuron signaling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptor-mediated signaling and regulation of BDNF in microglia, as well as the implications for microglia-neuron interactions in the pathobiology of neuropathic pain.

  17. Neither cortisol nor brain-derived neurotrophic factor is associated with serotonin transporter in bipolar disorder.

    PubMed

    Chou, Yuan-Hwa; Lirng, Jiing-Feng; Hsieh, Wen-Chi; Chiu, Yen-Chen; Tu, Yi-An; Wang, Shyh-Jen

    2016-02-01

    Converging evidence indicates the hypothalamus-pituitary-adrenal axis and serotonergic neurons exert reciprocal modulatory actions. Likewise, brain-derived neurotrophic factor (BDNF) has been implicated as a growth and differentiation factor in the development of serotonergic neurons. The aim of this study was to examine the interaction of cortisol and BDNF on serotonin transporter (SERT) in bipolar disorder (BD). Twenty-eight BD and 28 age- and gender-matched healthy controls (HCs) were recruited. (123)I-ADAM with single-photon emission computed tomography (SPECT) was applied for measurement of SERT availability in the brain, which included the midbrain, thalamus, putamen and caudate. Ten milliliters of venous blood was withdrawn, when the subject underwent SPECT, for the measurement of the plasma concentration of cortisol and BDNF. SERT availability was significantly decreased in the midbrain and caudate of BD compared with HCs, whereas plasma concentration of cortisol and BDNF did not show a significant difference. The linear mixed-effect model revealed that there was a significant interaction of group and cortisol on SERT availability of the midbrain, but not BDNF. Linear regression analyses by groups revealed that cortisol was associated with SERT availability in the midbrain in the HCs, but not in BD. Considering previous studies, which showed a significant association of cortisol with SERT availability in the HCs and major depressive disorder (MDD), our result replicated a similar finding in HCs. However, the negative finding of the association of cortisol and SERT availability in BD, which was different from MDD, suggests a different role for cortisol in the pathophysiology of mood disorder.

  18. Safety of repeated transplantations of neurotrophic factors-secreting human mesenchymal stromal stem cells

    PubMed Central

    2014-01-01

    Background Therapies based on mesenchymal stem cells (MSC) have been shown to have potential benefit in several clinical studies. We have shown that, using a medium-based approach, MSC can be induced to secrete elevated levels of neurotropic factors, which have been shown to have protective effects in animal models of neurodegenerative diseases. These cells, designated MSC-NTF cells (Neurotrophic factor-secreting MSC, also known as NurOwn™) derived from the patient's own bone marrow, have been recently used for Phase I/II and Phase IIa clinical studies in patients with Amyotrophic Lateral Sclerosis (ALS). In these studies, ALS patients were subjected to a single administration of autologous MSC-NTF cells. The data from these studies indicate that the single administration of MSC-NTF cells is safe and well tolerated. In a recently published case report, it was shown that repeated MSC-NTF injections in an ALS patient treated on a compassionate basis were safe and well tolerated [Muscle Nerve 49:455-457, 2014]. Methods In the current study we studied the toxicity and tolerability of three consecutive intramuscular injections (IM) of cryopreserved human MSC-NTF cells in C57BL/B6 mice to investigate the effect of repeated administration of these cells. Results Monitoring of clinical signs and immune reactions showed that repeated injections of the cells did not lead to any serious adverse events. Pathology, histology and blood biochemistry parameters tested were found to be within normal ranges with no sign of tumor formation. Conclusions Based on these results we conclude that repeated injections of human MSC-NTF are well tolerated in mice. The results of this study suggest that if the outcomes of additional clinical studies point to the need for repeated treatments, such option can be considered safe. PMID:25097724

  19. Effects of the neurotrophic factor artemin on sensory afferent development and sensitivity

    PubMed Central

    Shu-Ying, Wang; Elitt, Christopher M.; Malin, Sacha A.; Albers, Kathryn M.

    2009-01-01

    Artemin is a neuronal survival and differentiation factor in the glial cell line-derived neurotrophic factor family. Its receptor GFRα3 is expressed by a subpopulation of nociceptor type sensory neurons in the dorsal root and trigeminal ganglia (DRG and TG). These neurons co-express the heat, capsaicin and proton-sensitive channel TRPV1 and the cold and chemical-sensitive channel TRPA1. To further investigate the effects of artemin on sensory neurons, we isolated transgenic mice (ART-OE mice) that overexpress artemin in keratinocytes of the skin and tongue. Enhanced levels of artemin led to a 20% increase in the total number of DRG neurons and increases in the level of mRNA encoding TRPV1 and TRPA1. Calcium imaging showed that isolated sensory neurons from ART-OE mice were hypersensitive to the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. Behavioral testing of ART-OE mice also showed an increased sensitivity to heat, cold, capsaicin and mustard oil stimuli applied either to the skin or in the drinking water. Sensory neurons from wildtype mice also exhibited potentiated capsaicin responses following artemin addition to the media. In addition, injection of artemin into hindpaw skin produced transient thermal hyperalgesia. These findings indicate that artemin can modulate sensory function and that this regulation may occur through changes in channel gene expression. Because artemin mRNA expression is up-regulated in inflamed tissue and following nerve injury, it may have a significant role in cellular changes that underlie pain associated with pathological conditions. Manipulation of artemin expression may therefore offer a new pain treatment strategy. PMID:18958361

  20. Effects of the neurotrophic factor artemin on sensory afferent development and sensitivity.

    PubMed

    Wang, Shuying; Elitt, Christopher M; Malin, Sacha A; Albers, Kathryn M

    2008-10-25

    Artemin is a neuronal survival and differentiation factor in the glial cell line-derived neurotrophic factor family. Its receptor GFRalpha3 is expressed by a subpopulation of nociceptor type sensory neurons in the dorsal root and trigeminal ganglia (DRG and TG). These neurons co-express the heat, capsaicin and proton-sensitive channel TRPV1 and the cold and chemical-sensitive channel TRPA1. To further investigate the effects of artemin on sensory neurons, we isolated transgenic mice (ARTN-OE mice) that overexpress artemin in keratinocytes of the skin and tongue. Enhanced levels of artemin led to a 20% increase in the total number of DRG neurons and increases in the level of mRNA encoding TRPV1 and TRPA1. Calcium imaging showed that isolated sensory neurons from ARTN-OE mice were hypersensitive to the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. Behavioral testing of ARTN-OE mice also showed an increased sensitivity to heat, cold, capsaicin and mustard oil stimuli applied either to the skin or in the drinking water. Sensory neurons from wildtype mice also exhibited potentiated capsaicin responses following artemin addition to the media. In addition, injection of artemin into hindpaw skin produced transient thermal hyperalgesia. These findings indicate that artemin can modulate sensory function and that this regulation may occur through changes in channel gene expression. Because artemin mRNA expression is up-regulated in inflamed tissue and following nerve injury, it may have a significant role in cellular changes that underlie pain associated with pathological conditions. Manipulation of artemin expression may therefore offer a new pain treatment strategy.

  1. cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle.

    PubMed

    Thompson, Michael A; Britt, Rodney D; Kuipers, Ine; Stewart, Alecia; Thu, James; Pandya, Hitesh C; MacFarlane, Peter; Pabelick, Christina M; Martin, Richard J; Prakash, Y S

    2015-10-01

    Moderate hyperoxic exposure in preterm infants contributes to subsequent airway dysfunction and to risk of developing recurrent wheeze and asthma. The regulatory mechanisms that can contribute to hyperoxia-induced airway dysfunction are still under investigation. Recent studies in mice show that hyperoxia increases brain-derived neurotrophic factor (BDNF), a growth factor that increases airway smooth muscle (ASM) proliferation and contractility. We assessed the mechanisms underlying effects of moderate hyperoxia (50% O2) on BDNF expression and secretion in developing human ASM. Hyperoxia increased BDNF secretion, but did not alter endogenous BDNF mRNA or intracellular protein levels. Exposure to hyperoxia significantly increased [Ca2+]i responses to histamine, an effect blunted by the BDNF chelator TrkB-Fc. Hyperoxia also increased ASM cAMP levels, associated with reduced PDE4 activity, but did not alter protein kinase A (PKA) activity or adenylyl cyclase mRNA levels. However, 50% O2 increased expression of Epac2, which is activated by cAMP and can regulate protein secretion. Silencing RNA studies indicated that Epac2, but not Epac1, is important for hyperoxia-induced BDNF secretion, while PKA inhibition did not influence BDNF secretion. In turn, BDNF had autocrine effects of enhancing ASM cAMP levels, an effect inhibited by TrkB and BDNF siRNAs. Together, these novel studies suggest that hyperoxia can modulate BDNF secretion, via cAMP-mediated Epac2 activation in ASM, resulting in a positive feedback effect of BDNF-mediated elevation in cAMP levels. The potential functional role of this pathway is to sustain BDNF secretion following hyperoxic stimulus, leading to enhanced ASM contractility and proliferation.

  2. Developmental traumatic brain injury decreased brain derived neurotrophic factor expression late after injury.

    PubMed

    Schober, Michelle Elena; Block, Benjamin; Requena, Daniela F; Hale, Merica A; Lane, Robert H

    2012-06-01

    Pediatric traumatic brain injury (TBI) is a major cause of acquired cognitive dysfunction in children. Hippocampal Brain Derived Neurotrophic Factor (BDNF) is important for normal cognition. Little is known about the effects of TBI on BDNF levels in the developing hippocampus. We used controlled cortical impact (CCI) in the 17 day old rat pup to test the hypothesis that CCI would first increase rat hippocampal BDNF mRNA/protein levels relative to SHAM and Naïve rats by post injury day (PID) 2 and then decrease BDNF mRNA/protein by PID14. Relative to SHAM, CCI did not change BDNF mRNA/protein levels in the injured hippocampus in the first 2 days after injury but did decrease BDNF protein at PID14. Surprisingly, BDNF mRNA decreased at PID 1, 3, 7 and 14, and BDNF protein decreased at PID 2, in SHAM and CCI hippocampi relative to Naïve. In conclusion, TBI decreased BDNF protein in the injured rat pup hippocampus 14 days after injury. BDNF mRNA levels decreased in both CCI and SHAM hippocampi relative to Naïve, suggesting that certain aspects of the experimental paradigm (such as craniotomy, anesthesia, and/or maternal separation) may decrease the expression of BDNF in the developing hippocampus. While BDNF is important for normal cognition, no inferences can be made regarding the cognitive impact of any of these factors. Such findings, however, suggest that meticulous attention to the experimental paradigm, and possible inclusion of a Naïve group, is warranted in studies of BDNF expression in the developing brain after TBI.

  3. Neurobiological actions by three distinct subtypes of brain-derived neurotrophic factor: Multi-ligand model of growth factor signaling.

    PubMed

    Mizui, Toshiyuki; Ishikawa, Yasuyuki; Kumanogoh, Haruko; Kojima, Masami

    2016-03-01

    Brain-derived neurotrophic factor (BDNF) is one of the most active members of the neurotrophin family. BDNF not only regulates neuronal survival and differentiation, but also functions in activity-dependent plasticity processes such as long-term potentiation (LTP), long-term depression (LTD), learning, and memory. Like other growth factors, BDNF is produced by molecular and cellular mechanisms including transcription and translation, and functions as a bioactive molecule in the nervous system. Among these mechanisms, a particular post-translational mechanism, namely the conversion of precursor BDNF into mature BDNF by proteolytic cleavage, was not fully understood. In this review, we discuss the manner through which this post-translational mechanism alters the biological actions of BDNF protein. In addition to the initially elucidated findings on BDNF, the biological roles of precursor BDNF and the BDNF pro-peptide, especially synaptic plasticity, will be extensively discussed. Recent findings on the BDNF pro-peptide will provide new insights for understanding the mechanisms of action of the pro-peptides of growth factors.

  4. Neuroprotection elicited by nerve growth factor and brain-derived neurotrophic factor released from astrocytes in response to methylmercury.

    PubMed

    Takemoto, Takuya; Ishihara, Yasuhiro; Ishida, Atsuhiko; Yamazaki, Takeshi

    2015-07-01

    The protective roles of astrocytes in neurotoxicity induced by environmental chemicals, such as methylmercury (MeHg), are largely unknown. We found that conditioned medium of MeHg-treated astrocytes (MCM) attenuated neuronal cell death induced by MeHg, suggesting that astrocytes-released factors can protect neuronal cells. The increased expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) was observed in MeHg-treated astrocytes. NGF and BDNF were detected in culture media as homodimers, which are able to bind specific tyrosine kinase receptors, tropomyosin related kinase (Trk) A and TrkB, respectively. The TrkA antagonist and TrkB antagonist abolished the protective effects of MCM in neuronal cell death induced by MeHg. Taken together, astrocytes synthesize and release NGF and BDNF in response to MeHg to protect neurons from MeHg toxicity. This study is considered to show a novel defense mechanism against MeHg-induced neurotoxicity.

  5. Presynaptic modulation of spinal nociceptive transmission by glial cell line-derived neurotrophic factor (GDNF).

    PubMed

    Salio, Chiara; Ferrini, Francesco; Muthuraju, Sangu; Merighi, Adalberto

    2014-10-08

    The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was mimicked by capsaicin challenge. Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I-II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin+ cells expressing GDNF and the nonpeptidergic IB4+ neurons expressing the GFRα1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LIIid) harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFRα1/IB4 labeling (GIa). LIIid thus represents the preferential site for ligand-receptor interactions. Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin+ nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca(2+) imaging and patch-clamp experiments with bath-applied GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction of the capsaicin-evoked [Ca(2+)]i rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFRα1. Therefore, GDNF released from peptidergic CGRP/somatostatin+ nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4+ nociceptors at glomeruli in LIIid. These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of pain modalities.

  6. The role of brain-derived neurotrophic factor and its single nucleotide polymorphisms in stroke patients.

    PubMed

    Kotlęga, Dariusz; Peda, Barbara; Zembroń-Łacny, Agnieszka; Gołąb-Janowska, Monika; Nowacki, Przemysław

    2017-03-06

    Stroke is the main cause of motoric and neuropsychological disability in adults. Recent advances in research into the role of the brain-derived neurotrophic factor in neuroplasticity, neuroprotection and neurogenesis might provide important information for the development of new poststroke-rehabilitation strategies. It plays a role as a mediator in motor learning and rehabilitation after stroke. Concentrations of BDNF are lower in acute ischemic-stroke patients compared to controls. Lower levels of BDNF are correlated with an increased risk of stroke, worse functional outcomes and higher mortality. BDNF signalling is dependent on the genetic variation which could affect an individual's response to recovery after stroke. Several single nucleotide polymorphisms of the BDNF gene have been studied with regard to stroke patients, but most papers analyse the rs6265 which results in a change from valine to methionine in the precursor protein. Subsequently a reduction in BDNF activity is observed. There are studies indicating the role of this polymorphism in brain plasticity, functional and morphological changes in the brain. It may affect the risk of ischemic stroke, post-stroke outcomes and the efficacy of the rehabilitation process within physical exercise and transcranial magnetic stimulation. There is a consistent trend of Met alleles' being connected with worse outcomes and prognoses after stroke. However, there is no satisfactory data confirming the importance of Met allele in stroke epidemiology and the post-stroke rehabilitation process. We present the current data on the role of BDNF and polymorphisms of the BDNF gene in stroke patients, concentrating on human studies.

  7. Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus

    PubMed Central

    Greenwood, Benjamin N.; Strong, Paul V.; Foley, Teresa E.; Thompson, Robert; Fleshner, Monika

    2007-01-01

    Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 hours later. Finally, bilateral injections of BDNF (1 μg) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not

  8. Emotional Fronto-Cingulate Cortex Activation and Brain Derived Neurotrophic Factor Polymorphism in Premenstrual Dysphoric Disorder

    PubMed Central

    Erika, Comasco; Andreas, Hahn; Sebastian, Ganger; Malin, Gingnell; Elin, Bannbers; Lars, Oreland; Johan, Wikström; Neill, Epperson C.; Rupert, Lanzenberger; Inger, Sundström-Poromaa

    2014-01-01

    Premenstrual dysphoric disorder (PMDD) is the prototypical sex-specific disorder in which symptom onset and offset require a particular hormonal milieu and for which there is moderate heritability. The present study investigated brain emotion processing in PMDD and healthy controls, as well as functional polymorphisms in two candidate genes for PMDD, the serotonin transporter (5-HTT) and brain derived neurotrophic factor (BDNF). The 5-HTT linked polymorphic region (5-HTTLPR) and BDNF Val66Met polymorphisms were genotyped in 31 patients with PMDD and 31 healthy controls. A subset of 16 patients and 15 controls participated in two functional magnetic resonance imaging-sessions performing an emotion processing task; once in the mid-follicular, and once in the late luteal phase which corresponds with maximum severity of mood symptoms. Genotypes were not directly associated with PMDD. A main effect of group was found in the whole brain analysis, with patients having lower activation of the pre-genual anterior cingulate and ventro-medial prefrontal cortex, independent of menstrual cycle phase. Post-hoc functional ROI analyses in the fronto-cingulate cluster showed no effect of 5-HTTLPR genotype but a genotype-by-group-by-phase interaction effect of BDNF Val66Met. Women with PMDD who were carriers of the Met-allele had lower fronto-cingulate cortex activation in the luteal phase compared to Met-allele carrying controls. The results provide suggestive evidence of impaired emotion-induced fronto-cingulate cortex activation in PMDD patients. Although limited by a small sample, the potential influence of BDNF Val66Met in PMDD is in line with preclinical research. PMID:24615932

  9. Serum Brain-derived Neurotrophic Factor Levels among Euthymic Adolescents with Bipolar Disorder Type I

    PubMed Central

    CEVHER BİNİCİ, Nagihan; İNAL EMİROĞLU, Fatma Neslihan; RESMİ, Halil; ELLİDOKUZ, Hülya

    2016-01-01

    Introduction Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity and cellular resilience in brain regions that are involved in mood and that affect regulation. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that regulates neuroplasticity. The aims of the current study were to compare serum BDNF levels in euthymic adolescents with BD type I with those in controls and to investigate the relationship between clinical variables and serum BDNF levels in adolescents with BD type I. Methods Twenty-five adolescents diagnosed with BD type I and 17 healthy control subjects within the age range of 15–19 years were recruited. Diagnoses were made by two experienced research clinicians using the Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version and the affective module of Washington University in St. Louis Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia-Present State and Lifetime. Blood samples were taken during euthymia, which was defined as Young Mania Rating Scale and Hamilton Depression Rating Scale scores below 7. Results The comparison of BDNF serum levels between the case and healthy control groups revealed no significant differences. In the case group, BDNF levels were significantly lower in patients being currently treated with lithium. Conclusion Similar to normal BDNF levels in adult patients with BD, the normal BDNF serum levels that we found in the euthymic state in adolescents and early adulthood may be related to the developmental brain stage in our study group. It may also show a common neurobiological basis of pediatric and adult BD. Further investigations evaluating BDNF levels in different mood states could help identify the role of BDNF in the underlying pathophysiology of BD. PMID:28373806

  10. Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease.

    PubMed

    Coelho, Flávia Gomes de Melo; Vital, Thays Martins; Stein, Angelica Miki; Arantes, Franciel José; Rueda, André Veloso; Camarini, Rosana; Teodorov, Elizabeth; Santos-Galduróz, Ruth Ferreira

    2014-01-01

    Studies indicate the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer's disease (AD). Decreased BDNF levels may constitute a lack of trophic support and contribute to cognitive impairment in AD. The benefits of acute and chronic physical exercise on BDNF levels are well-documented in humans, however, exercise effects on BDNF levels have not been analyzed in older adults with AD. The aim of this study was to investigate the effects of acute aerobic exercise on BDNF levels in older adults with AD and to verify associations among BDNF levels, aerobic fitness, and level of physical activity. Using a controlled design, twenty-one patients with AD (76.3 ± 6.2 years) and eighteen healthy older adults (74.6 ± 4.7 years) completed an acute aerobic exercise. The outcomes included measures of BDNF plasma levels, aerobic fitness (treadmill grade, time to exhaustion, VO2, and maximal lactate) and level of physical activity (Baecke Questionnaire Modified for the Elderly). The independent t-test shows differences between groups with respect to the BDNF plasma levels at baseline (p = 0.04; t = 4.53; df = 37). In two-way ANOVA, a significant effect of time was found (p = 0.001; F = 13.63; df = 37), the aerobic exercise significantly increased BDNF plasma levels in AD patients and healthy controls. A significant correlation (p = 0.04; r = 0.33) was found between BDNF levels and the level of physical activity. The results of our study suggest that aerobic exercise increases BDNF plasma levels in patients with AD and healthy controls. In addition to that, BDNF levels had association with level of physical activity.

  11. Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum.

    PubMed

    De Chiara, Valentina; Angelucci, Francesco; Rossi, Silvia; Musella, Alessandra; Cavasinni, Francesca; Cantarella, Cristina; Mataluni, Giorgia; Sacchetti, Lucia; Napolitano, Francesco; Castelli, Maura; Caltagirone, Carlo; Bernardi, Giorgio; Maccarrone, Mauro; Usiello, Alessandro; Centonze, Diego

    2010-06-16

    The role of brain-derived neurotrophic factor (BDNF) in emotional processes suggests an interaction with the endocannabinoid system. Here, we addressed the functional interplay between BDNF and cannabinoid CB(1) receptors (CB(1)Rs) in the striatum, a brain area in which both BDNF and CB(1)s play a role in the emotional consequences of stress and of rewarding experiences. BDNF potently inhibited CB(1)R function in the striatum, through a mechanism mediated by altered cholesterol metabolism and membrane lipid raft function. The effect of BDNF was restricted to CB(1)Rs controlling GABA-mediated IPSCs (CB(1)R(GABA)), whereas CB(1)Rs modulating glutamate transmission and GABA(B) receptors were not affected. The action of BDNF on CB(1)R(GABA) function was tyrosine kinase dependent and was complete even after receptor sensitization with cocaine or environmental manipulations activating the dopamine (DA)-dependent reward system. In mice lacking one copy of the BDNF gene (BDNF(+/-)), CB(1)R(GABA) responses were potentiated and were preserved from the action of haloperidol, a DA D(2) receptor (D(2)R) antagonist able to fully abolish CB(1)R(GABA) function in rewarded animals. Haloperidol also enhanced BDNF levels in the striatum, suggesting that this neurotrophin may act as a downstream effector of D(2)Rs in the modulation of cannabinoid signaling. Accordingly, 5 d cocaine exposure both reduced striatal BDNF levels and increased CB(1)R(GABA) activity, through a mechanism dependent on D(2)Rs. The present study identifies a novel mechanism of CB(1)R regulation mediated by BDNF and cholesterol metabolism and provides some evidence that DA D(2)R-dependent modulation of striatal CB(1)R activity is mediated by this neurotrophin.

  12. The relationship between serum brain-derived neurotrophic factor (BDNF) and cardiometabolic indices in schizophrenia.

    PubMed

    Nurjono, Milawaty; Tay, Yi Hang; Lee, Jimmy

    2014-08-01

    Brain derived neurotrophic factor (BDNF), which has been implicated in the pathogenesis of schizophrenia, has been recently shown to be involved in the regulation of metabolism and energy homeostasis. This study seeks to examine the relationship between BDNF, metabolic indices and cardiovascular (CVD) risk in patients with schizophrenia. Medical histories, demographic information and anthropometric measurements were collected and analyzed from 61 participants with schizophrenia. Fasting glucose and lipids were measured in a central laboratory, and serum BDNF was analyzed using commercially available enzyme-linked immunosorbent assay (ELISA). The 10-year CVD risk for each participant was computed using the Framingham risk score (FRS). Linear regressions were performed to examine the relationships between serum BDNF with body mass index (BMI), blood pressure (BP), triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C) and glucose. To examine the relationship between serum BDNF and FRS, serum BDNF was categorized into quartiles, and a multiple regression was performed. After adjusting for age, gender and current smoking status, diastolic BP (dBP) (p=0.045) and TG (p=0.015) were found to be significantly associated with serum BDNF. Participants in the highest quartile of serum BDNF had a 3.3 times increase in FRS over those in the lowest quartile. Our findings support the possible regulatory role of BDNF in metabolism and cardiovascular homeostasis among patients with schizophrenia similar to that observed among the non-mentally ill. Serum BDNF not only present itself as a candidate biomarker of schizophrenia but also might be a viable marker of metabolic co-morbidities associated with schizophrenia.

  13. Glial cell line-derived neurotrophic factor gene delivery via a polyethylene imine grafted chitosan carrier.

    PubMed

    Peng, Yu-Shiang; Lai, Po-Liang; Peng, Sydney; Wu, His-Chin; Yu, Siang; Tseng, Tsan-Yun; Wang, Li-Fang; Chu, I-Ming

    2014-01-01

    Parkinson's disease is known to result from the loss of dopaminergic neurons. Direct intracerebral injections of high doses of recombinant glial cell line-derived neurotrophic factor (GDNF) have been shown to protect adult nigral dopaminergic neurons. Because GDNF does not cross the blood-brain barrier, intracerebral gene transfer is an ideal option. Chitosan (CHI) is a naturally derived material that has been used for gene transfer. However, the low water solubility often leads to decreased transfection efficiency. Grafting of highly water-soluble polyethylene imines (PEI) and polyethylene glycol onto polymers can increase their solubility. The purpose of this study was to design a non-viral gene carrier with improved water solubility as well as enhanced transfection efficiency for treating Parkinsonism. Two molecular weights (Mw =600 and 1,800 g/mol) of PEI were grafted onto CHI (PEI600-g-CHI and PEI1800-g-CHI, respectively) by opening the epoxide ring of ethylene glycol diglycidyl ether (EX-810). This modification resulted in a non-viral gene carrier with less cytotoxicity. The transfection efficiency of PEI600-g-CHI/deoxyribonucleic acid (DNA) polyplexes was significantly higher than either PEI1800-g-CHI/DNA or CHI/DNA polyplexes. The maximal GDNF expression of PEI600-g-CHI/DNA was at the polymer:DNA weight ratio of 10:1, which was 1.7-fold higher than the maximal GDNF expression of PEI1800-g-CHI/DNA. The low toxicity and high transfection efficiency of PEI600-g-CHI make it ideal for application to GDNF gene therapy, which has potential for the treatment of Parkinson's disease.

  14. Glial cell line-derived neurotrophic factor gene delivery via a polyethylene imine grafted chitosan carrier

    PubMed Central

    Peng, Yu-Shiang; Lai, Po-Liang; Peng, Sydney; Wu, His-Chin; Yu, Siang; Tseng, Tsan-Yun; Wang, Li-Fang; Chu, I-Ming

    2014-01-01

    Parkinson’s disease is known to result from the loss of dopaminergic neurons. Direct intracerebral injections of high doses of recombinant glial cell line-derived neurotrophic factor (GDNF) have been shown to protect adult nigral dopaminergic neurons. Because GDNF does not cross the blood–brain barrier, intracerebral gene transfer is an ideal option. Chitosan (CHI) is a naturally derived material that has been used for gene transfer. However, the low water solubility often leads to decreased transfection efficiency. Grafting of highly water-soluble polyethylene imines (PEI) and polyethylene glycol onto polymers can increase their solubility. The purpose of this study was to design a non-viral gene carrier with improved water solubility as well as enhanced transfection efficiency for treating Parkinsonism. Two molecular weights (Mw =600 and 1,800 g/mol) of PEI were grafted onto CHI (PEI600-g-CHI and PEI1800-g-CHI, respectively) by opening the epoxide ring of ethylene glycol diglycidyl ether (EX-810). This modification resulted in a non-viral gene carrier with less cytotoxicity. The transfection efficiency of PEI600-g-CHI/deoxyribonucleic acid (DNA) polyplexes was significantly higher than either PEI1800-g-CHI/DNA or CHI/DNA polyplexes. The maximal GDNF expression of PEI600-g-CHI/DNA was at the polymer:DNA weight ratio of 10:1, which was 1.7-fold higher than the maximal GDNF expression of PEI1800-g-CHI/DNA. The low toxicity and high transfection efficiency of PEI600-g-CHI make it ideal for application to GDNF gene therapy, which has potential for the treatment of Parkinson’s disease. PMID:25061293

  15. Effects of multiparity on recognition memory, monoaminergic neurotransmitters, and brain-derived neurotrophic factor (BDNF).

    PubMed

    Macbeth, Abbe H; Scharfman, Helen E; Maclusky, Neil J; Gautreaux, Claris; Luine, Victoria N

    2008-06-01

    Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes.

  16. Imipramine ameliorates pain-related negative emotion via induction of brain-derived neurotrophic factor.

    PubMed

    Yasuda, Seiko; Yoshida, Mitsuhiro; Yamagata, Hirotaka; Iwanaga, Yasutake; Suenaga, Hiromi; Ishikawa, Kozo; Nakano, Masako; Okuyama, Satoshi; Furukawa, Yoshiko; Furukawa, Shoei; Ishikawa, Toshizo

    2014-11-01

    Depression-like behavior is often complicated by chronic pain. Antidepressants including imipramine (IMI) are widely used to treat chronic pain, but the mechanisms are not fully understood. Brain-derived neurotrophic factor (BDNF) is a neuromodulator that reduces depression by regulating synaptic transmission. We aimed to characterize the antidepressant effects of IMI without analgesia based on BDNF (trkB)-mediated signaling and gene expression in chronic pain. A chronic constriction injury (CCI) model was constructed in Sprague-Dawley (SD) rats. IMI (5 mg/kg, i.p.) was administered from day 10 after CCI. The pain response was assessed using the paw withdrawal latency (PWL) and depression was judged from the immobility time in a forced swim test. Anti-BDNF antibody, K252a, or 5,7-dihydroxytryptamine (5,7-DHT) were used to examine the antidepressant effects of imipramine. Changes in pERK1/2 (immunohistochemistry), 5-HT and BDNF (ELISA), and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC), rostral ventromedial medulla (RVM), and spinal cord. After CCI, rats showed decreased PWL and increased immobility time. A low dose of IMI reduced the immobility time without having analgesic effects. This antidepressant effect was reversed by anti-BDNF antibody, K252a, and 5,7-DHT. IMI reduced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA, and these changes were reversed by 5,7-DHT. These results show that IMI reduces pain-related negative emotion without influencing pain and that this effect is diminished by denervation of 5-HT neurons and by anti-BDNF treatment. IMI also normalizes derangement of ERK/CREB coupling, which leads to induction of BDNF. This suggests a possible interaction between 5-HT and BDNF.

  17. Genetic increase in brain-derived neurotrophic factor levels enhances learning and memory.

    PubMed

    Nakajo, Yukako; Miyamoto, Susumu; Nakano, Yoshikazu; Xue, Jing-Hui; Hori, Takuya; Yanamoto, Hiroji

    2008-11-19

    Brain-derived neurotrophic factor (BDNF), a neurotrophin, is known to promote neuronal differentiation stimulating neurite outgrowth in the developing CNS, and is also known to modulate synaptic plasticity, thereby contributing to learning and memory in the mature brain. Here, we investigated the role of increased levels of intracerebral BDNF in learning and memory function. Using genetically engineered transgenic BDNF overexpressing mice (RTG-BDNF), young adult, homozygous (+/+), heterozygous (+/-), or wild-type (-/-) littermates, we analyzed escape latency to a hidden-platform and swimming velocity in the Morris Water Maze test (MWM) with modifications for the mice. The MWM comprised 4 trials per day over 5 consecutive days (sessions) without prior or subsequent training. In a separate set of animals, BDNF protein levels in the cortex, thalamostriatum and the hippocampus were measured quantitatively using ELISA. In the BDNF (+/-) mice, the BDNF levels in the cortex, the thalamostriatum and the hippocampus were significantly high, compared to the wild-type littermates; 238%, 158%, and 171%, respectively (P<0.01, one-way ANOVA and a post-hoc test in each region). The BDNF levels in the BDNF (+/+) mice were not elevated. The BDNF (+/-), but not the (+/+) mice, demonstrated significantly shorter escape latency, shorter total path length in the MWM, and more frequent arrivals at the location where the platform had been placed previously in the probe trial, compared with the wild-type littermates (P<0.05, at each time pint). Because the maximum swimming velocity was not affected in the BDNF-transgenic mice, increased BDNF levels in the brain were found to enhance spatial learning and memory function. Although it has been postulated that excessive BDNF is deteriorating for neuronal survival or neurite outgrowth, further investigations are needed to clarify the mechanism of paradoxical lack of increase in BDNF levels in the (+/+) mouse brain.

  18. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation.

    PubMed

    Szeszko, P R; Lipsky, R; Mentschel, C; Robinson, D; Gunduz-Bruce, H; Sevy, S; Ashtari, M; Napolitano, B; Bilder, R M; Kane, J M; Goldman, D; Malhotra, A K

    2005-07-01

    Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers.

  19. Longitudinal Study of Cone Photoreceptors during Retinal Degeneration and in Response to Ciliary Neurotrophic Factor Treatment

    PubMed Central

    Talcott, Katherine E.; Ratnam, Kavitha; Sundquist, Sanna M.; Lucero, Anna S.; Lujan, Brandon J.; Tao, Weng; Porco, Travis C.; Roorda, Austin

    2011-01-01

    Purpose. To study cone photoreceptor structure and function in patients with inherited retinal degenerations treated with sustained-release ciliary neurotrophic factor (CNTF). Methods. Two patients with retinitis pigmentosa and one with Usher syndrome type 2 who participated in a phase 2 clinical trial received CNTF delivered by an encapsulated cell technology implant in one eye and sham surgery in the contralateral eye. Patients were followed longitudinally over 30 to 35 months. Adaptive optics scanning laser ophthalmoscopy (AOSLO) provided high-resolution images at baseline and at 3, 6, 12, 18, and 24 months. AOSLO measures of cone spacing and density and optical coherence tomography measures of retinal thickness were correlated with visual function, including visual acuity (VA), visual field sensitivity, and full-field electroretinography (ERG). Results. No significant changes in VA, visual field sensitivity, or ERG responses were observed in either eye of the three patients over 24 months. Outer retinal layers were significantly thicker in CNTF-treated eyes than in sham-treated eyes (P < 0.005). Cone spacing increased by 2.9% more per year in sham-treated eyes than in CNTF-treated eyes (P < 0.001, linear mixed model), and cone density decreased by 9.1%, or 223 cones/degree2 more per year in sham-treated than in CNTF-treated eyes (P = 0.002, linear mixed model). Conclusions. AOSLO images provided a sensitive measure of disease progression and treatment response in patients with inherited retinal degenerations. Larger studies of cone structure using high-resolution imaging techniques are urgently needed to evaluate the effect of CNTF treatment in patients with inherited retinal degenerations. (ClinicalTrials.gov number, NCT00447980.) PMID:21087953

  20. Expression and Distribution of Mesencephalic Astrocyte-Derived Neurotrophic Factor in the Retina and Optic Nerve

    PubMed Central

    Gao, Feng-Juan; Zhang, Sheng-Hai; Li, Ting-Ting; Wu, Ji-Hong; Wu, Qiang

    2017-01-01

    Mesencephalic astrocyte-derived neurotrophic factor (MANF), otherwise named Arginine-Rich, Mutated in Early-stage Tumors (ARMET), is a secretory endoplasmic reticulum stress (ERS) protein that is widely expressed in mammalian tissues. To date, little is known about the distribution and expression of MANF in the retina and optic nerve (ON). Therefore, we studied the expression and distribution of MANF in the ON and retina by real-time PCR, immunofluorescence staining and western blotting. Results from rat and mouse were highly consistent in the retina. MANF was detected in both tissues in rat, wherein it was principally localized to the ganglion cell layer (GCL), followed by the inner nuclear layer (INL). The MANF protein levels in the rat retina were 3.33-fold higher than in the rat ON. Additionally, MANF was robustly expressed by retinal ganglion cells (RGCs) in the human retina. In human ON, MANF was partially co-localized with glial fibrillary acidic protein (GFAP), suggesting that it was not restricted to astrocytes. In vitro studies confirmed that MANF could be robustly expressed in RGCs and was found principally within the cytoplasm. Hypoxia can stimulate up-regulation by of MANF expression over time, suggesting that MANF may play a vital role in the functional regulation of RGCs both in health and disease. We believe that the present study improves our understanding of the distribution and expression of MANF in the retina and ON and could help in further analysis of its interact and correlate with the relevant ophthalmic diseases. PMID:28154531

  1. Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking

    PubMed Central

    Barker, Jacqueline M.; Taylor, Jane R.; De Vries, Taco J.; Peters, Jamie

    2015-01-01

    Many abused drugs lead to changes in endogenous brain-derived neurotrophic factor (BDNF) expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels. Specific neural circuits are responsible for storing and executing drug-procuring motor programs, whereas other neural circuits are responsible for the active suppression of these “seeking” systems. These seeking-circuits are established as associations are formed between drug-associated cues and the conditioned responses they elicit. Such conditioned responses (e.g. drug seeking) can be diminished either through a passive weakening of seeking-circuits or an active suppression of those circuits through extinction. Extinction learning occurs when the association between cues and drug are violated, for example, by cue exposure without the drug present. Cue exposure therapy has been proposed as a therapeutic avenue for the treatment of addictions. Here we explore the role of BDNF in extinction circuits, compared to seeking-circuits that “incubate” over prolonged withdrawal periods. We begin by discussing the role of BDNF in extinction memory for fear and cocaine-seeking behaviors, where extinction circuits overlap in infralimbic prefrontal cortex (PFC). We highlight the ability of estrogen to promote BDNF-like effects in hippocampal–prefrontal circuits and consider the role of sex differences in extinction and incubation of drug-seeking behaviors. Finally, we examine how opiates and alcohol “break the mold” in terms of BDNF function in extinction circuits. PMID:25451116

  2. Brain-Derived Neurotrophic Factor Expression in Asthma. Association with Severity and Type 2 Inflammatory Processes.

    PubMed

    Watanabe, Tetsuya; Fajt, Merritt L; Trudeau, John B; Voraphani, Nipasiri; Hu, Haizhen; Zhou, Xiuxia; Holguin, Fernando; Wenzel, Sally E

    2015-12-01

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, exists in several isoforms, which differentially impacts neuronal and immune cell survival and differentiation. The role of BDNF and its isoforms in asthma remains unclear. The objectives of this study were to compare the BDNF protein isoforms and specific splice variant expression in sputum and bronchoscopic samples from healthy control subjects and participants with asthma, and to relate these changes to findings in IL-13-stimulated human airway epithelial cells. Sputum and bronchoscopic samples from healthy control subjects and participants with asthma were evaluated for BDNF protein (ELISA and Western blot) and BDNF mRNA (gel and quantitative real-time PCR) in relation to asthma severity and type 2 inflammatory processes. BDNF mRNA was measured in cultured primary human airway epithelial cells after IL-13 stimulation. Total BDNF protein differed among the groups, and its mature isoform was significantly higher in sputum from subjects with severe asthma compared with healthy control subjects (overall P = 0.008, P = 0.027, respectively). Total BDNF was higher in those with elevated fractional exhaled nitric oxide and sputum eosinophilia. In vitro, IL-13 increased BDNF exon VIb splice variant and the ratio to BDNF common exon IX mRNA (P < 0.001, P = 0.003, respectively). Epithelial brushing exon VIb mRNA and total BDNF protein differed among the groups and were higher in subjects with severe asthma than in healthy control subjects (overall P = 0.01, P = 0.02, respectively). The mature BDNF isoform and the exon VIb splice variant are increased in human asthmatic airways. The in vitro increase in response to IL-13 suggests that type 2 cytokines regulate BDNF levels and activity in asthma.

  3. Brain-derived neurotrophic factor mediates the suppression of alcohol self-administration by memantine.

    PubMed

    Jeanblanc, Jérôme; Coune, Fabien; Botia, Béatrice; Naassila, Mickaël

    2014-09-01

    Brain-derived neurotrophic factor (BDNF) within the striatum is part of a homeostatic pathway regulating alcohol consumption. Memantine, a non-competitive antagonist of N-methyl-D-aspartate receptors, induces expression of BDNF in several brain regions including the striatum. We hypothesized that memantine could decrease ethanol (EtOH) consumption via activation of the BNDF signalling pathway. Effects of memantine were evaluated in Long-Evans rats self-administering moderate or high amounts of EtOH 6, 30 and 54 hours after an acute injection (12.5 and 25 mg/kg). Motivation to consume alcohol was investigated through a progressive ratio paradigm. The possible role for BDNF in the memantine effect was tested by blockade of the TrkB receptor using the pharmacological agent K252a and by the BDNF scavenger TrkB-Fc. Candidate genes expression was also assessed by polymerase chain reaction array 4 and 28 hours after memantine injection. We found that memantine decreased EtOH self-administration and motivation to consume EtOH 6 and 30 hours post-injection. In addition, we found that inhibition or blockade of the BDNF signalling pathway prevented the early, but not the delayed decrease in EtOH consumption induced by memantine. Finally, Bdnf expression was differentially regulated between the early and delayed timepoints. These results demonstrate that an acute injection of memantine specifically reduces EtOH self-administration and motivation to consume EtOH for at least 30 hours. Moreover, we showed that BDNF was responsible for the early effect, but that the delayed effect was BDNF-independent.

  4. Brain-derived neurotrophic factor regulates expression of vasoactive intestinal polypeptide in retinal amacrine cells.

    PubMed

    Cellerino, Alessandro; Arango-González, Blanca; Pinzón-Duarte, Germán; Kohler, Konrad

    2003-12-01

    Brain-derived neurotrophic-factor (BDNF) is expressed in the retina and controls the development of subtypes of amacrine cells. In the present study we investigated the effects of BDNF on amacrine cells expressing vasoactive intestinal polypeptide (VIP). Rats received three intraocular injections of BDNF on postnatal days (P) 16, 18, and 20. The animals were sacrificed on P22, P40, P60, P80, and P120, and VIP expression in their retinas was detected by immunohistochemistry (P22, P40) and by radioimmunoassay (RIA; P22, P40, P60, P80, P120) to assess the time course of BDNF effects on VIP. A significant increase in the density of VIP-positive amacrine cells was detected in BDNF-treated retinas, and VIP concentration was up-regulated by 150% both at P22 and at P40 with respect to untreated controls. VIP concentration then slowly declined in the treated retinas over a period of 3 months; however, a statistically significant increase of 50% was still detectable on P120. The impact of endogenous BDNF on the regulation of VIP expression in the retina was analyzed in mice homozygous for a targeted deletion of the BDNF gene locus (bdnf-/-). VIP immunohistochemistry revealed a marked reduction of VIP-positive amacrine cells and of VIP-immunopositive processes in the inner plexiform layer of the BDNF knockout mice. Mice lacking BDNF expressed only 5% of the VIP protein in their retinas compared with the retinas of wild-type mice as measured by RIA. Our data show that BDNF is a major regulator of VIP expression in retinal amacrine cells and exerts long-lasting effects on VIP content.

  5. Altered regulation of brain-derived neurotrophic factor protein in hippocampus following slice preparation.

    PubMed

    Danzer, S C; Pan, E; Nef, S; Parada, L F; McNamara, J O

    2004-01-01

    Brain-derived neurotrophic factor (BDNF) and its cognate receptor tyrosine kinase B (TrkB) play important roles in regulating survival, structure, and function of CNS neurons. One method of studying the functions of these molecules has utilized in vitro hippocampal slice preparations. An important caveat to using slices, however, is that slice preparation itself might alter the expression of BDNF, thereby confounding experimental results. To address this concern, BDNF immunoreactivity was examined in rodent slices using two different methods of slice preparation. Rapid and anatomically selective regulation of BDNF content followed slice preparation using both methodologies; however, different patterns of altered BDNF immunoreactivity were observed. First, in cultured slices, BDNF content decreased in the dentate molecular layer and increased in the CA3 pyramidal cell layer and the mossy fiber pathway of the hippocampus after 30 min. Furthermore, an initially "punctate" pattern of BDNF labeling observed in the mossy fiber pathway of control sections changed to homogenous labeling of the pathway in vitro. In contrast to these findings, slices prepared as for acute slice physiology exhibited no change in BDNF content in the molecular layer and mossy fiber pathway 30 min after slicing, but exhibited significant increases in the dentate granule and CA3 pyramidal cell layers. These findings demonstrate that BDNF protein content is altered following slice preparation, that different methods of slice preparation produce different patterns of BDNF regulation, and raise the possibility that BDNF release and TrkB activation may also be regulated. These consequences of hippocampal slice preparation may confound analyses of exogenous or endogenous BDNF on hippocampal neuronal structure or function.

  6. Brain-derived neurotrophic factor and substrate utilization following acute aerobic exercise in obese individuals.

    PubMed

    Slusher, A L; Whitehurst, M; Zoeller, R F; Mock, J T; Maharaj, A; Huang, C-J

    2015-05-01

    Brain-derived neurotrophic factor (BDNF) serves as a vital regulator of neuronal proliferation and survival, and has been shown to regulate energy homeostasis, glucose metabolism and body weight maintenance. Elevated concentrations of plasma BDNF have been associated with obesity and type 2 diabetes mellitus. Acute aerobic exercise transiently increases circulating BDNF, potentially correcting obesity-related metabolic impairment. The present study aimed to compare acute aerobic exercise elicited BDNF responses in obese and normal-weight subjects. Furthermore, we aimed to investigate whether acute exercise-induced plasma BDNF elevations would be associated with improved indices of insulin resistance, as well as substrate utilization [carbohydrate oxidation (CHOoxi) and fat oxidation (FAToxi)]. Twenty-two healthy, untrained subjects [11 obese (four men and seven women; age = 22.91 ± 4.44 years; body mass index = 35.72 ± 4.17 kg/m(2)) and 11 normal-weight (five men and six women; age = 23.27 ± 2.24 years; body mass index = 21.89 ± 1.63 kg/m(2))] performed 30 min of continuous submaximal aerobic exercise at 75% maximal oxygen consumption. Our analyses showed that the BDNF response to acute aerobic exercise was similar in obese and normal-weight subjects across time (time: P = 0.015; group: P = not significant) and was not associated with indices of IR. Although no differences in the rates of CHOoxi and FAToxi were found between both groups, total relative energy expenditure was significantly lower in obese subjects compared to normal-weight subjects (3.53 ± 0.25 versus 5.59 ± 0.85; P < 0.001). These findings suggest that acute exercise-elicited BDNF elevation may not be sufficient to modulate indices of IR or the utilization of either carbohydrates or fats in obese individuals.

  7. Music exposure differentially alters the levels of brain-derived neurotrophic factor and nerve growth factor in the mouse hypothalamus.

    PubMed

    Angelucci, Francesco; Ricci, Enzo; Padua, Luca; Sabino, Andrea; Tonali, Pietro Attilio

    2007-12-18

    It has been reported that music may have physiological effects on blood pressure, cardiac heartbeat, respiration, and improve mood state in people affected by anxiety, depression and other psychiatric disorders. However, the physiological bases of these phenomena are not clear. Hypothalamus is a brain region involved in the regulation of body homeostasis and in the pathophysiology of anxiety and depression through the modulation of hypothalamic-pituitary-adrenal (HPA) axis. Hypothalamic functions are also influenced by the presence of the neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are proteins involved in the growth, survival and function of neurons in the central nervous system. The aim of this study was to investigate the effect of music exposure in mice on hypothalamic levels of BDNF and NGF. We exposed young adult mice to slow rhythm music (6h per day; mild sound pressure levels, between 50 and 60 dB) for 21 consecutive days. At the end of the treatment mice were sacrificed and BDNF and NGF levels in the hypothalamus were measured by enzyme-linked immunosorbent assay (ELISA). We found that music exposure significantly enhanced BDNF levels in the hypothalamus. Furthermore, we observed that music-exposed mice had decreased NGF hypothalamic levels. Our results demonstrate that exposure to music in mice can influence neurotrophin production in the hypothalamus. Our findings also suggest that physiological effects of music might be in part mediated by modulation of neurotrophins.

  8. Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists.

    PubMed Central

    Di Marco, A; Gloaguen, I; Graziani, R; Paonessa, G; Saggio, I; Hudson, K R; Laufer, R

    1996-01-01

    Ciliary neurotrophic factor (CNTF) drives the sequential assembly of a receptor complex containing the ligand-specific alpha-receptor subunit (CNTFR alpha) and the signal transducers gp130 and leukemia inhibitory factor receptor-beta (LIFR). The D1 structural motif, located at the beginning of the D-helix of human CNTF, contains two amino acid residues, F152 and K155, which are conserved among all cytokines that signal through LIFR. The functional importance of these residues was assessed by alanine mutagenesis. Substitution of either F152 or K155 with alanine was found to specifically inhibit cytokine interaction with LIFR without affecting binding to CNTFR alpha or gp130. The resulting variants behaved as partial agonists with varying degrees of residual bioactivity in different cell-based assays. Simultaneous alanine substitution of both F152 and K155 totally abolished biological activity. Combining these mutations with amino acid substitutions in the D-helix, which enhance binding affinity for the CNTFR alpha, gave rise to a potent competitive CNTF receptor antagonist. This protein constitutes a new tool for studies of CNTF function in normal physiology and disease. Images Fig. 1 Fig. 6 PMID:8799186

  9. Angelica injection reduces cognitive impairment during chronic cerebral hypoperfusion through brain-derived neurotrophic factor and nerve growth factor.

    PubMed

    Zheng, Ping; Zhang, Junjian; Liu, Hanxing; Xu, Xiaojuan; Zhang, Xiaolian

    2008-02-01

    The current study investigated whether chronic cerebral hypoperfusion produced by permanent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) induced cognitive impairment and whether angelica injections alleviated the impairment. Furthermore, the study examined whether 2-VO altered the expression patterns of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of rats and whether angelica injections attenuated the alteration. Rats were divided into four groups to receive either 2-VO surgery or sham surgery followed by either angelica injections or saline injections for eight weeks. Spatial learning in Morris water maze and the expression patterns of BDNF and NGF in the hippocampus of all rats were examined. The results showed that 2-VO significantly impaired spatial learning and memory, and angelica injections significantly reversed the learning and memory impairment. Furthermore, 2-VO resulted in significantly decreased BDNF protein, NGF protein, and NGF mRNA expression in the hippocampus. Angelica injections significantly attenuated the decreased expression. Moreover, spatial learning in Morris water maze was positively correlated to the expression of BDNF and NGF in the hippocampus. Thus, angelica injections might alleviate cognitive impairment during chronic cerebral hypoperfusion through BDNF and NGF.

  10. Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells.

    PubMed

    Lin, Chih-Yang; Hung, Shih-Ya; Chen, Hsien-Te; Tsou, Hsi-Kai; Fong, Yi-Chin; Wang, Shih-Wei; Tang, Chih-Hsin

    2014-10-15

    Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.

  11. Long-Term Protection of Retinal Ganglion Cells and Visual Function by Brain-Derived Neurotrophic Factor in Mice With Ocular Hypertension

    PubMed Central

    Feng, Liang; Chen, Hui; Yi, Ji; Troy, John B.; Zhang, Hao F.; Liu, Xiaorong

    2016-01-01

    Purpose Glaucoma, frequently associated with elevated intraocular pressure (IOP), is characterized by progressive retinal ganglion cell (RGC) death and vision loss. Brain-derived neurotrophic factor (BDNF) has been studied as a candidate for neuroprotection in rodent models of experimental glaucoma, yet it remains to be determined whether BDNF exerts long-term protection for subtype RGCs and vision against chronic IOP elevation. Methods We induced modest and sustained IOP elevation by laser illumination and microbead injection in mice. Using a tamoxifen-induced Cre recombinase system, BDNF was upregulated in the mouse retina when sustained IOP elevation was induced. We then examined whether overexpression of BDNF protected RGCs and vision during the period of ocular hypertension. Given that BDNF modulates axon growth and dendritic formation in a subtype-dependent manner, we tested whether BDNF protects RGC dendritic structure against the hypertensive insult also in a subtype-dependent manner. Results Sustained IOP elevation was induced and lasted up to 6 months. Overexpression of BDNF delayed progressive RGC and axon loss in hypertensive eyes. Brain-derived neurotrophic factor overexpression also helped to preserve acuity against the chronic hypertensive insult. We classified RGCs into ON and ON–OFF subtypes based on their dendritic lamination pattern in the inner plexiform layer and found that BDNF prevented ON–RGC dendritic degeneration in mice with sustained ocular hypertension. Conclusions Our data demonstrated that BDNF can protect the dendritic fields of ON RGCs and reduce RGC and vision loss in mice with sustained ocular hypertension. PMID:27421068

  12. The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes.

    PubMed

    Zvonic, Sanjin; Cornelius, Peter; Stewart, William C; Mynatt, Randall L; Stephens, Jacqueline M

    2003-01-24

    Ciliary neurotrophic factor (CNTF) is primarily known for its roles as a lesion factor released by the ruptured glial cells that prevent neuronal degeneration. However, CNTF has also been shown to cause weight loss in a variety of rodent models of obesity/type II diabetes, whereas a modified form also causes weight loss in humans. CNTF administration can correct or improve hyperinsulinemia, hyperphagia, and hyperlipidemia associated with these models of obesity. In order to investigate the effects of CNTF on fat cells, we examined the expression of CNTF receptor complex proteins (LIFR, gp130, and CNTFRalpha) during adipocyte differentiation and the effects of CNTF on STAT, Akt, and MAPK activation. We also examined the ability of CNTF to regulate the expression of adipocyte transcription factors and other adipogenic proteins. Our studies clearly demonstrate that the expression of two of the three CNTF receptor complex components, CNTFRalpha and LIFR, decreases during adipocyte differentiation. In contrast, gp130 expression is relatively unaffected by differentiation. In addition, preadipocytes are more sensitive to CNTF treatment than adipocytes, as judged by both STAT 3 and Akt activation. Despite decreased levels of CNTFRalpha expression in fully differentiated 3T3-L1 adipocytes, CNTF treatment of these cells resulted in a time-dependent activation of STAT 3. Chronic treatment of adipocytes resulted in a substantial decrease in fatty-acid synthase and a notable decline in SREBP-1 levels but had no effect on the expression of peroxisome proliferator-activated receptor gamma, acrp30, adipocyte-expressed STAT proteins, or C/EBPalpha. However, CNTF resulted in a significant increase in IRS-1 expression. CNTFRalpha receptor expression was substantially induced in the fat pads of four rodent models of obesity/type II diabetes as compared with lean littermates. Moreover, we demonstrated that CNTF can activate STAT 3 in adipose tissue and skeletal muscle in vivo. In

  13. The homeostatic regulation of REM sleep: A role for localized expression of brain-derived neurotrophic factor in the brainstem.

    PubMed

    Datta, Subimal; Knapp, Clifford M; Koul-Tiwari, Richa; Barnes, Abigail

    2015-10-01

    Homeostatic regulation of REM sleep plays a key role in neural plasticity and deficits in this process are implicated in the development of many neuropsychiatric disorders. Little is known, however, about the molecular mechanisms that underlie this homeostatic regulation process. This study examined the hypothesis that, during selective REM sleep deprivation (RSD), increased brain-derived neurotrophic factor (BDNF) expression in REM sleep regulating areas is critical for the development of homeostatic drive for REM sleep, as measured by an increase in the number of REM sleep transitions. Rats were assigned to RSD, non-sleep deprived (BSL), or total sleep deprivation (TSD) groups. Physiological recordings were obtained from cortical, hippocampal, and pontine EEG electrodes over a 6h period, in which sleep deprivation occurred during the first 3h. In the RSD, but not the other conditions, homeostatic drive for REM sleep increased progressively. BDNF protein expression was significantly greater in the pedunculopontine tegmentum (PPT) and subcoeruleus nucleus (SubCD) in the RSD as compared to the TSD and BSL groups, areas that regulate REM sleep, but not in the medial preoptic area, which regulates non-REM sleep. There was a significant positive correlation between RSD-induced increases in number of REM sleep episodes and increased BDNF expression in the PPT and SubCD. These increases positively correlated with levels of homeostatic drive for REM sleep. These results, for the first time, suggest that selective RSD-induced increased expression of BDNF in the PPT and SubCD are determinant factors in the development of the homeostatic drive for REM sleep.

  14. Binding characteristics of brain-derived neurotrophic factor to its receptors on neurons from the chick embryo

    SciTech Connect

    Rodriguez-Tebar, A.; Barde, Y.A.

    1988-09-01

    Brain-derived neurotrophic factor (BDNF), a protein known to support the survival of embryonic sensory neurons and retinal ganglion cells, was derivatized with 125I-Bolton-Hunter reagent and obtained in a biologically active, radioactive form (125I-BDNF). Using dorsal root ganglion neurons from chick embryos at 9 d of development, the basic physicochemical parameters of the binding of 125I-BDNF with its receptors were established. Two different classes of receptors were found, with dissociation constants of 1.7 x 10(-11) M (high-affinity receptors) and 1.3 x 10(-9) M (low-affinity receptors). Unlabeled BDNF competed with 125I-BDNF for binding to the high-affinity receptors with an inhibition constant essentially identical to the dissociation constant of the labeled protein: 1.2 x 10(-11) M. The association and dissociation rates from both types of receptors were also determined, and the dissociation constants calculated from these kinetic experiments were found to correspond to the results obtained from steady-state binding. The number of high-affinity receptors (a few hundred per cell soma) was 15 times lower than that of low-affinity receptors. No high-affinity receptors were found on sympathetic neurons, known not to respond to BDNF, although specific binding of 125I-BDNF to these cells was detected at a high concentration of the radioligand. These results are discussed and compared with those obtained with nerve growth factor on the same neuronal populations.

  15. Topographical Distribution of Morphological Changes in a Partial Model of Parkinson's Disease--Effects of Nanoencapsulated Neurotrophic Factors Administration.

    PubMed

    Requejo, C; Ruiz-Ortega, J A; Bengoetxea, H; Garcia-Blanco, A; Herrán, E; Aristieta, A; Igartua, M; Ugedo, L; Pedraz, J L; Hernández, R M; Lafuente, J V

    2015-10-01

    Administration of various neurotrophic factors is a promising strategy against Parkinson's disease (PD). An intrastriatal infusion of 6-hydroxidopamine (6-OHDA) in rats is a suitable model to study PD. This work aims to describe stereological parameters regarding rostro-caudal gradient, in order to characterize the model and verify its suitability for elucidating the benefits of therapeutic strategies. Administration of 6-OHDA induced a reduction in tyrosine hidroxylase (TH) reactivity in the dorsolateral part of the striatum, being higher in the caudal section than in the rostral one. Loss of TH-positive neurons and axodendritic network was highly significant in the external third of substantia nigra (e-SN) in the 6-OHDA group versus the saline one. After the administration of nanospheres loaded with neurotrophic factors (NTF: vascular endothelial growth factor (VEGF) + glial cell line-derived neurotrophic factor (GDNF)), parkinsonized rats showed more TH-positive fibers than those of control groups; this recovery taking place chiefly in the rostral sections. Neuronal density and axodendritic network in e-SN was more significant than in the entire SN; the topographical analysis showed that the highest difference between NTF versus control group was attained in the middle section. A high number of bromodeoxyuridine (BrdU)-positive cells were found in sub- and periventricular areas in the group receiving NTF, where most of them co-expressed doublecortin. Measurements on the e-SN achieved more specific and significant results than in the entire SN. This difference in rostro-caudal gradients underpins the usefulness of a topological approach to the assessment of the lesion and therapeutic strategies. Findings confirmed the neurorestorative, neurogenic, and synergistic effects of VEGF+GDNF administration.

  16. Neurotrophic factors in women with crack cocaine dependence during early abstinence: the role of early life stress

    PubMed Central

    Viola, Thiago Wendt; Tractenberg, Saulo Gantes; Levandowski, Mateus Luz; Pezzi, Júlio Carlos; Bauer, Moisés Evandro; Teixeira, Antonio Lúcio; Grassi-Oliveira, Rodrigo

    2014-01-01

    Background Neurotrophic factors have been investigated in the pathophysiology of alcohol and drug dependence and have been related to early life stress driving developmental programming of neuroendocrine systems. Methods We conducted a follow-up study that aimed to assess the plasma levels of glial cell line–derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5) in crack users during 3 weeks of early abstinence in comparison with healthy controls. We performed a comprehensive clinical assessment in female inpatients with crack cocaine dependence (separated into 2 groups: participants with (CSA+) and without (CSA−) a history of childhood sexual abuse) and a group of nonuser control participants. Results Our sample included 104 women with crack cocaine dependence and 22 controls; of the women who used crack cocaine, 22 had a history of childhood sexual abuse and 82 did not. The GDNF plasma levels in the CSA+ group increased dramatically during 3 weeks of detoxification. In contrast, those in the CSA− group showed lower and stable levels of GDNF under the same conditions. Compared with the control group, BDNF plasma levels remained elevated and NGF levels were reduced during early abstinence. We found no differences in NT3 and NT4/5 between the patients and controls. However, within-group analyses showed that the CSA+ group exhibited higher levels of NT4/5 than the CSA− group at the end of detoxification. Limitations Some of the participants were using neuroleptics, mood stabilizers or antidepressants; our sample included only women; memory bias could not be controlled; and we did not investigate the possible confounding effects of other forms of stress during childhood. Conclusion This study supports the association between early life stress and peripheral neurotrophic factor levels in crack cocaine users. During early abstinence, plasmastic GDNF and NT4/5 were

  17. Structural and functional characterization of oversulfated chondroitin sulfate/dermatan sulfate hybrid chains from the notochord of hagfish. Neuritogenic and binding activities for growth factors and neurotrophic factors.

    PubMed

    Nandini, Chilkunda D; Mikami, Tadahisa; Ohta, Mitsuhiro; Itoh, Nobuyuki; Akiyama-Nambu, Fumiko; Sugahara, Kazuyuki

    2004-12-03

    Oversulfated chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains were purified from the notochord of hagfish. The chains (previously named CS-H for hagfish) have an average molecular mass of 18 kDa. Composition analysis using various chondroitinases demonstrated a variety of D-glucuronic acid (GlcUA)- and L-iduronic acid (IdoUA)-containing disaccharides variably sulfated with a higher proportion of GlcUA/IdoUA-GalNAc 4,6-O-disulfate, revealing complex CS/DS hybrid features. The hybrid chains showed neurite outgrowth-promoting activity of an axonic nature, which resembled the activity of squid cartilage CS-E and which was abolished fully by chondroitinase ABC digestion and partially by chondroitinase AC-I or B digestion, suggesting the involvement of both GlcUA and IdoUA in neuritogenic activity. Purified CS-H exhibited interactions in a BIAcore system with various heparin-binding proteins and neurotrophic factors (viz. fibroblast growth factor-2, -10, -16, and -18; midkine; pleiotrophin; heparin-binding epidermal growth factor-like growth factor; vascular endothelial growth factor; brain-derived neurotrophic factor; and glial cell line-derived neurotrophic factor), most of which are expressed in the brain, although fibroblast growth factor-1 and ciliary neurotrophic factor showed no binding. Kinetic analysis revealed high affinity binding of these growth factors and, for the first time, of the neurotrophic factors. Competitive inhibition revealed the involvement of both IdoUA and GlcUA in the binding of these growth factors, suggesting the importance of the hybrid nature of CS-H for the efficient binding of these growth factors. These findings, together with those from the recent analysis of brain CS/DS chains from neonatal mouse and embryonic pig (Bao, X., Nishimura, S., Mikami, T., Yamada, S., Itoh, N., and Sugahara, K. (2004) J. Biol. Chem. 279, 9765-9776), suggest physiological roles of the hybrid chains in the development of the brain.

  18. Action of Administered Ciliary Neurotrophic Factor on the Mouse Dorsal Vagal Complex

    PubMed Central

    Senzacqua, Martina; Severi, Ilenia; Perugini, Jessica; Acciarini, Samantha; Cinti, Saverio; Giordano, Antonio

    2016-01-01

    Ciliary neurotrophic factor (CNTF) induces weight loss in obese rodents and humans through activation of the hypothalamic Jak-STAT (Janus kinase-signal transducer and activator of transcription) signaling pathway. Here, we tested the hypothesis that CNTF also affects the brainstem centers involved in feeding and energy balance regulation. To this end, wild-type and leptin-deficient (ob/ob and db/db) obese mice were acutely treated with intraperitoneal recombinant CNTF. Coronal brainstem sections were processed for immunohistochemical detection of STAT3, STAT1, STAT5 phosphorylation and c-Fos. In wild-type mice, CNTF treatment for 45 min induced STAT3, STAT1, and STAT5 phosphorylation in neurons as well as glial cells of the area postrema; here, the majority of CNTF-responsive cells activated multiple STAT isoforms, and a significant proportion of CNTF-responsive glial cells bore the immaturity and plasticity markers nestin and vimentin. After 120 min CNTF treatment, c-Fos expression was intense in glial cells and weak in neurons of the area postrema, it was intense in several neurons of the rostral and caudal solitary tract nucleus (NTS), and weak in some cholinergic neurons of the dorsal motor nucleus of the vagus. In the ob/ob and db/db mice, Jak-STAT activation and c-Fos expression were similar to those induced in wild-type mouse brainstem. Treatment with CNTF (120 min, to induce c-Fos expression) and leptin (25 min, to induce STAT3 phosphorylation) demonstrated the co-localization of the two transcription factors in a small neuron population in the caudal NTS portion. Finally, weak immunohistochemical CNTF staining, detected in funiculus separans, and meningeal glial cells, matched the modest amount of CNTF found by RT-qPCR in micropunched area postrema tissue, which in contrast exhibited a very high amount of CNTF receptor. Collectively, the present findings show that the area postrema and the NTS exhibit high, distinctive responsiveness to circulating

  19. Elevated levels of plasma brain derived neurotrophic factor in rapid cycling bipolar disorder patients.

    PubMed

    Munkholm, Klaus; Pedersen, Bente Klarlund; Kessing, Lars Vedel; Vinberg, Maj

    2014-09-01

    Impaired neuroplasticity may be implicated in the pathophysiology of bipolar disorder, involving peripheral alterations of the neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3). Evidence is limited by methodological issues and is based primarily on case-control designs. The aim of this study was to investigate whether BDNF and NT-3 levels differ between patients with rapid cycling bipolar disorder and healthy control subjects and whether BDNF and NT-3 levels alter with affective states in rapid cycling bipolar disorder patients. Plasma levels of BDNF and NT-3 were measured in 37 rapid cycling bipolar disorder patients and in 40 age- and gender matched healthy control subjects using enzyme-linked immunosorbent assay (ELISA). In a longitudinal design, repeated measurements of BDNF and NT-3 were evaluated in various affective states in bipolar disorder patients during a 6-12 months period and compared with repeated measurements in healthy control subjects. Careful attention was given to standardization of all procedures and adjustment for potential confounders of BDNF and NT-3. In linear mixed models, adjusting for demographical and lifestyle factors, levels of BDNF were significantly elevated in bipolar disorder patients in euthymic- (p<0.05), depressed- (p<0.005) and manic/hypomanic (p<0.005) states compared with healthy control subjects. Within bipolar disorder patients, adjusting for medication, there was no significant difference in BDNF levels between affective states, with equally elevated levels present in euthymic-, depressive- and manic/hypomanic patients. Levels of BDNF were higher in patients with longer duration of illness compared with patients with shorter duration of illness. We found no difference in NT-3 levels between bipolar disorder patients in any affective state compared with healthy control subjects and no difference in NT-3 levels between affective states in bipolar disorder patients. The results suggest that

  20. Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids.

    PubMed

    Das, Undurti N

    2013-10-01

    Autism has a strong genetic and environmental basis in which inflammatory markers and factors concerned with synapse formation, nerve transmission, and information processing such as brain-derived neurotrophic factor (BDNF), polyunsaturated fatty acids (PUFAs): arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA) and their products and neurotransmitters: dopamine, serotonin, acetylcholine, γ-aminobutyric acid, and catecholamines and cytokines are altered. Antioxidants, vitamins, minerals, and trace elements are needed for the normal metabolism of neurotrophic factors, eicosanoids, and neurotransmitters, supporting reports of their alterations in autism. But, the exact relationship among these factors and their interaction with genes and proteins concerned with brain development and growth is not clear. It is suggested that maternal infections and inflammation and adverse events during intrauterine growth of the fetus could lead to alterations in the gene expression profile and proteomics that results in dysfunction of the neuronal function and neurotransmitters, alteration(s) in the metabolism of PUFAs and their metabolites resulting in excess production of proinflammatory eicosanoids and cytokines and a deficiency of anti-inflammatory cytokines and bioactive lipids that ultimately results in the development of autism. Based on these evidences, it is proposed that selective delivery of BDNF and methods designed to augment the production of anti-inflammatory cytokines and eicosanoids and PUFAs may prevent, arrest, or reverse the autism disease process.

  1. Activated microglia provide a neuroprotective role by balancing glial cell-line derived neurotrophic factor and tumor necrosis factor-α secretion after subacute cerebral ischemia.

    PubMed

    Wang, Jianping; Yang, Zhitang; Liu, Cong; Zhao, Yuanzheng; Chen, Yibing

    2013-01-01

    Microglia are the major immune cells in the central nervous system and play a key role in brain injury pathology. However, the role of activated microglia after subacute cerebral ischemia (SCI) remains unknown. To address this issue, we established a permanent middle cerebral artery occlusion (pMCAO) rat model and treated pMCAO rats with N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) (an inhibitor of microglial activation), or with vehicle alone. Finally, we determined the differences between the PJ34-and vehicle-treated rats with respect to neurological deficits, infarct volume, neuronal loss and the expression of CD11b (a marker of microglial activation), glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-α (TNF-α) at 1, 3 and 7 days after treatment. We found that the PJ34-treated rats had more severe neurological deficits and a larger infarct volume and exhibited a decreased CD11b expression, more neuronal loss, decreased expression of GDNF mRNA and protein but increased expression of TNF-α mRNA and protein compared with the vehicle-treated rats at 3 and 7 days after treatment. These results indicate that activated microglia provide a neuroprotective role through balancing GDNF and TNF-α expression following SCI.

  2. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer's disease.

    PubMed

    Zhang, Fang; Kang, Zhilong; Li, Wen; Xiao, Zhicheng; Zhou, Xinfu

    2012-07-01

    Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly. It is characterized by extracellular deposition of the neurotoxic peptide, amyloid-beta (Aβ) peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. However, the pathogenesis of AD is not fully understood. The aim of this review is to discuss the possible role of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signalling in the development of AD, focusing on BDNF/TrkB signalling in the production of Aβ, tau hyperphosphorylation and cognition decline, and exploring new possibilities for AD intervention.

  3. Changes in compressed neurons from dogs with acute and severe cauda equina constrictions following intrathecal injection of brain-derived neurotrophic factor-conjugated polymer nanoparticles☆

    PubMed Central

    Tan, Junming; Shi, Jiangang; Shi, Guodong; Liu, Yanling; Liu, Xiaohong; Wang, Chaoyang; Chen, Dechun; Xing, Shunming; Shen, Lianbing; Jia, Lianshun; Ye, Xiaojian; He, Hailong; Li, Jiashun

    2013-01-01

    This study established a dog model of acute multiple cauda equina constriction by experimental constriction injury (48 hours) of the lumbosacral central processes in dorsal root ganglia neurons. The repair effect of intrathecal injection of brain-derived neurotrophic factor with 15 mg encapsulated biodegradable poly(lactide-co-glycolide) nanoparticles on this injury was then analyzed. Dorsal root ganglion cells (L7) of all experimental dogs were analyzed using hematoxylin-eosin staining and immunohistochemistry at 1, 2 and 4 weeks following model induction. Intrathecal injection of brain-derived neurotrophic factor can relieve degeneration and inflammation, and elevate the expression of brain-derived neurotrophic factor in sensory neurons of compressed dorsal root ganglion. Simultaneously, intrathecal injection of brain-derived neurotrophic factor obviously improved neurological function in the dog model of acute multiple cauda equina constriction. Results verified that sustained intraspinal delivery of brain-derived neurotrophic factor encapsulated in biodegradable nanoparticles promoted the repair of histomorphology and function of neurons within the dorsal root ganglia in dogs with acute and severe cauda equina syndrome. PMID:25206593

  4. High voltage electric potentials to enhance brain-derived neurotrophic factor levels in the brain.

    PubMed

    Yanamoto, Hiroji; Nakajo, Yukako; Kataoka, Hiroharu; Iihara, Koji

    2013-01-01

    Development of a safe method to increase brain-derived neurotrophic factor (BDNF) levels in the brain is expected to enhance learning and memory, induce tolerance to cerebral infarction or tolerance to depressive state, improve glucose metabolism, and suppress appetite and body weight. We have shown that repetitive applications of high-voltage electric potential (HELP) to the body increase BDNF levels in the brain, improving learning and memory in mice. Here, we investigated the effects of HELP treatment for a chronic period on the BDNF levels in the mouse brain, and on body weight in mice and humans. Adult mice were exposed to 3.1 or 5.4 kV HELP (on the body), 5 h a day for 24 weeks, and BDNF levels in the brain and alterations in body weight were analyzed. Humans [age, 53.2 ± 15.5 years old; BMI, 27.8 ± 5.6 (mean ± SD, n = 6)] were exposed to 3.9 kV HELP (on the body) for 1 h a day, continuing for 33 months (2.8 years) under the monitor of body weight. In mice, the HELP application elevated BDNF levels in the brain at least temporarily, affecting body weight in a voltage- and time-dependent manner. In humans, the HELP treatment reduced body weight compared to the pretreated initial values without any aversive effects (p < 0.002, one-way ANOVA with the post hoc Holm-Sidak test). The results in mice indicated that 3.1 kV HELP was considered insufficient for a continuous elevation of intracerebral BDNF, and 5.4 kV HELP was considered as excessive. HELP with an appropriate voltage can be utilized to increase BDNF levels in the brain for a prolonged period. We anticipate further investigations to clarify the effect of the optimal-leveled HELP therapy on memory disturbances, neurological deficits after stroke, depression, diabetes, obesity and metabolic syndrome.

  5. Circulating Brain-Derived Neurotrophic Factor Has Diagnostic and Prognostic Value in Traumatic Brain Injury

    PubMed Central

    Diaz-Arrastia, Ramon; Wu, Alan H. B.; Yue, John K.; Manley, Geoffrey T.; Sair, Haris I.; Van Eyk, Jennifer; Everett, Allen D.; Okonkwo, David O.; Valadka, Alex B.; Gordon, Wayne A.; Maas, Andrew I.R.; Mukherjee, Pratik; Yuh, Esther L.; Lingsma, Hester F.; Puccio, Ava M.; Schnyer, David M.

    2016-01-01

    Abstract Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and regeneration. We investigated the diagnostic and prognostic values of serum BDNF in traumatic brain injury (TBI). We examined serum BDNF in two independent cohorts of TBI cases presenting to the emergency departments (EDs) of the Johns Hopkins Hospital (JHH; n = 76) and San Francisco General Hospital (SFGH, n = 80), and a control group of JHH ED patients without TBI (n = 150). Findings were subsequently validated in the prospective, multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study (n = 159). We investigated the association between BDNF, glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) and recovery from TBI at 6 months in the TRACK-TBI Pilot cohort. Incomplete recovery was defined as having either post-concussive syndrome or a Glasgow Outcome Scale Extended score <8 at 6 months. Median day-of-injury BDNF concentrations (ng/mL) were lower among TBI cases (JHH TBI, 17.5 and SFGH TBI, 13.8) than in JHH controls (60.3; p = 0.0001). Among TRACK-TBI Pilot subjects, median BDNF concentrations (ng/mL) were higher in mild (8.3) than in moderate (4.3) or severe TBI (4.0; p = 0.004. In the TRACK-TBI cohort, the 75 (71.4%) subjects with very low BDNF values (i.e.,

  6. Time-Dependent Serum Brain-Derived Neurotrophic Factor Decline During Methamphetamine Withdrawal

    PubMed Central

    Ren, Wenwei; Tao, Jingyan; Wei, Youdan; Su, Hang; Zhang, Jie; Xie, Ying; Guo, Jun; Zhang, Xiangyang; Zhang, Hailing; He, Jincai

    2016-01-01

    Abstract Methamphetamine (METH) is a widely abused illegal psychostimulant, which is confirmed to be neurotoxic and of great damage to human. Studies on the role of brain-derived neurotrophic factor (BDNF) in human METH addicts are limited and inconsistent. The purposes of this study are to compare the serum BDNF levels between METH addicts and healthy controls during early withdrawal, and explore the changes of serum BDNF levels during the first month after METH withdrawal. 179 METH addicts and 90 age- and gender-matched healthy controls were recruited in this study. We measured serum BDNF levels at baseline (both METH addicts and healthy controls) and at 1 month after abstinence of METH (METH addicts only). Serum BDNF levels of METH addicts at baseline were significantly higher than controls (1460.28 ± 490.69 vs 1241.27 ± 335.52 pg/mL; F = 14.51, P < 0.001). The serum BDNF levels of 40 METH addicts were re-examined after 1 month of METH abstinence, which were significantly lower than that at baseline (1363.70 ± 580.59 vs 1621.41 ± 591.07 pg/mL; t = 2.26, P = .03), but showed no differences to the controls (1363.70 ± 580.59 vs 1241.27 ± 335.52 pg/mL; F = 2.29, P = 0.13). Our study demonstrated that serum BDNF levels were higher in METH addicts than controls during early withdrawal, and were time dependent decreased during the first month of abstinence. These findings may provide further evidence that increased serum BDNF levels may be associated with the pathophysiology of METH addiction and withdrawal and may be a protective response against the subsequent METH-induced neurotoxicity. Besides, these findings may also promote the development of medicine in the treatment of METH addiction and withdrawal. PMID:26844469

  7. Time-Dependent Serum Brain-Derived Neurotrophic Factor Decline During Methamphetamine Withdrawal.

    PubMed

    Ren, Wenwei; Tao, Jingyan; Wei, Youdan; Su, Hang; Zhang, Jie; Xie, Ying; Guo, Jun; Zhang, Xiangyang; Zhang, Hailing; He, Jincai

    2016-02-01

    Methamphetamine (METH) is a widely abused illegal psychostimulant, which is confirmed to be neurotoxic and of great damage to human. Studies on the role of brain-derived neurotrophic factor (BDNF) in human METH addicts are limited and inconsistent. The purposes of this study are to compare the serum BDNF levels between METH addicts and healthy controls during early withdrawal, and explore the changes of serum BDNF levels during the first month after METH withdrawal.179 METH addicts and 90 age- and gender-matched healthy controls were recruited in this study. We measured serum BDNF levels at baseline (both METH addicts and healthy controls) and at 1 month after abstinence of METH (METH addicts only).Serum BDNF levels of METH addicts at baseline were significantly higher than controls (1460.28  ±  490.69 vs 1241.27  ±  335.52  pg/mL; F = 14.51, P < 0.001). The serum BDNF levels of 40 METH addicts were re-examined after 1 month of METH abstinence, which were significantly lower than that at baseline (1363.70  ±  580.59 vs 1621.41  ±  591.07  pg/mL; t = 2.26, P = .03), but showed no differences to the controls (1363.70  ±  580.59 vs 1241.27  ±  335.52  pg/mL; F = 2.29, P = 0.13).Our study demonstrated that serum BDNF levels were higher in METH addicts than controls during early withdrawal, and were time dependent decreased during the first month of abstinence. These findings may provide further evidence that increased serum BDNF levels may be associated with the pathophysiology of METH addiction and withdrawal and may be a protective response against the subsequent METH-induced neurotoxicity. Besides, these findings may also promote the development of medicine in the treatment of METH addiction and withdrawal.

  8. Astrocytes Promote Oligodendrogenesis after White Matter Damage via Brain-Derived Neurotrophic Factor

    PubMed Central

    Miyamoto, Nobukazu; Maki, Takakuni; Shindo, Akihiro; Liang, Anna C.; Maeda, Mitsuyo; Egawa, Naohiro; Itoh, Kanako; Lo, Evan K.; Lok, Josephine; Ihara, Masafumi

    2015-01-01

    Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAPcre/BDNFwt/fl) in which BDNF expression is downregulated specifically in GFAP+ astrocytes. Both wild-type (GFAPwt/BDNFwt/fl mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF. SIGNIFICANCE STATEMENT The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white

  9. Circulating Brain-Derived Neurotrophic Factor Has Diagnostic and Prognostic Value in Traumatic Brain Injury.

    PubMed

    Korley, Frederick K; Diaz-Arrastia, Ramon; Wu, Alan H B; Yue, John K; Manley, Geoffrey T; Sair, Haris I; Van Eyk, Jennifer; Everett, Allen D; Okonkwo, David O; Valadka, Alex B; Gordon, Wayne A; Maas, Andrew I R; Mukherjee, Pratik; Yuh, Esther L; Lingsma, Hester F; Puccio, Ava M; Schnyer, David M

    2016-01-15

    Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and regeneration. We investigated the diagnostic and prognostic values of serum BDNF in traumatic brain injury (TBI). We examined serum BDNF in two independent cohorts of TBI cases presenting to the emergency departments (EDs) of the Johns Hopkins Hospital (JHH; n = 76) and San Francisco General Hospital (SFGH, n = 80), and a control group of JHH ED patients without TBI (n = 150). Findings were subsequently validated in the prospective, multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study (n = 159). We investigated the association between BDNF, glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) and recovery from TBI at 6 months in the TRACK-TBI Pilot cohort. Incomplete recovery was defined as having either post-concussive syndrome or a Glasgow Outcome Scale Extended score <8 at 6 months. Median day-of-injury BDNF concentrations (ng/mL) were lower among TBI cases (JHH TBI, 17.5 and SFGH TBI, 13.8) than in JHH controls (60.3; p = 0.0001). Among TRACK-TBI Pilot subjects, median BDNF concentrations (ng/mL) were higher in mild (8.3) than in moderate (4.3) or severe TBI (4.0; p = 0.004. In the TRACK-TBI cohort, the 75 (71.4%) subjects with very low BDNF values (i.e.,

  10. Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study.

    PubMed

    Munoz, Miranda J; Kumar, Raj G; Oh, Byung-Mo; Conley, Yvette P; Wang, Zhensheng; Failla, Michelle D; Wagner, Amy K

    2017-01-01

    Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0-6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in "younger patients" (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF(*)GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance.

  11. Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus.

    PubMed

    Solum, Derek T; Handa, Robert J

    2002-04-01

    During development, estrogen has a variety of effects on morphological and electrophysiological properties of hippocampal neurons. Brain-derived neurotrophic factor (BDNF) also plays an important role in the survival and differentiation of neurons during development. We examined the effects of gonadectomy with and without estrogen replacement on the mRNA and protein of BDNF and its receptor, trkB, during early postnatal development of the rat hippocampus. We used immunocytochemistry to demonstrate that estrogen receptor alpha (ERalpha) and BDNF were localized to the same cells within the developing hippocampus. BDNF and ERalpha were colocalized in pyramidal cells of the CA3 subregion and to a lesser extent in CA1. To determine whether BDNF mRNA was regulated by estrogen during development, we gonadectomized male rat pups at postnatal day 0 (P0) and examined mRNA and protein levels from P0 to P25 using real-time reverse transcription-PCR and Western blot analysis. After gonadectomy, BDNF mRNA levels are significantly reduced on P7, but after treatment of gonadectomized animals with estradiol benzoate on P0, levels at all ages were similar to those in intact animals. BDNF mRNA changes after gonadectomy are accompanied by an increase in the levels of BDNF protein, which were reduced by estrogen treatment at P0. We also examined the effect of postnatal estrogen treatment on trkB. There were no significant changes in trkB mRNA or protein in gonadectomized or estrogen-replaced animals. These results suggest that a direct interaction may exist between ERalpha and BDNF to alter hippocampal physiology during development in the rat.

  12. Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor.

    PubMed

    Harada, Shinichi; Yamazaki, Yui; Tokuyama, Shogo

    2013-01-01

    Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A.

  13. Involvement of brain-derived neurotrophic factor and neurogenesis in oestradiol neuroprotection of the hippocampus of hypertensive rats.

    PubMed

    Pietranera, L; Lima, A; Roig, P; De Nicola, A F

    2010-10-01

    The hippocampus of spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats shows decreased cell proliferation and astrogliosis as well as a reduced number of hilar cells. These defects are corrected after administration of 17β-oestradiol (E(2) ) for 2 weeks. The present work investigated whether E(2) treatment of SHR and of hypertensive DOCA-salt male rats modulated the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in hippocampal neurogenesis. The neurogenic response to E(2) was simultaneously determined by counting the number of doublecortin-immunopositive immature neurones in the subgranular zone of the dentate gyrus. Both hypertensive models showed decreased expression of BDNF mRNA in the granular zone of the dentate gyrus, without changes in CA1 or CA3 pyramidal cell layers, decreased BDNF protein levels in whole hippocampal tissue, low density of doublecortin (DCX)-positive immature neurones in the subgranule zone and decreased length of DCX+ neurites in the dentate gyrus. After s.c. implantation of a single E(2) pellet for 2 weeks, BDNF mRNA in the dentate gyrus, BDNF protein in whole hippocampus, DCX immunopositive cells and the length of DCX+ neurites were significantly raised in both SHR and DOCA-salt-treated rats. These results indicate that: (i) low BDNF expression and deficient neurogenesis distinguished the hippocampus of SHR and DOCA-salt hypertensive rats and (ii) E(2) was able to normalise these biologically important functions in the hippocampus of hypertensive animals.

  14. Imipramine activates glial cell line-derived neurotrophic factor via early growth response gene 1 in astrocytes.

    PubMed

    Kim, Yeni; Kim, Se Hyun; Kim, Yong Sik; Lee, Young Han; Ha, Kyooseob; Shin, Soon Young

    2011-06-01

    Recent evidence has suggested that deficits in glial plasticity contribute to the pathophysiology of depressive disorders. The present study explored early growth response 1 (EGR-1) transcriptional regulation of imipramine-induced glial cell line-derived neurotrophic factor (GDNF) expression in astrocytes. After we observed the induction of GDNF mRNA expression in rat astrocytes in response to imipramine, deletion mutant studies showed that the proximal region between -493 and -114 of the GDNF promoter, which contains three binding sites for EGR-1, was essential for maximal imipramine-induced activation of GDNF promoter. The dose-dependent upregulation of EGR-1 by imipramine, the activation of GDNF by the over-expression of EGR-1 without imipramine and the reduction in the imipramine-induced GDNF mRNA expression after silencing of endogenous EGR-1 demonstrated that EGR-1 is upregulated by imipramine to activate the GDNF promoter. Furthermore, imipramine-induced GDNF mRNA expression was strongly attenuated in primary astrocytes from Egr-1(-/-) mice, and the immunoreactivity to an anti-GDNF antibody in glial fibrillary acidic protein-positive cells was lower in imipramine-treated astrocytes from Egr-1(-/-) mice than in those from Egr-1(+/-) mice. To determine whether mitogen-activated protein kinases (MAPKs) were associated with imipramine-induced EGR-1 expression, we examined the induction of MAPK phosphorylation in response to imipramine. Pretreatment of rat primary astrocytes with the MAPK kinase inhibitor U0126 or the JNK inhibitor SP600125 strongly inhibited imipramine-stimulated EGR-1 expression. In conclusion, we found that imipramine induction of EGR-1 upregulated GDNF in astrocytes in a dose-dependent manner. This upregulation may occur through the MEK/ERK and JNK MAPK pathways, which suggests a new therapeutic mechanism of action for depressive disorders.

  15. Reduced Hippocampal Brain-Derived Neurotrophic Factor (BDNF) in Neonatal Rats after Prenatal Exposure to Propylthiouracil (PTU)

    PubMed Central

    Chakraborty, Goutam; Magagna-Poveda, Alejandra; Parratt, Carolyn; Umans, Jason G.; MacLusky, Neil J.

    2012-01-01

    Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy. PMID:22253429

  16. Reduced intestinal brain-derived neurotrophic factor increases vagal sensory innervation of the intestine and enhances satiation.

    PubMed

    Biddinger, Jessica E; Fox, Edward A

    2014-07-30

    Brain-derived neurotrophic factor (BDNF) is produced by developing and mature gastrointestinal (GI) tissues that are heavily innervated by autonomic neurons and may therefore control their development or function. To begin investigating this hypothesis, we compared the morphology, distribution, and density of intraganglionic laminar endings (IGLEs), the predominant vagal GI afferent, in mice with reduced intestinal BDNF (INT-BDNF(-/-)) and controls. Contrary to expectations of reduced development, IGLE density and longitudinal axon bundle number in the intestine of INT-BDNF(-/-) mice were increased, but stomach IGLEs were normal. INT-BDNF(-/-) mice also exhibited increased vagal sensory neuron numbers, suggesting that their survival was enhanced. To determine whether increased intestinal IGLE density or other changes to gut innervation in INT-BDNF(-/-) mice altered feeding behavior, meal pattern and microstructural analyses were performed. INT-BDNF(-/-) mice ate meals of much shorter duration than controls, resulting in reduced meal size. Increased suppression of feeding in INT-BDNF(-/-) mice during the late phase of a scheduled meal suggested that increased satiation signaling contributed to reduced meal duration and size. Furthermore, INT-BDNF(-/-) mice demonstrated increases in total daily intermeal interval and satiety ratio, suggesting that satiety signaling was augmented. Compensatory responses maintained normal daily food intake and body weight in INT-BDNF(-/-) mice. These findings suggest a target organ-derived neurotrophin suppresses development of that organ's sensory innervation and sensory neuron survival and demonstrate a role for BDNF produced by peripheral tissues in short-term controls of feeding, likely through its regulation of development or function of gut innervation, possibly including augmented intestinal IGLE innervation.

  17. Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study

    PubMed Central

    Munoz, Miranda J.; Kumar, Raj G.; Oh, Byung-Mo; Conley, Yvette P.; Wang, Zhensheng; Failla, Michelle D.; Wagner, Amy K.

    2017-01-01

    Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0–6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in “younger patients” (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance. PMID:28337122

  18. Effect of dehydroepiandrosterone (DHEA) on memory and brain derived neurotrophic factor (BDNF) in a rat model of vascular dementia.

    PubMed

    Sakr, H F; Khalil, K I; Hussein, A M; Zaki, M S A; Eid, R A; Alkhateeb, M

    2014-02-01

    The effect of dehydroepiandrosterone (DHEA) on memory and cognition in experimental animals is well known, but its efficacy in clinical dementia is unproven. So, the aim of the present study was to investigate the effect of DHEA on learning and memory activities in a rat model of vascular dementia (VD). Forty-eight male rats that positively passed the holeboard memory test were chosen for the study before bilateral permanent occlusion of the common carotid artery. They were divided into four groups (n=12, each) as follows (i) untreated control, (ii) rats exposed to surgical permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion, (iii) rats exposed to BCCAO then received DHEA (BCCAO + DHEA) and (i.v.) rats exposed to BCCAO then received donepezil (BCCAO + DON). Holeboard memory test was used to assess the time, latency, working memory and reference memory. Central level of acetylcholine, norepinephrine and dopamine in the hippocampus were measured. Furthermore, the expression of brain derived neurotrophic factor (BDNF) in the hippocampus was determined. Histopathological studies of the cerebral cortex and transmission electron microscope of the hippocampus were performed. BCCAO decreased the learning and memory activities in the holeboard memory. Also, it decreased the expression of BDNF as well as the central level of acetylcholine, noradrenaline and dopamine as compared to control rats. Treatment with DHEA and donepezil increased the working and reference memories, BDNF expression as well as the central acetylcholine in the hippocampus as compared to BCCAO rats. DHEA produced neuroprotective effects through increasing the expression of BDNF as well as increasing the central level of acetylcholine and catecholamines which are non-comparable to donepezil effects.

  19. Expression and cell localization of brain-derived neurotrophic factor and TrkB during zebrafish retinal development.

    PubMed

    Germanà, A; Sánchez-Ramos, C; Guerrera, M C; Calavia, M G; Navarro, M; Zichichi, R; García-Suárez, O; Pérez-Piñera, P; Vega, Jose A

    2010-09-01

    Brain-derived neurotrophic factor (BDNF) signaling through TrkB regulates different aspects of neuronal development, including survival, axonal and dendritic growth, and synapse formation. Despite recent advances in our understanding of the functional significance of BDNF and TrkB in the retina, the cell types in the retina that express BDNF and TrkB, and the variations in their levels of expression during development, remain poorly defined. The goal of the present study is to determine the age-dependent changes in the levels of expression and localization of BDNF and TrkB in the zebrafish retina. Zebrafish retinas from 10 days post-fertilization (dpf) to 180 dpf were used to perform PCR, Western blot and immunohistochemistry. Both BDNF and TrkB mRNAs, and BDNF and full-length TrkB proteins were detected at all ages sampled. The localization of these proteins in the retina was very similar at all time points studied. BDNF immunoreactivity was found in the outer nuclear layer, the outer plexiform layer and the inner plexiform layer, whereas TrkB immunoreactivity was observed in the inner plexiform layer and, to a lesser extent, in the ganglion cell layer. These results demonstrate that the pattern of expression of BDNF and TrkB in the retina of zebrafish remains unchanged during postembryonic development and adult life. Because TrkB expression in retina did not change with age, cells expressing TrkB may potentially be able to respond during the entire lifespan of zebrafish to BDNF either exogenously administered or endogenously produced, acting through paracrine mechanisms.

  20. Differential effects of brain-derived neurotrophic factor and neurotrophin-3 on hindlimb function in paraplegic rats.

    PubMed

    Boyce, Vanessa S; Park, Jihye; Gage, Fred H; Mendell, Lorne M

    2012-01-01

    We compared the effect of viral administration of brain-derived neurotrophic factor (BDNF) or neurotrophin 3 (NT-3) on locomotor recovery in adult rats with complete thoracic (T10) spinal cord transection injuries, in order to determine the effect of chronic neurotrophin expression on spinal plasticity. At the time of injury, BDNF, NT-3 or green fluorescent protein (GFP) (control) was delivered to the lesion via adeno-associated virus (AAV) constructs. AAV-BDNF was significantly more effective than AAV-NT-3 in eliciting locomotion. In fact, AAV-BDNF-treated rats displayed plantar, weight-supported hindlimb stepping on a stationary platform, that is, without the assistance of a moving treadmill and without step training. Rats receiving AAV-NT-3 or AAV-GFP were incapable of hindlimb stepping during this task, despite provision of balance support. AAV-NT-3 treatment did promote the recovery of treadmill-assisted stepping, but this required continuous perineal stimulation. In addition, AAV-BDNF-treated rats were sensitized to noxious heat, whereas AAV-NT-3-treated and AAV-GFP-treated rats were not. Notably, AAV-BDNF-treated rats also developed hindlimb spasticity, detracting from its potential clinical applicability via the current viral delivery method. Intracellular recording from triceps surae motoneurons revealed that AAV-BDNF significantly reduced motoneuron rheobase, suggesting that AAV-BDNF promoted the recovery of over-ground stepping by enhancing neuronal excitability. Elevated nuclear c-Fos expression in interneurons located in the L2 intermediate zone after AAV-BDNF treatment indicated increased activation of interneurons in the vicinity of the locomotor central pattern generator. AAV-NT-3 treatment reduced motoneuron excitability, with little change in c-Fos expression. These results support the potential for BDNF delivery at the lesion site to reorganize locomotor circuits.

  1. The brain-uterus connection: brain derived neurotrophic factor (BDNF) and its receptor (Ntrk2) are conserved in the mammalian uterus.

    PubMed

    Wessels, Jocelyn M; Wu, Liang; Leyland, Nicholas A; Wang, Hongmei; Foster, Warren G

    2014-01-01

    The neurotrophins are neuropeptides that are potent regulators of neurite growth and survival. Although mainly studied in the brain and nervous system, recent reports have shown that neurotrophins are expressed in multiple target tissues and cell types throughout the body. Additionally, dysregulation of neurotrophins has been linked to several disease conditions including Alzheimer's, Parkinson's, Huntington's, psychiatric disorders, and cancer. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that elicits its actions through the neurotrophic tyrosine receptor kinase type 2 (Ntrk2). Together BDNF and Ntrk2 are capable of activating the adhesion, angiogenesis, apoptosis, and proliferation pathways. These pathways are prominently involved in reproductive physiology, yet a cross-species examination of BDNF and Ntrk2 expression in the mammalian uterus is lacking. Herein we demonstrated the conserved nature of BDNF and Ntrk2 across several mammalian species by mRNA and protein sequence alignment, isolated BDNF and Ntrk2 transcripts in the uterus by Real-Time PCR, localized both proteins to the glandular and luminal epithelium, vascular smooth muscle, and myometrium of the uterus, determined that the major isoforms expressed in the human endometrium were pro-BDNF, and truncated Ntrk2, and finally demonstrated antibody specificity. Our findings suggest that BDNF and Ntrk2 are transcribed, translated, and conserved across mammalian species including human, mouse, rat, pig, horse, and the bat.

  2. Intracerebroventricular administration of α-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats.

    PubMed

    Wisniewski, Miriam S W; Carvalho-Silva, Milena; Gomes, Lara M; Zapelini, Hugo G; Schuck, Patrícia F; Ferreira, Gustavo C; Scaini, Giselli; Streck, Emilio L

    2016-04-01

    Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine as well as their corresponding transaminated branched-chain α-ketoacids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. However, the effect of accumulating α-ketoacids in MSUD on neurotrophic factors has not been investigated. Thus, the objective of the present study was to evaluate the effects of acute intracerebroventricular administration of α-ketoisocaproic acid (KIC) on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the brains of young male rats. Ours results showed that intracerebroventricular administration of KIC decreased BDNF levels in hippocampus, striatum and cerebral cortex, without induce a detectable change in pro-BDNF levels. Moreover, NGF levels in the hippocampus were reduced after intracerebroventricular administration of KIC. In conclusion, these data suggest that the effects of KIC on demyelination and memory processes may be mediated by reduced trophic support of BDNF and NGF. Moreover, lower levels of BDNF and NGF are consistent with the hypothesis that a deficit in this neurotrophic factor may contribute to the structural and functional alterations of brain underlying the psychopathology of MSUD, supporting the hypothesis of a neurodegenerative process in MSUD.

  3. Brain-Derived Neurotrophic Factor and Suicide in Schizophrenia: Critical Role of Neuroprotective Mechanisms as an Emerging Hypothesis

    PubMed Central

    Shrivastava, Amresh; De Sousa, Avinash; Rao, G. Prasad

    2016-01-01

    Suicide is a common occurrence in psychiatric disorders and is a cause of increased healthcare utilization worldwide. Schizophrenia is one of the most common psychiatric disorders worldwide and posited to be seen in 1% of the population worldwide. Suicide is a common occurrence in schizophrenia with 25%–30% patients with schizophrenia attempting suicide and 8%–10% completing it. There is a need for valid biological markers to help clinicians identify patients with schizophrenia that may be at a risk of suicide and thus help in them receiving better care and interventions at the earliest even before a suicide attempt occurring. There are clear neurobiological changes at a genetic, neuroimaging, and neurochemical level that occurs in patients with schizophrenia that attempt suicide. There is a new theory that postulates neuronal plasticity and neuroprotection to have a role in the biological changes that ensue when suicidal thoughts and feelings occur in patients with schizophrenia. Neurotrophic growth factors like brain-derived neurotrophic factor (BDNF) have been documented to play a role in the protection of neurons and in the prevention of neurobiological changes that may lead to suicide both in schizophrenia and depression. The present paper presents a commentary that looks at the role of BDNF as a protective factor and neurobiological marker for suicide in schizophrenia. PMID:28031582

  4. Association study of 37 genes related to serotonin and dopamine neurotransmission and neurotrophic factors in cocaine dependence.

    PubMed

    Fernàndez-Castillo, N; Roncero, C; Grau-Lopez, L; Barral, C; Prat, G; Rodriguez-Cintas, L; Sánchez-Mora, C; Gratacòs, M; Ramos-Quiroga, J A; Casas, M; Ribasés, M; Cormand, B

    2013-02-01

    Cocaine dependence is a neuropsychiatric disorder in which both environmental and genetic factors are involved. Several processes, that include reward and neuroadaptations, mediate the transition from use to dependence. In this regard, dopamine and serotonin neurotransmission systems are clearly involved in reward and other cocaine-related effects, whereas neurotrophic factors may be responsible for neuroadaptations associated with cocaine dependence. We examined the contribution to cocaine dependence of 37 genes related to the dopaminergic and serotoninergic systems, neurotrophic factors and their receptors through a case-control association study with 319 single nucleotide polymorphisms selected according to genetic coverage criteria in 432 cocaine-dependent patients and 482 sex-matched unrelated controls. Single marker analyses provided evidence for association of the serotonin receptor HTR2A with cocaine dependence [rs6561333; nominal P-value adjusted for age = 1.9e-04, odds ratio = 1.72 (1.29-2.30)]. When patients were subdivided according to the presence or absence of psychotic symptoms, we confirmed the association between cocaine dependence and HTR2A in both subgroups of patients. Our data show additional evidence for the involvement of the serotoninergic system in the genetic susceptibility to cocaine dependence.

  5. Glycans and glycan-binding proteins in brain: galectin-1-induced expression of neurotrophic factors in astrocytes.

    PubMed

    Endo, Tamao

    2005-06-01

    Astrocytes are a major cell type in the central nervous system (CNS). They are considered to act in cooperation with neurons and other glial cells and to participate in the development and maintenance of functions of the CNS. Immature astrocytes possess a polygonal shape and have no processes, and continue to proliferate, while mature astrocytes have a stellate cell morphology, increased glial fibrillary acidic protein expression, and proliferate slowly. Stellate astrocytes, which immediately appear at the site of brain lesions by ischemia or other brain injuries, are thought to produce several neurotrophic factors to protect neurons from delayed post-lesion death. Previously we reported that galectin-1, a member of the family of beta-galactoside-binding proteins, induced astrocyte differentiation, and the differentiated astrocytes greatly enhanced their production of brain-derived neurotrophic factor (BDNF). BDNF is known to promote neuronal survival, guide axonal pathfinding, and participate in activity-dependent synaptic plasticity during development. The effect of galectin-1 is astrocyte-specific and does not have any effect on neurons. Prevention of neuronal loss during CNS injuries is important to maintain brain function. Induction of neuroprotective factors in astrocytes by an endogenous mammalian lectin may be a new mechanism for preventing neuronal loss after brain injury, and may be useful for the treatment of neurodegenerative disorders.

  6. Effects of acetylcholine and electrical stimulation on glial cell line-derived neurotrophic factor production in skeletal muscle cells.

    PubMed

    Vianney, John-Mary; Miller, Damon A; Spitsbergen, John M

    2014-11-07

    Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor required for survival of neurons in the central and peripheral nervous system. Specifically, GDNF has been characterized as a survival factor for spinal motor neurons. GDNF is synthesized and secreted by neuronal target tissues, including skeletal muscle in the peripheral nervous system; however, the mechanisms by which GDNF is synthesized and released by skeletal muscle are not fully understood. Previous results suggested that cholinergic neurons regulate secretion of GDNF by skeletal muscle. In the current study, GDNF production by skeletal muscle myotubes following treatment with acetylcholine was examined. Acetylcholine receptors on myotubes were identified with labeled alpha-bungarotoxin and were blocked using unlabeled alpha-bungarotoxin. The question of whether electrical stimulation has a similar effect to that of acetylcholine was also investigated. Cells were stimulated with voltage pulses; at 1 and 5 Hz frequencies for times ranging from 30 min to 48 h. GDNF content in myotubes and GDNF in conditioned culture medium were quantified by enzyme-linked immunosorbant assay. Results suggest that acetylcholine and short-term electrical stimulation reduce GDNF secretion, while treatment with carbachol or long-term electrical stimulation enhances GDNF production by skeletal muscle.

  7. Higher levels of brain derived neurotrophic factor but similar nerve growth factor in human milk in women with preeclampsia.

    PubMed

    Dangat, Kamini; Kilari, Anitha; Mehendale, Savita; Lalwani, Sanjay; Joshi, Sadhana

    2013-05-01

    Children born to mothers with preeclampsia have consistently been suggested to be at risk for cognitive and behavioral disorders in later life. Breastfeeding is said to be associated with better neurodevelopment outcomes. Our earlier studies indicated higher levels of docosahexaenoic acid (DHA) in human milk in women with preeclampsia. DHA is known to regulate the expression of neurotrophins and together they play a vital role in neurodevelopment and cognitive performance. The present study examines the levels of maternal plasma and milk neurotrophins [(nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF)] in women with preeclampsia and compares them with normotensive women who served as controls. Singleton pregnant women diagnosed with preeclampsia (n=72) and controls (n=102) were recruited for this study from Bharati Hospital, Pune. Plasma and milk samples were analyzed for NGF and BDNF levels using the Emax Immuno Assay System using promega kits. Maternal plasma NGF and BDNF levels were lower (p<0.01 for both) in women with preeclampsia as compared to the control women. Milk NGF levels were similar while milk BDNF levels were higher (p<0.05) in the preeclampsia group as compared to controls. Plasma NGF levels were positively correlated with milk NGF levels in the control group. Our results indicate the differential regulation of milk NGF and BDNF levels in women with preeclampsia. The present study suggests a role for both NGF and BDNF in human milk for postnatal brain development. Further studies need to examine the associations of DHA and BDNF in human milk with cognition at later ages.

  8. Short-term ethanol exposure causes imbalanced neurotrophic factor allocation in the basal forebrain cholinergic system: a novel insight into understanding the initial processes of alcohol addiction.

    PubMed

    Miki, Takanori; Kusaka, Takashi; Yokoyama, Toshifumi; Ohta, Ken-ichi; Suzuki, Shingo; Warita, Katsuhiko; Jamal, Mostofa; Wang, Zhi-Yu; Ueki, Masaaki; Liu, Jun-Qian; Yakura, Tomiko; Tamai, Motoki; Sumitani, Kazunori; Hosomi, Naohisa; Takeuchi, Yoshiki

    2014-02-01

    Alcohol ingestion affects both motor and cognitive functions. One brain system that is influenced by ethanol is the basal forebrain (BF) cholinergic projection system, which projects to diverse neocortical and limbic areas. The BF is associated with memory and cognitive function. Our primary interest is the examination of how regions that receive BF cholinergic projections are influenced by short-term ethanol exposure through alterations in the mRNA levels of neurotrophic factors [nerve growth factor/TrkA, brain-derived neurotrophic factor/TrkB, and glial-derived neurotrophic factor (GDNF)/GDNF family receptor α1]. Male BALB/C mice were fed a liquid diet containing 5 % (v/v) ethanol. Pair-fed control mice were maintained on an identical liquid diet, except that the ethanol was isocalorically substituted with sucrose. Mice exhibiting signs of ethanol intoxication (stages 1-2) were used for real-time reverse transcription-polymerase chain reaction analyses. Among the BF cholinergic projection regions, decreased levels of GDNF mRNA and increased levels of TrkB mRNA were observed in the basal nucleus, and increased levels of TrkB mRNA were observed in the cerebral cortex. There were no significant alterations in the levels of expression of relevant neurotrophic factors in the septal nucleus and hippocampus. Given that neurotrophic factors function in retrograde/anterograde or autocrine/paracrine mechanisms and that BF cholinergic projection regions are neuroanatomically connected, these findings suggested that an imbalanced allocation of neurotrophic factor ligands and receptors is an initial phenomenon in alcohol addiction. The exact mechanisms underlying this phenomenon in the BF cholinergic system are unknown. However, our results provide a novel notion for the understanding of the initial processes in alcohol addiction.

  9. Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway in depressive disorder.

    PubMed

    Wang, Hongyan; Zhang, Yingquan; Qiao, Mingqi

    2013-03-25

    The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.

  10. Effect of propofol on brain-derived neurotrophic factor and tyrosine kinase receptor B in the hippocampus of aged rats with chronic cerebral ischemia.

    PubMed

    Chen, Gang; Fu, Qiang; Cao, Jiangbei; Mi, Weidong

    2012-07-25

    We intraperitoneally injected 10 and 50 mg/kg of propofol for 7 consecutive days to treat a rat model of chronic cerebral ischemia. A low-dose of propofol promoted the expression of brain-derived neurotrophic factor, tyrosine kinase receptor B, phosphorylated cAMP response element binding protein, and cAMP in the hippocampus of aged rats with chronic cerebral ischemia, but a high-dose of propofol inhibited their expression. Results indicated that the protective effect of propofol against cerebral ischemia in aged rats is related to changes in the expression of brain-derived neurotrophic factor and tyrosine kinase receptor B in the hippocampus, and that the cAMP-cAMP responsive element binding protein pathway is involved in the regulatory effect of propofol on brain-derived neurotrophic factor expression.

  11. Genetically modified Schwann cells producing glial cell line-derived neurotrophic factor inhibit neuronal apoptosis in rat spinal cord injury.

    PubMed

    Liu, Guomin; Wang, Xukai; Shao, Guoxi; Liu, Qinyi

    2014-04-01

    Schwann cells (SCs) are the major cells constituting the peripheral nerve structure and function, and also secret a variety of neurotrophic factors. Schwann cell (SC) transplantation has recently emerged as a promising therapeutic strategy for spinal cord injury (SCI). In the present study, the ability of genetically modified SCs producing high levels of glial cell line‑derived neurotrophic factor (GDNF) to promote spinal cord repair was assessed. The GDNF gene was transduced into SCs. The engineered SCs were characterized by their ability to express and secrete biologically active GDNF, which was shown to inhibit apoptosis of primary rat neurons induced by radiation, and upregulate the expression of B‑cell lymphoma 2 (Bcl‑2) and downregulate the expression of Bcl‑2 associated X protein (Bax) in vitro. Following SC implantation into the spinal cord of adult rats with SCI induced by weight‑drop impact, the survival of rats with transplanted SCs, histology of the spinal cord and expression levels of Bcl‑2 and Bax were examined. Transplantation of unmodified and genetically modified SCs producing GDNF attenuated SCI by inhibiting apoptosis via the Bcl‑2/Bax pathways. The genetically modified SCs demonstrated markedly improved recovery of SCI as compared with unmodified SCs. The present study combined the outgrowth‑promoting property of SCs with the neuroprotective effects of overexpressed GDNF and identified this as a potential novel therapeutic strategy for SCI.

  12. Mechanisms of anti-inflammatory property of conserved dopamine neurotrophic factor: inhibition of JNK signaling in lipopolysaccharide-induced microglia.

    PubMed

    Zhao, Hua; Cheng, Lei; Liu, Yi; Zhang, Wen; Maharjan, Sailendra; Cui, Zhaoqiang; Wang, Xingli; Tang, Dongqi; Nie, Lin

    2014-02-01

    Microglia are important resident immune cells in the central nervous system (CNS) and involved in the neuroinflammation caused by CNS disorders, including brain trauma, ischemia, stroke, infections, inflammation, and neurodegenerative diseases. Our study explores the hypothesis that conserved dopamine neurotrophic factor (CDNF), a secretory neurotrophic factor, may provide a novel therapy for associated with neuroinflammation related to the microglia. We observed that CDNF was upregulated in rat primary microglia treated with 1 μg/mL lipopolysaccharide, an inflammatory inducer, for 24 h. Thus, we hypothesize that CDNF may play a role, mediator or inhibitor, in regulating the inflammation in microglial cells induced by LPS. Finally, our data showed that CDNF significantly attenuated the production of proinflammatory cytokines (PGE2 and IL-1β) and remarkably alleviated the cytotoxicity (percentage of lactate dehydrogenase released) in the LPS-induced microglia by suppressing the phosphorylation of JNK, but not the P38 or ERK pathways. These results demonstrate the anti-inflammatory property of CDNF by inhibition of JNK signaling in LPS-induced microglia, suggesting that CDNF may be a potential novel agent for the treatment of neuroinflammation in the CNS disorders.

  13. Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease.

    PubMed

    Maswood, Navin; Young, Jennifer; Tilmont, Edward; Zhang, Zhiming; Gash, Don M; Gerhardt, Greg A; Grondin, Richard; Roth, George S; Mattison, Julie; Lane, Mark A; Carson, Richard E; Cohen, Robert M; Mouton, Peter R; Quigley, Christopher; Mattson, Mark P; Ingram, Donald K

    2004-12-28

    We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.

  14. Endurance exercise regimens induce differential effects on brain-derived neurotrophic factor, synapsin-I and insulin-like growth factor I after focal ischemia.

    PubMed

    Ploughman, M; Granter-Button, S; Chernenko, G; Tucker, B A; Mearow, K M; Corbett, D

    2005-01-01

    The optimal amount of endurance exercise required to elevate proteins involved in neuroplasticity during stroke rehabilitation is not known. This study compared the effects of varying intensities and durations of endurance exercise using both motorized and voluntary running wheels after endothelin-I-induced focal ischemia in rats. Hippocampal levels of brain-derived neurotrophic factor, insulin-like growth factor I and synapsin-I were elevated in the ischemic hemisphere even in sedentary animals suggesting an intrinsic restorative response 2 weeks after ischemia. In the sensorimotor cortex and the hippocampus of the intact hemisphere, one episode of moderate walking exercise, but not more intense running, resulted in the greatest increases in levels of brain-derived neurotrophic factor and synapsin-I. Exercise did not increase brain-derived neurotrophic factor, insulin-like growth factor I or synapsin-I in the ischemic hemisphere. In voluntary running animals, both brain and serum insulin-like growth factor I appeared to be intensity dependent and were associated with decreasing serum levels of insulin-like growth factor I and increasing hippocampal levels of insulin-like growth factor I in the ischemic hemisphere. This supports the notion that exercise facilitates the movement of insulin-like growth factor I across the blood-brain barrier. Serum corticosterone levels were elevated by all exercise regimens and were highest in rats exposed to motorized running of greater speed or duration. The elevation of corticosterone did not seem to alter the expression of the proteins measured, however, graduated exercise protocols may be indicated early after stroke. These findings suggest that relatively modest exercise intervention can increase proteins involved in synaptic plasticity in areas of the brain that likely subserve motor relearning after stroke.

  15. Brain-derived neurotrophic factor in neuroimmunology: lessons learned from multiple sclerosis patients and experimental autoimmune encephalomyelitis models.

    PubMed

    Lühder, Fred; Gold, Ralf; Flügel, Alexander; Linker, Ralf A

    2013-04-01

    The concept of neuroprotective autoimmunity implies that immune cells, especially autoantigen-specific T cells, infiltrate the central nervous system (CNS) after injury and contribute to neuroregeneration and repair by secreting soluble factors. Amongst others, neurotrophic factors and neurotrophins such as brain-derived neurotropic factor (BDNF) are considered to play an important role in this process. New data raise the possibility that this concept could also be extended to neuroinflammatory diseases such as multiple sclerosis (MS) where autoantigen-specific T cells infiltrate the CNS, causing axonal/neuronal damage on the one hand, but also providing neuroprotective support on the other hand. In this review, we summarize the current knowledge on BDNF levels analyzed in MS patients in different compartments and its correlation with clinical parameters. Furthermore, new approaches in experimental animal models are discussed that attempt to decipher the functional relevance of BDNF in autoimmune demyelination.

  16. Basic fibroblast growth factor priming increases the responsiveness of immortalized hypothalamic luteinizing hormone releasing hormone neurones to neurotrophic factors.

    PubMed

    Gallo, F; Morale, M C; Tirolo, C; Testa, N; Farinella, Z; Avola, R; Beaudet, A; Marchetti, B

    2000-10-01

    The participation of growth factors (GFs) in the regulation of luteinizing hormone releasing hormone (LHRH) neuronal function has recently been proposed, but little is known about the role played by GFs during early LHRH neurone differentiation. In the present study, we have used combined biochemical and morphological approaches to study the ability of a number of GFs normally expressed during brain development, including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) to induce survival, differentiation, proliferation, and phenotypic expression of immortalized (GT1-1) LHRH neurones in vitro, at early (3-days in vitro, 3-DIV) and late (8-DIV) stages of neuronal differentiation. Comparison of GF-treated vs untreated neurones grown in serum-deprived (SD) medium demonstrated bFGF to be the most potent, and insulin the least active in promoting neuronal differentiation. Thus, at both 3-DIV and 8-DIV, but especially at 8-DIV, bFGF induced the greatest increase in the total length and number of LHRH processes/cell and in growth cone surface area. bFGF was also the most active at 3-DIV, and IGF-I at 8-DIV, in counteracting SD-induced cell death, whereas EGF was the most potent in increasing [3H]thymidine incorporation. All GFs studied decreased the spontaneous release of LHRH from GT1-1 cells when applied at 3-DIV or 8-DIV, except for insulin which was inactive at both time-points and bFGF which was inactive at 8-DIV. Pre-treatment of GT1-1 cells with a suboptimal ('priming') dose of bFGF for 12 h followed by application of the different GFs induced a sharp potentiation of the neurotrophic and proliferative effects of the latter and particularly of those of IGF-I. Moreover, bFGF priming counteracted EGF-induced decrease in LHRH release and significantly stimulated LHRH secretion following IGF-I or insulin application, suggesting that bFGF may sensitize LHRH neurones to differentiating effects of

  17. Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val[superscript 66]Met Polymorphism?

    ERIC Educational Resources Information Center

    Mueller, Sven C.; Aouidad, Aveline; Gorodetsky, Elena; Goldman, David; Pine, Daniel S.; Ernst, Monique

    2013-01-01

    Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val[superscript 66]Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based…

  18. New sesquiterpene from Vietnamese agarwood and its induction effect on brain-derived neurotrophic factor mRNA expression in vitro.

    PubMed

    Ueda, Jun-ya; Imamura, Lisa; Tezuka, Yasuhiro; Tran, Quan L; Tsuda, Masaaki; Kadota, Shigetoshi

    2006-05-15

    Agarwood, one of the valuable non-timber products in tropical forest, is a fragrant wood, whose ethereal fragrance has been prized in Asia for incense in ceremony, as well as sedatives in traditional medicine. We separated the 70% EtOH extract of Vietnamese agarwood, which showed significant induction effect on brain-derived neurotrophic factor (BDNF) mRNA expression in rat cultured neuronal cells, to isolate a new compound and a 2-(2-phenylethyl)chromone derivative. The new compound was determined to be a spirovetivane-type sesquiterpene, (4R,5R,7R)-1(10)-spirovetiven-11-ol-2-one, by spectroscopic data and showed induction effect of BDNF mRNA.

  19. In vitro evaluation of gene expression changes for gonadotropin-releasing hormone 1, brain-derived neurotrophic factor and neurotrophic tyrosine kinase, receptor, type 2, in response to bisphenol A treatment.

    PubMed

    Warita, Katsuhiko; Mitsuhashi, Tomoko; Ohta, Ken-ichi; Suzuki, Shingo; Hoshi, Nobuhiko; Miki, Takanori; Takeuchi, Yoshiki

    2013-03-01

    We evaluated the effects of bisphenol A (BPA) on embryonic mouse hypothalamic cells. Real-time reverse transcription polymerase chain reaction (RT-PCR) indicated that gonadotropin-releasing hormone 1 (Gnrh1) expression in 0.02-20 μM BPA-treated cells did not differ from that in control cells but decreased significantly in 200 μMBPAtreated cells. The mRNA level for brain-derived neurotrophic factor (Bdnf), which participates in GNRH1 secretory system development, decreased significantly in 200 μM BPA-treated cells, but that for neurotrophic tyrosine kinase, receptor, type 2 (Ntrk2), did not change. This indicates that Gnrh1 gene expression in mice fetuses is not affected by exposure to <20 μM BPA and that the adverse effects of BPA on the BDNF-NTRK2 neurotrophin system are induced by decrease in the mRNA level of the ligand, not of its receptor.

  20. Modulatory effects of sex steroid hormones on brain-derived neurotrophic factor-tyrosine kinase B expression during adolescent development in C57Bl/6 mice.

    PubMed

    Hill, R A; Wu, Y W C; Kwek, P; van den Buuse, M

    2012-05-01

    Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the adolescent brain and have been implicated in the pathogenesis of neurodevelopmental disorders, including mental illness. We aimed to determine the association between altered levels of sex steroid hormones during adolescent development and neurotrophic signalling in the C57Bl/6 mouse. We first performed a week by week analysis from pre-pubescence to adulthood in male and female C57Bl/6 mice, measuring serum levels of testosterone and oestradiol in conjunction with western blot analysis of neurotrophin expression in the forebrain and hippocampal regions. Second, we manipulated adolescent sex steroid hormone levels by gonadectomy and hormone replacement at the pre-pubescent age of 5 weeks. Young-adult forebrain and hippocampal neurotrophin expression was then determined. Male mice showed significant changes in brain-derived neurotrophic factor (BDNF) expression in the forebrain regions during weeks 7-10, which corresponded significantly with a surge in serum testosterone. Castration and testosterone or di-hydrotestosterone replacement experiments revealed an androgen receptor-dependent effect on BDNF-tyrosine kinase (Trk) B signalling in the forebrain and hippocampal regions during adolescence. Female mice showed changes in BDNF-TrkB signalling at a much earlier time point (weeks 4-8) in the forebrain and hippocampal regions and these did not correspond with changes in serum oestradiol. Ovariectomy actually increased BDNF expression but decreased TrkB phosphorylation in the forebrain regions. 17β-Oestradiol replacement had no effect, suggesting a role for other ovarian hormones in regulating BDNF-TrkB signalling in the adolescent female mouse brain. These results suggest the differential actions of sex steroid hormones in modulating BDNF-TrkB signalling during adolescence. These data provide insight into how the male and female brain changes in response to altered levels of

  1. Extracellular poly(ADP-ribose) is a neurotrophic signal that upregulates glial cell line-derived neurotrophic factor (GDNF) levels in vitro and in vivo.

    PubMed

    Nakajima, Hidemitsu; Itakura, Masanori; Sato, Keishi; Nakamura, Sunao; Azuma, Yasu-Taka; Takeuchi, Tadayoshi

    2017-03-04

    Synthesis of poly(ADP-ribose) (PAR) is catalyzed by PAR polymerase-1 (PARP-1) in neurons. PARP1 plays a role in various types of brain damage in neurodegenerative disorders. In neurons, overactivation of PARP-1 during oxidative stress induces robust PAR formation, which depletes nicotinamide adenine dinucleotide levels and leads to cell death. However, the role of the newly-formed PAR in neurodegenerative disorders remains elusive. We hypothesized that the effects of PAR could occur in the extracellular space after it is leaked from damaged neurons. Here we report that extracellular PAR (EC-PAR) functions as a neuroprotective molecule by inducing the synthesis of glial cell line-derived neurotrophic factor (GDNF) in astrocytes during neuronal cell death, both in vitro and in vivo. In primary rat astrocytes, exogenous treatment with EC-PAR produced GDNF but not other neurotrophic factors. The effect was concentration-dependent and did not affect cell viability in rat C6 astrocytoma cells. Topical injection of EC-PAR into rat striatum upregulated GDNF levels in activated astrocytes and improved pathogenic rotation behavior in a unilateral 6-hydroxydopamine model of Parkinson disease in rats. These findings indicate that EC-PAR acts as a neurotrophic enhancer by upregulating GDNF levels. This effect protects the remaining neurons following oxidative stress-induced brain damage, such as that seen with Parkinson disease.

  2. Resistance Training Alters the Proportion of Skeletal Muscle Fibers but Not Brain Neurotrophic Factors in Young Adult Rats

    PubMed Central

    Antonio-Santos, José; Ferreira, Diórginis José S.; Gomes Costa, Gizelle L.; Matos, Rhowena Jane B.; Toscano, Ana E.; Manhães-de-Castro, Raul

    2016-01-01

    Abstract Antonio-Santos, J, Ferreira, DJS, Gomes Costa, GL, Matos, RJB, Toscano, AE, Manhães-de-Castro, R, and Leandro, CG. Resistance training alters the proportion of skeletal muscle fibers but not brain neurotrophic factors in young adult rats. J Strength Cond Res 30(12): 3531–3538, 2016—Resistance training (RT) is related to improved muscular strength and power output. Different programs of RT for rats have been developed, but peripheral and central response has not been evaluated directly in the same animal. To test the hypothesis that RT induces central and peripheral adaptations, this study evaluated the effects of a RT on the performance of a weekly maximum overload test, fiber-type typology, and brain neurotrophic factors in young adult rats. Thirty-one male Wistar rats (65 ± 5 days) were divided in 2 groups: nontrained (NT, n = 13) and trained (T, n = 18). Trained group was submitted to a program of RT ladder climbing, gradually added mass, 5 days per week during 8 weeks at 80% of individual maximum overload. This test was weekly performed to adjust the individual load throughout the weeks for both groups. After 48 hours from the last session of exercise, soleus and extensor digital longus (EDL) muscles were removed for myofibrillar ATPase staining analysis. Spinal cord, motor cortex, and cerebellum were removed for RT-PCR analysis of BDNF and insulin-like growth factor-1 (IGF-1) gene expression. In EDL muscle, T animals showed an increase in the proportion of type IIb fibers and a reduction of type IIa fibers. Insulin-like growth factor-1 gene expression was reduced in the cerebellum of T animals (NT: 1.025 ± 0.12; T: 0.57 ± 0.11). Our data showed that 8 weeks of RT were enough to increase maximum overload capacity and the proportion of glycolytic muscle fibers, but there were no associations with the expression of growth neurotrophic factors. PMID:27870699

  3. Assessment of oxidative stress parameters of brain-derived neurotrophic factor heterozygous mice in acute stress model

    PubMed Central

    Hacioglu, Gulay; Senturk, Ayse; Ince, Imran; Alver, Ahmet

    2016-01-01

    Objective(s): Exposing to stress may be associated with increased production of reactive oxygen species (ROS). Therefore, high level of oxidative stress may eventually give rise to accumulation of oxidative damage and development of numerous neurodegenerative diseases. It has been presented that brain-derived neurotrophic factor (BDNF) supports neurons against various neurodegenerative conditions. Lately, there has been growing evidence that changes in the cerebral neurotrophic support and especially in the BDNF expression and its engagement with ROS might be important in various disorders and neurodegenerative diseases. Hence, we aimed to investigate protective effects of BDNF against stress-induced oxidative damage. Materials and Methods: Five- to six-month-old male wild-type and BDNF knock-down mice were used in this study. Activities of catalase (CAT) and superoxide dismutase (SOD) enzymes, and the amount of malondialdehyde (MDA) were assessed in the cerebral homogenates of studied groups in response to acute restraint stress. Results: Exposing to acute physiological stress led to significant elevation in the markers of oxidative stress in the cerebral cortexes of experimental groups. Conclusion: As BDNF-deficient mice were observed to be more susceptible to stress-induced oxidative damage, it can be suggested that there is a direct interplay between oxidative stress indicators and BDNF levels in the brain. PMID:27279982

  4. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis.

    PubMed

    Taliaz, D; Stall, N; Dar, D E; Zangen, A

    2010-01-01

    Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.

  5. Cross-sex hormone treatment in male-to-female transsexual persons reduces serum brain-derived neurotrophic factor (BDNF).

    PubMed

    Fuss, Johannes; Hellweg, Rainer; Van Caenegem, Eva; Briken, Peer; Stalla, Günter K; T'Sjoen, Guy; Auer, Matthias K

    2015-01-01

    Serum levels of brain-derived neurotrophic factor (BDNF) are reduced in male-to-female transsexual persons (MtF) compared to male controls. It was hypothesized before that this might reflect either an involvement of BDNF in a biomechanism of transsexualism or to be the result of persistent social stress due to the condition. Here, we demonstrate that 12 month of cross-sex hormone treatment reduces serum BDNF levels in male-to-female transsexual persons independent of anthropometric measures. Participants were acquired through the European Network for the Investigation of Gender Incongruence (ENIGI). Reduced serum BDNF in MtF thus seems to be a result of hormonal treatment rather than a consequence or risk factor of transsexualism.

  6. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin.

    PubMed

    Hidaka, Takanori; Ogawa, Eisaku; Kobayashi, Eri H; Suzuki, Takafumi; Funayama, Ryo; Nagashima, Takeshi; Fujimura, Taku; Aiba, Setsuya; Nakayama, Keiko; Okuyama, Ryuhei; Yamamoto, Masayuki

    2017-01-01

    Atopic dermatitis is increasing worldwide in correlation with air pollution. Various organic components of pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). Through the use of AhR-CA mice, whose keratinocytes express constitutively active AhR and that develop atopic-dermatitis-like phenotypes, we identified Artn as a keratinocyte-specific AhR target gene whose product (the neurotrophic factor artemin) was responsible for epidermal hyper-innervation that led to hypersensitivity to pruritus. The activation of AhR via air pollutants induced expression of artemin, alloknesis, epidermal hyper-innervation and inflammation. AhR activation and ARTN expression were positively correlated in the epidermis of patients with atopic dermatitis. Thus, AhR in keratinocytes senses environmental stimuli and elicits an atopic-dermatitis pathology. We propose a mechanism of air-pollution-induced atopic dermatitis via activation of AhR.

  7. Decrease of glial cell-derived neurotrophic factor contributes to anesthesia- and surgery-induced learning and memory dysfunction in neonatal rats.

    PubMed

    Gui, Lingli; Lei, Xi; Zuo, Zhiyi

    2017-04-01

    Long duration of anesthesia may induce toxicity in the developing brain. However, little is known about the effects of the combination of surgery and anesthesia on the developing brain. The mechanisms for the effects are not clear. To determine these effects, postnatal day 7 male and female Sprague-Dawley rats were exposed to 3% sevoflurane for 2 h with or without right common carotid exposure. Pyrrolidine dithiocarbamate (PDTC), an anti-inflammatory agent, was given 30 min before and 6 h after the carotid exposure. Anti-glial cell-derived neurotrophic factor (GDNF) antibody or GDNF was given at the end of sevoflurane exposure. We found that anesthesia-surgery induced learning and memory impairment assessed by Barnes maze and fear conditioning. Anesthesia-surgery also induced neuroinflammation and reduced the level of glial cell-derived neurotrophic factor (GDNF, 10.6 ± 0.6 pg/mg protein of control rats vs. 7.7 ± 0.4 pg/mg protein of anesthesia-surgery rats, n = 17, p = 0.007) and neurogenesis in the hippocampus. PDTC inhibited these surgical effects (GDNF level 9.7 ± 0.6 pg/mg protein of anesthesia-surgery plus PDTC rats, n = 17, p = 0.763 vs. control rats). Intracerebroventricular injection of an anti-GDNF antibody but not its heat-inactivated form induced learning and memory impairment in control rats. Intracerebroventricular injection of GDNF attenuated learning and memory impairment after anesthesia-surgery. We conclude that anesthesia-surgery in neonatal rats induces neuroinflammation, which then leads to a decreased level of GDNF and neurogenesis in the hippocampus and cognitive impairment. GDNF decrease plays an important role in anesthesia-surgery-induced cognitive impairment.

  8. Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson’s is associated with histone acetylation and up-regulation of neurotrophic factors

    PubMed Central

    Harrison, Ian F; Crum, William R; Vernon, Anthony C; Dexter, David T

    2015-01-01

    Background and Purpose Histone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD. Experimental Approach The irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague–Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects. Key Results Despite producing a distinct pattern of structural re-modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors. Conclusions and Implications The histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however

  9. Brain-derived neurotrophic factor (BDNF) and TrkB in the piglet brainstem after post-natal nicotine and intermittent hypercapnic hypoxia.

    PubMed

    Tang, Samantha; Machaalani, Rita; Waters, Karen A

    2008-09-26

    Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a significant role in the regulation of cell growth, survival and death during central nervous system development. The expression of BDNF and TrkB is affected by noxious insults. Two insults during the early post-natal period that are of interest to our laboratory are exposure to nicotine and to intermittent hypercapnic hypoxia (IHH). Piglet models were used to mimic the conditions associated with the risk factors for the sudden infant death syndrome (SIDS) including post-natal cigarette smoke exposure (nicotine model) and prone sleeping where the infant is subjected to re-breathing of expired gases (IHH model). We aimed to determine the effects of nicotine and IHH, alone or in combination, on pro- and rhBDNF and TrkB expression in the developing piglet brainstem. Four piglet groups were studied, with equal gender ratios in each: control (n=14), nicotine (n=14), IHH (n=10) and nic+IHH (n=14). Applying immunohistochemistry, and studying six nuclei of the caudal medulla, we found that compared to controls, TrkB was the only protein significantly decreased after nicotine and nic+IHH exposure regardless of gender. For pro-BDNF and rhBDNF however, observed changes were more evident in males than females exposed to nicotine and nic+IHH. The implications of these findings are that a prior nicotine exposure makes the developing brainstem susceptible to greater changes in the neurotrophic effects of BDNF and its receptor TrkB in the face of a hypoxic insult, and that the effects are greater in males than females.

  10. Reduced levels of brain derived neurotrophic factor (BDNF) in the serum of diabetic retinopathy patients and in the retina of diabetic rats.

    PubMed

    Ola, M Shamsul; Nawaz, Mohd Imtiaz; El-Asrar, Ahmed Abu; Abouammoh, Marwan; Alhomida, Abdullah S

    2013-04-01

    Diabetic retinopathy (DR) is widely recognized as a neurovascular disease. Retina, being a neuronal tissue of the eye, produces neurotrophic factors for its maintenance. However, diabetes dysregulates their levels and thereby may damage the retina. Among neurotrophins, brain derived neurotrophic factor (BDNF) is the most abundant in the retina. In this study, we investigated the level of BDNF in the serum of patients with DR and also in the serum and retina of streptozotocin-induced diabetic rats. The level of BDNF was significantly decreased in the serum of proliferative diabetic retinopathy patients as compared to that of non-diabetic healthy controls (25.5 ± 8.5-10.0 ± 8.1 ng/ml, p < 0.001) as well as compared to that of diabetic patients with no retinopathy (21.8 ± 4.7-10.0 ± 8.1 ng/ml, p < 0.001), as measured by ELISA techniques. The levels of BDNF in the serum and retina of diabetic rats were also significantly reduced compared to that of non-diabetic controls (p < 0.05). In addition, the expression level of tropomyosin-related kinase B (TrkB) was significantly decreased in diabetic rat retina compared to that of non-diabetic controls as determined by Western blotting technique. Caspase-3 activity was increased in diabetic rat retina after 3 weeks of diabetes and remained elevated until 10 weeks, which negatively correlated with the level of BDNF (r = -0.544, p = 0.013). Our results indicate that reduced levels of BDNF in diabetes may cause apoptosis and neurodegeneration early in diabetic retina, which may lead to neuro-vascular damage later in DR.

  11. Low plasma levels of brain derived neurotrophic factor are potential risk factors for diabetic retinopathy in Chinese type 2 diabetic patients.

    PubMed

    Liu, Shao-Yi; Du, Xiao-Fang; Ma, Xiang; Guo, Jian-Lian; Lu, Jian-Min; Ma, Lu-Sheng

    2016-01-15

    Previous studies suggested that neurotrophins play a role in the diabetic retinopathy (DR). We therefore evaluated the role of plasma brain derived neurotrophic factor (BDNF) levels in Chinese type 2 diabetic patients with and without diabetic retinopathy (DR). Plasma levels of BDNF were determined in type 2 diabetic patients (N=344). At baseline, the demographical and clinical data were taken. Multivariate analyses were performed using logistic regression models. Receiver operating characteristic curves (ROC) was used to test the overall predict accuracy of BDNF and other markers. Diabetic patients with DR and vision-threatening diabetic retinopathy (VTDR) had significantly lower BDNF levels on admission (P<0.0001 both). BDNF improved the area under the receiver operating characteristic curve of the diabetes duration for DR from 0.76 (95% confidence interval [CI], 0.71-0.82) to 0.89 (95% CI, 0.82-0.95; P<0.01) and for VDTR from 0.84 (95% CI, 0.78-0.92) to 0.95 (95% CI, 0.90-0.98; P<0.01). Multivariate logistic regression analysis adjusted for common risk factors showed that plasma BDNF levels≤12.4 ng/mL(1(rd) quartiles) was an independent marker of DR (OR=3.92; 95%CI: 2.31-6.56) and VTDR (OR=4.88; 95%CI: 2.21-9.30). The present study demonstrated that decreased plasma levels of BDNF were independent markers for DR and VDTR in Chinese type 2 diabetic patients, suggesting a possible role of BDNF in the pathogenesis of DR complications.

  12. Chronic sleep restriction elevates brain interleukin-1 beta and tumor necrosis factor-alpha and attenuates brain-derived neurotrophic factor expression.

    PubMed

    Zielinski, Mark R; Kim, Youngsoo; Karpova, Svetlana A; McCarley, Robert W; Strecker, Robert E; Gerashchenko, Dmitry

    2014-09-19

    Acute sleep loss increases pro-inflammatory and synaptic plasticity-related molecules in the brain, including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and brain-derived neurotrophic factor (BDNF). These molecules enhance non-rapid eye movement sleep slow wave activity (SWA), also known as electroencephalogram delta power, and modulate neurocognitive performance. Evidence suggests that chronic sleep restriction (CSR), a condition prevalent in today's society, does not elicit the enhanced SWA that is seen after acute sleep loss, although it cumulatively impairs neurocognitive functioning. Rats were continuously sleep deprived for 18h per day and allowed 6h of ad libitum sleep opportunity for 1 (SR1), 3 (SR3), or 5 (SR5) successive days (i.e., CSR). IL-1β, TNF-α, and BDNF mRNA levels were determined in the somatosensory cortex, frontal cortex, hippocampus, and basal forebrain. Largely, brain IL-1β and TNF-α expression were significantly enhanced throughout CSR. In contrast, BDNF mRNA levels were similar to baseline values in the cortex after 1 day of SR and significantly lower than baseline values in the hippocampus after 5 days of SR. In the basal forebrain, BDNF expression remained elevated throughout the 5 days of CSR, although IL-1β expression was significantly reduced. The chronic elevations of IL-1β and TNF-α and inhibition of BDNF might contribute to the reported lack of SWA responses reported after CSR. Further, the CSR-induced enhancements in brain inflammatory molecules and attenuations in hippocampal BDNF might contribute to neurocognitive and vigilance detriments that occur from CSR.

  13. Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells.

    PubMed

    Brun, Paola; Gobbo, Serena; Caputi, Valentina; Spagnol, Lisa; Schirato, Giulia; Pasqualin, Matteo; Levorato, Elia; Palù, Giorgio; Giron, Maria Cecilia; Castagliuolo, Ignazio

    2015-09-01

    those from WT-EGCs or WT-MΦ/DCs corrected the altered neuronal phenotype of TLR2(-/-) mice. Supplementation of TLR2(-/-) neuronal cultures with GDNF recapitulated the WT-SMC co-culture effect whereas the knockdown of GDNF expression in WT-SMCs using shRNA interference abolished the effect on TLR2(-/-) neurons. These data revealed that by exploiting the repertoire of TLRs to decode gut-microbial signals, intestinal SMCs elaborate a cocktail of neurotrophic factors that in turn supports neuronal phenotype. In this view, the SMCs represent an attractive target for novel therapeutic strategies.

  14. Methylphenidate regulates activity regulated cytoskeletal associated but not brain-derived neurotrophic factor gene expression in the developing rat striatum.

    PubMed

    Chase, T; Carrey, N; Soo, E; Wilkinson, M

    2007-02-09

    Methylphenidate (MPH) is a psychostimulant drug used to treat attention deficit hyperactivity disorder in children. To explore the central effects of chronic MPH, we investigated the expression of an effector immediate early gene, activity regulated cytoskeletal associated (arc), and the neurotrophin, brain-derived neurotrophic factor (bdnf) in the brain of immature and adult rats following repeated MPH. Prepubertal (postnatal day (PD) 25-38) and adult (PD 53-66) male rats were injected once daily for: a) 14 days with saline or MPH (2 or 10 mg/kg; s.c.) or b) 13 days with saline followed by a single dose of MPH (2 or 10 mg/kg; s.c.). To determine possible long-term effects of MPH, prepubertal rats were allowed a drug-free period of 4 weeks following the 14 days of treatment, and then were given a challenge dose of MPH. We demonstrated, for the first time, that an acute injection of MPH increased levels of activity-regulated cytoskeletal protein (ARC) and arc mRNA in the prepubertal rat striatum and cingulate/frontal cortex. This response was significantly attenuated by chronic MPH. The desensitization in arc expression observed in prepubertal rats persisted in the adult striatum following a later MPH challenge. In contrast to these data we observed little effect of MPH on bdnf expression. We also developed an effective, non-stressful technique to treat freely moving immature rats with oral MPH. Consistent with the results described above, we observed that oral MPH (7.5 and 10 mg/kg) also increased arc expression in the prepubertal rat striatum. However, unlike the effects of injected MPH, repeated oral MPH (7.5 mg/kg) did not alter the normal arc response. This result raises the important possibility that oral doses of MPH that reproduce clinically relevant blood levels of MPH may not down-regulate gene expression, at least in the short term (14 days). We confirmed, using mass spectrometry, that the oral doses of MPH used in our experiments yielded blood levels

  15. Diagnostic Accuracy of Brain-derived Neurotrophic Factor and Nitric Oxide in Patients with Schizophrenia: A pilot study

    PubMed Central

    Lazarević, Dušan; Ćosić, Vladan; Knežević, Marinela Z.; Djordjević, Vidosava B.; Stojanović, Ivana

    2016-01-01

    Summary Background Brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) play multiple roles in the developing and adult CNS. Since BDNF and NO metabolisms are dysregulated in schizophrenia, we measured these markers simultaneously in the blood of schizophrenics and assessed their diagnostic accuracy. Methods Thirty-eight patients with schizophrenia classified according to demographic characteristics, symptomatologyand therapy and 39 age- and gender-matched healthy controls were enrolled. BDNF was determined by the ELISA technique while the concentration of nitrite/nitrate (NO2−/NO3−) was measured by the colorimetric method. Results Serum BDNF levels were significantly lower (20.38±3.73 ng/mL, P = 1.339E-05), whilst plasma NO2−/NO3− concentrations were significantly higher (84.3 (72–121) μmol/L, P=4.357E-08) in patients with schizophrenia than in healthy controls (25.65±4.32 ng/mL; 60.9 (50–76) μmol/L, respectively). The lowest value of BDNF (18.14±3.26 ng/mL) and the highest NO2−/NO3− concentration (115.3 (80–138) μmol/L) were found in patients treated with second-generation antipsychotics (SGA). The patients diseased before the age of 24 and the patients suffering for up to one year had significantly lower serum BDNF levels than those diseased after the age of 24 and the patients who were ill longer than one year. Both BDNF and NO2−/NO3− showed good diagnostic accuracy, but BDNF had better ROC curve characteristics, especially in patients with negative symptomatology. Conclusions BDNF and nitrite/nitrate showed inverse changes in schizophrenic patients. The most pronounced changes were found in patients treated with second-generation antipsychotics. Although BDNF is not specific of schizophrenia, it may be a clinically useful biomarker for the diagnosis of patients expressing predominantly negative symptoms. PMID:28356859

  16. Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment.

    PubMed

    De Foubert, G; Carney, S L; Robinson, C S; Destexhe, E J; Tomlinson, R; Hicks, C A; Murray, T K; Gaillard, J P; Deville, C; Xhenseval, V; Thomas, C E; O'Neill, M J; Zetterström, T S C

    2004-01-01

    Recent studies indicate that brain-derived neurotrophic factor (BDNF) may be implicated in the clinical action of antidepressant drugs. Repeated (2-3 weeks) administration of antidepressant drugs increases BDNF gene expression. The onset of this response as well as concomitant effects on the corresponding BDNF protein is however, unclear. The present study investigated the effects of acute and chronic administration of the selective serotonin reuptake inhibitor, fluoxetine (10mg/kg p.o.), upon regional rat brain levels of BDNF mRNA and protein expression. To improve the clinical significance of the study, fluoxetine was administered orally and mRNA and protein levels were determined ex vivo using the techniques of in situ hybridisation histochemistry and immunocytochemistry respectively. Direct measurement of BDNF protein was also carried out using enzyme-linked immunosorbent assay (ELISA). Four days of once daily oral administration of fluoxetine induced decreases in BDNF mRNA (hippocampus, medial habenular and paraventricular thalamic nuclei). Whilst 7 days of treatment showed a non-significant increase in BDNF mRNA, there were marked and region-specific increases following 14 days of treatment. BDNF protein levels remained unaltered until 21 days of fluoxetine treatment, when the numbers of BDNF immunoreactive cells were increased, reaching significance in the pyramidal cell layer of CA1 and CA3 regions of Ammon's horn (CA1 and CA3) but not in the other sub-regions of the hippocampus. Indicative of the highly regional change within the hippocampus, the ELISA method failed to demonstrate significant up-regulation at 21 days, measuring levels of BDNF protein in the whole hippocampus. In contrast to the detected time dependent and biphasic response of the BDNF gene, activity-regulated, cytoskeletal-associated protein (Arc) mRNA showed a gradual increase during the 14-day course of treatment. The results presented here show that BDNF is expressed differentially

  17. Intraspinal Rewiring of the Corticospinal Tract Requires Target-Derived Brain-Derived Neurotrophic Factor and Compensates Lost Function after Brain Injury

    ERIC Educational Resources Information Center

    Ueno, Masaki; Hayano, Yasufumi; Nakagawa, Hiroshi; Yamashita, Toshihide

    2012-01-01

    Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery…

  18. Neuroprotective effects of extremely low-frequency electromagnetic fields on a Huntington's disease rat model: effects on neurotrophic factors and neuronal density.

    PubMed

    Tasset, I; Medina, F J; Jimena, I; Agüera, E; Gascón, F; Feijóo, M; Sánchez-López, F; Luque, E; Peña, J; Drucker-Colín, R; Túnez, I

    2012-05-03

    There is evidence to suggest that the neuroprotective effect of exposure of extremely low-frequency electromagnetic fields (ELF-EMF) may be due, at least in part, to the effect of these fields on neurotrophic factors levels and cell survival, leading to an improvement in behavior. This study was undertaken to investigate the neuroprotective effects of ELFEF in a rat model of 3-nitropropionic acid (3NP)-induced Huntington's disease. Behavior patterns were evaluated, and changes in neurotrophic factor, cell damage, and oxidative stress biomarker levels were monitored in Wistar rats. Rats were given 3NP over four consecutive days (20 mg/kg body weight), whereas ELFEF (60 Hz and 0.7 mT) was applied over 21 days, starting after the last injection of 3NP. Rats treated with 3NP exhibited significantly different behavior in the open field test (OFT) and the forced swim test (FST), and displayed significant differences in neurotrophic factor levels and oxidative stress biomarkers levels, together with a neuronal damage and diminished neuronal density, with respect neuronal controls. ELFEF improved neurological scores, enhanced neurotrophic factor levels, and reduced both oxidative damage and neuronal loss in 3NP-treated rats. ELFEF alleviates 3NP-induced brain injury and prevents loss of neurons in rat striatum, thus showing considerable potential as a therapeutic tool.

  19. Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles

    NASA Astrophysics Data System (ADS)

    Baseri, Babak; Choi, James J.; Deffieux, Thomas; Samiotaki, Gesthimani; Tung, Yao-Sheng; Olumolade, Oluyemi; Small, Scott A.; Morrison, Barclay, III; Konofagou, Elisa E.

    2012-04-01

    The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.

  20. Enhanced brain-derived neurotrophic factor delivery by ultrasound and microbubbles promotes white matter repair after stroke.

    PubMed

    Rodríguez-Frutos, Berta; Otero-Ortega, Laura; Ramos-Cejudo, Jaime; Martínez-Sánchez, Patricia; Barahona-Sanz, Inés; Navarro-Hernanz, Teresa; Gómez-de Frutos, María Del Carmen; Díez-Tejedor, Exuperio; Gutiérrez-Fernández, María

    2016-09-01

    Ultrasound-targeted microbubble destruction (UTMD) has been shown to be a promising tool to deliver proteins to select body areas. This study aimed to analyze whether UTMD was able to deliver brain-derived neurotrophic factor (BDNF) to the brain, enhancing functional recovery and white matter repair, in an animal model of subcortical stroke induced by endothelin (ET)-1. UTMD was used to deliver BDNF to the brain 24 h after stroke. This technique was shown to be safe, given there were no cases of hemorrhagic transformation or blood brain barrier (BBB) leakage. UTMD treatment was associated with increased brain BDNF levels at 4 h after administration. Targeted ultrasound delivery of BDNF improved functional recovery associated with fiber tract connectivity restoration, increasing oligodendrocyte markers and remyelination compared to BDNF alone administration in an experimental animal model of white matter injury.

  1. Brain-derived neurotrophic factor inhibits calcium channel activation, exocytosis, and endocytosis at a central nerve terminal.

    PubMed

    Baydyuk, Maryna; Wu, Xin-Sheng; He, Liming; Wu, Ling-Gang

    2015-03-18

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic function and plasticity and plays important roles in neuronal development, survival, and brain disorders. Despite such diverse and important roles, how BDNF, or more generally speaking, neurotrophins affect synapses, particularly nerve terminals, remains unclear. By measuring calcium currents and membrane capacitance during depolarization at a large mammalian central nerve terminal, the rat calyx of Held, we report for the first time that BDNF slows down calcium channel activation, including P/Q-type channels, and inhibits exocytosis induced by brief depolarization or single action potentials, inhibits slow and rapid endocytosis, and inhibits vesicle mobilization to the readily releasable pool. These presynaptic mechanisms may contribute to the important roles of BDNF in regulating synapses and neuronal circuits and suggest that regulation of presynaptic calcium channels, exocytosis, and endocytosis are potential mechanisms by which neurotrophins achieve diverse neuronal functions.

  2. Positive association between the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder in the Han Chinese population.

    PubMed

    Xu, Jie; Liu, Yun; Wang, Peng; Li, Sheng; Wang, Yabing; Li, Jun; Zhou, Daizhan; Chen, Zhuo; Zhao, Teng; Wang, Ting; Xu, He; Yang, Yifeng; Feng, Guoyin; He, Lin; Yu, Lan

    2010-01-05

    Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and services many biological functions such as neural survival, differentiation, and plasticity. Previous studies have suggested that the Val66Met (also known as rs6265 or G196A) variant of BDNF is associated with bipolar disorder (BPD), but the results have been inconclusive. We therefore genotyped the Val66Met polymorphism in a Han Chinese population sample (498 cases and 501 control subjects). We found that the BDNF genotype is associated with BPD in this population (chi(2) = 9.4666, df = 2, P = 0.00884). Furthermore, our data suggested that the Met allele rather than the Val allele increased the risk for BPD in our Han population (OR = 1.44; 95% CI = 1.070-1.950; P = 0.016). Further studies are necessary to elucidate the involvement of the BDNF gene in the pathophysiology of BPD.

  3. No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis.

    PubMed

    Blanco, Y; Gómez-Choco, M; Arostegui, J L; Casanova, B; Martínez-Rodríguez, J E; Boscá, I; Munteis, E; Yagüe, J; Graus, F; Saiz, A

    2006-04-03

    Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).

  4. Infusion of brain-derived neurotrophic factor into the ventral tegmental area switches the substrates mediating ethanol motivation.

    PubMed

    Ting-A-Kee, Ryan; Vargas-Perez, Hector; Bufalino, Mary-Rose; Bahi, Amine; Dreyer, Jean-Luc; Tyndale, Rachel F; van der Kooy, Derek

    2013-03-01

    Recent work has shown that infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) promotes a switch in the mechanisms mediating morphine motivation, from a dopamine-independent to a dopamine-dependent pathway. Here we showed that a single infusion of intra-VTA BDNF also promoted a switch in the mechanisms mediating ethanol motivation, from a dopamine-dependent to a dopamine-independent pathway (exactly opposite to that seen with morphine). We suggest that intra-VTA BDNF, via its actions on TrkB receptors, precipitates a switch similar to that which occurs naturally when mice transit from a drug-naive, non-deprived state to a drug-deprived state. The opposite switching of the mechanisms underlying morphine and ethanol motivation by BDNF in previously non-deprived animals is consistent with their proposed actions on VTA GABAA receptors.

  5. Reg-2, A Downstream Signaling Protein in the Ciliary Neurotrophic Factor Survival Pathway, Alleviates Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Jiang, Hong; Tian, Ke-Wei; Zhang, Fan; Wang, Beibei; Han, Shu

    2016-01-01

    Ciliary neurotrophic factor (CNTF), originally described as a neurocytokine that could support the survival of neurons, has been recently found to alleviate demyelination, prevent axon loss, and improve functional recovery in a rat model of acute experimental autoimmune encephalomyelitis (EAE). However, poor penetration into the brain parenchyma and unfavorable side effects limit the utility of CNTF. Here, we evaluated the therapeutic potential of a protein downstream of CNTF, regeneration gene protein 2 (Reg-2). Using multiple morphological, molecular biology, and electrophysiological methods to assess neuroinflammation, axonal loss, demyelination, and functional impairment, we observed that Reg-2 and CNTF exert similar effects in the acute phase of EAE. Both treatments attenuated axonal loss and demyelination, improved neuronal survival, and produced functional improvement. With a smaller molecular weight and improved penetration into the brain parenchyma, Reg-2 may be a useful substitute for CNTF therapy in EAE and multiple sclerosis (MS). PMID:27242448

  6. Clinical correlates of plasma brain-derived neurotrophic factor in post-traumatic stress disorder spectrum after a natural disaster.

    PubMed

    Stratta, Paolo; Sanità, Patrizia; Bonanni, Roberto L; de Cataldo, Stefano; Angelucci, Adriano; Rossi, Rodolfo; Origlia, Nicola; Domenici, Luciano; Carmassi, Claudia; Piccinni, Armando; Dell'Osso, Liliana; Rossi, Alessandro

    2016-10-30

    Clinical correlates of plasma Brain-Derived Neurotrophic Factor (BDNF) have been investigated in a clinical population with Post Traumatic Stress Disorder (PTSD) symptoms and healthy control subjects who survived to the L'Aquila 2009 earthquake. Twenty-six outpatients and 14 control subjects were recruited. Assessments included: Structured Clinical Interview for DSM-IV Axis-I disorders Patient Version, Trauma and Loss Spectrum-Self Report (TALS-SR) for post-traumatic spectrum symptoms. Thirteen patients were diagnosed as Full PTSD and 13 as Partial PTSD. The subjects with full-blown PTSD showed lower BDNF level than subjects with partial PTSD and controls. Different relationship patterns of BDNF with post-traumatic stress spectrum symptoms have been reported in the three samples. Our findings add more insight on the mechanisms regulating BDNF levels in response to stress and further proofs of the utility of the distinction of PTSD into full and partial categories.

  7. The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans: A review.

    PubMed

    Huang, T; Larsen, K T; Ried-Larsen, M; Møller, N C; Andersen, L B

    2014-02-01

    The purpose of this study was to summarize the effects of physical activity and exercise on peripheral brain-derived neurotrophic factor (BDNF) in healthy humans. Experimental and observational studies were identified from PubMed, Web of Knowledge, Scopus, and SPORT Discus. A total of 32 articles met the inclusion criteria. Evidence from experimental studies suggested that peripheral BDNF concentrations were elevated by acute and chronic aerobic exercise. The majority of the studies suggested that strength training had no influence on peripheral BDNF. The results from most observational studies suggested an inverse relationship between the peripheral BDNF level and habitual physical activity or cardiorespiratory fitness. More research is needed to confirm the findings from the observational studies.

  8. New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases

    PubMed Central

    Adachi, Naoki; Numakawa, Tadahiro; Richards, Misty; Nakajima, Shingo; Kunugi, Hiroshi

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer’s disease, Huntington’s disease, depression and schizophrenia. PMID:25426265

  9. [EVALUATED SERUM LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTOR IN MEN AND WOMEN WITH CHRONIC BRAIN ISCHEMIA].

    PubMed

    Abramenko, Iu V; Sliusar', T A; Iakovlev, N A

    2015-01-01

    We measured serum levels of brain-derived neurotrophic factor (BDNF) in 25 elderly women in 23 men-patients with chronic brain ischemia (CBI), and in 26 gender and age matched healthy controls. The serum levels of BDNF were significantly lower in patients with CBI as compared to healthy controls. The serum levels of BDNF were also lower in men with CBI (7815,14 x 10 ng/ml) in comparison to women-patients (8466,05 x 10 ng/ml). The average serum levels of BDNF in patients with CBI proved to be significantly correlated with kinesthetic praxis disorders (p < 0.05), degree of cognitive impairment (p < 0.01), depression level (p < 0.01), especially in men. The obtained data may be important for individualization of therapeutic intervention.

  10. Brain-derived neurotrophic factor inhibits neuromuscular junction maturation in a cAMP-PKA-dependent way.

    PubMed

    Song, Wei; Jin, Xiwan Albert

    2015-03-30

    The development of neuromuscular junction (NMJ) is initiated by motor axon's contact with the skeletal muscle cell that is followed by synaptic maturation. Previous studies showed that brain-derived neurotrophic factor (BDNF) enhanced motoneurons' survival and growth but significantly inhibited synaptogenesis. Here, we report that chronic application of BDNF resulted in inhibition in the maturation process both physiologically and morphologically. The response to BDNF was mediated by its cognate receptor TrkB as the effects were abolished by Trk receptor inhibitor K252a. Protein kinase A (PKA) inhibitor reversed the effects of BDNF in inhibiting NMJ maturation. These results indicate that BDNF suppresses NMJ maturation through cAMP-PKA signaling pathway. Together with the previous studies, these results suggest that BDNF suppresses NMJ formation and maturation despite its effects in enhancing neuronal survival and growth.

  11. GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor.

    PubMed

    Marty, S; Berninger, B; Carroll, P; Thoenen, H

    1996-03-01

    Gamma-Aminobutyric acid (GABA) switches from enhancing to repressing brain-derived neurotrophic factor (BDNF) mRNA synthesis during the maturation of hippocampal neurons in vitro. Interneurons do not produce BDNF themselves, but BDNF enhances their differentiation. Therefore, the question arose whether hippocampal interneurons regulate their phenotype by regulating BDNF expression and release from adjacent cells. The GABA(A) receptor agonist muscimol and BDNF increased the size and neuropeptide Y (NPY) immunoreactivity of hippocampal interneurons. However, GABAergic stimulation failed to increase NPY immunoreactivity in cultures from BDNF knockout embryos. At later developmental stages, when GABA represses BDNF synthesis, treatment with muscimol induced a decrease in cell size and NPY immunoreactivity of interneurons. Interneurons might thus control their phenotype through the regulation of BDNF synthesis in, and release from, their target neurons.

  12. Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis.

    PubMed Central

    Vega, Q C; Worby, C A; Lechner, M S; Dixon, J E; Dressler, G R

    1996-01-01

    The receptor tyrosine kinase RET functions during the development of the kidney and the enteric nervous system, yet no ligand has been identified to date. This report demonstrates that the glial cell line-derived neurotrophic factor (GDNF) activates RET, as measured by tyrosine phosphorylation of the intracellular catalytic domain. GDNF also binds RET with a dissociation constant of 8 nM, and 125I-labeled GDNF can be coimmunoprecipitated with anti-RET antibodies. In addition, exogenous GDNF stimulates both branching and proliferation of embryonic kidneys in organ culture, whereas neutralizing antibodies against GDNF inhibit branching morphogenesis. These data indicate that RET and GDNF are components of a common signaling pathway and point to a role for GDNF in kidney development. Images Fig. 1 Fig. 2 Fig. 3 PMID:8855235

  13. The exposure to nicotine affects expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in neonate rats.

    PubMed

    Xiaoyu, Wang

    2015-02-01

    In the current study effect of nicotine on expression of neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) has been studied in hippocampus and frontal cortex during development of brain in rats. Neurotrophins are factors that help in development of brain among which BDNF and NGF are very important, expressed at different stages during the developmental process. Different sedatives are reported to alter the expression of these factors. In this study, three groups of neonate rats (1-5, 5-10 and 10-15 days age) were used each having 20 rats. Ten were subjected to a dose of 66 μg of nicotine while other ten received the same amount of saline at the same time interval. Then expression of the BDNF and NGF was observed in hippocampus and frontal cortex tissue using immunoassay. Western blotting was used to observe the presence of BDNF in hippocampus as well as frontal cortex. In all groups there was a significant decrease in concentration of neurotrophic factors where nicotine was applied as compared to control. The highest expression of BDNF and NGF in hippocampus and frontal cortex was observed in 10-15 days group (G3) and in 5-10 group (G2) as compared to the control, P < 0.01. It was concluded that exposure of neonate rats to nicotine causes a decrease in the expression of NGF and BDNF and it effects the development of brain in neonates that can further impair brain functions.

  14. Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits.

    PubMed

    Blaha, G R; Raghupathi, R; Saatman, K E; McIntosh, T K

    2000-01-01

    Brain-derived neurotrophic factor has been shown to be neuroprotective in models of excitotoxicity, axotomy and cerebral ischemia. The present study evaluated the therapeutic potential of brain-derived neurotrophic factor following traumatic brain injury in the rat. Male Sprague-Dawley rats (N=99) were anesthetized and subjected to lateral fluid percussion brain injury of moderate severity (2.4-2.8 atm) or sham injury. Four hours after injury, the animals were reanesthetized, an indwelling, intraparenchymal cannula was implanted, and infusion of brain-derived neurotrophic factor or phosphate-buffered saline vehicle was initiated from a mini-osmotic pump and continued for two weeks. In Study 1 (N=48), vehicle or 12 microg/day of brain-derived neurotrophic factor was infused into the dorsal hippocampus. In Study 2 (N=51), vehicle or brain-derived neurotrophic factor at a high (12 microg/day) or low dose (1.2 microg/day) was infused into the injured parietal cortex. All animals were evaluated for neurological motor function at two days, one week and two weeks post-injury. Cognitive function (learning and memory) was assessed at two weeks post-injury using a Morris Water Maze. At two weeks post-injury, neuronal loss in the hippocampal CA3 and dentate hilus and in the injured cortex was evaluated. In Study 2, neuronal loss was also quantified in the thalamic medial geniculate nucleus. All of the above outcome measures demonstrated significant deleterious effects of brain injury (P<0.05 compared to sham). However, post-traumatic brain-derived neurotrophic factor infusion did not significantly affect neuromotor function, learning, memory or neuronal loss in the hippocampus, cortex or thalamus when compared to vehicle infusion in brain-injured animals, regardless of the infusion site or infusion dose (P>0.05 for each). In contrast to previous studies of axotomy, ischemia and excitotoxicity, our data indicate that brain-derived neurotrophic factor is not protective against

  15. Localization and expression of ciliary neurotrophic factor (CNTF) in postmortem sciatic nerve from patients with motor neuron disease and diabetic neuropathy

    SciTech Connect

    Lee, D.A.; Gross, L.; Wittrock, D.A.; Windebank, A.J.

    1996-08-01

    Ciliary neurotrophic factor (CNTF) is thought to play an important role in the maintenance of the mature motor system. The factor is found most abundantly in myelinating Schwann cells in the adult sciatic nerve. Lack of neuronal growth factors has been proposed as one possible etiology of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Growth factor replacement therapies are currently being evaluated as a treatment for motor neuron disease. In this report we determined whether the expression of CNTF in sciatic nerve differed in patients with motor neuron disease compared to controls or patients with another form of axonopathy. We identified 8 patients (7 with ALS and 1 with SMA) with motor neuron disease and 6 patients with diabetic motor neuropathy who had autopsy material available. Immunoperoxidase staining showed reduced CNTF expression in nerves of patients with motor neuron disease but not in patients with diabetic motor neuropathy. Decreased CNTF appears be associated with primary motor neuron disease rather than a generalized process of axon loss. This result supports suggestions that CNTF deficiency may be an important factor in the development of motor neuron disease. 20 refs., 4 figs., 1 tab.

  16. Brain-derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast-spiking GABAergic interneurons.

    PubMed

    Berghuis, Paul; Dobszay, Marton B; Sousa, Kyle M; Schulte, Gunnar; Mager, Peter P; Härtig, Wolfgang; Görcs, Tamás J; Zilberter, Yuri; Ernfors, Patrik; Harkany, Tibor

    2004-09-01

    GABAergic interneurons with high-frequency firing, fast-spiking (FS) cells, form synapses on perisomatic regions of principal cells in the neocortex and hippocampus to control the excitability of cortical networks. Brain-derived neurotrophic factor (BDNF) is essential for the differentiation of multiple interneuron subtypes and the formation of their synaptic contacts. Here, we examined whether BDNF, alone or in conjunction with sustained KCl-induced depolarization, drives functional FS cell differentiation and the formation of inhibitory microcircuits. Homogeneous FS cell cultures were established by target-specific isolation using the voltage-gated potassium channel 3.1b subunit as the selection marker. Isolated FS cells expressed parvalbumin, were surrounded by perineuronal nets, formed immature inhibitory connections and generated slow action potentials at 12 days in vitro. Brain-derived neurotrophic factor (BDNF) promoted FS cell differentiation by increasing the somatic diameter, dendritic branching and the frequency of action potential firing. In addition, BDNF treatment led to a significant up-regulation of synaptophysin and vesicular GABA transporter expression, components of the synaptic machinery critical for GABA release, which was paralleled by an increase in synaptic strength. Long-term membrane depolarization alone was detrimental to dendritic branching. However, we observed that BDNF and KCl exerted additive effects, as reflected by the significantly accelerated maturation of synaptic contacts and high discharge frequencies, and was required for the formation of reciprocal connections between FS cells. Our results show that BDNF, along with membrane depolarization, is critical for FS cells to establish inhibitory circuitries during corticogenesis.

  17. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

    PubMed

    Qian, Qi; Liu, Qiuji; Zhou, Dongming; Pan, Hongyu; Liu, Zhiwei; He, Fangping; Ji, Suying; Wang, Dongpi; Bao, Wangxiao; Liu, Xinyi; Liu, Zhaoling; Zhang, Heng; Zhang, Xiaoqin; Zhang, Ling; Wang, Mingkai; Xu, Ying; Huang, Fude; Luo, Benyan; Sun, Binggui

    2017-02-13

    Efr3 is a newly identified plasma membrane protein and plays an important role in the phosphoinositide metabolism on the plasma membrane. However, although it is highly expressed in the brain, the functional significance of Efr3 in the brain is not clear. In the present study, we generated Efr3a(f/f) mice and then crossed them with Nestin-Cre mice to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. We found that brain-specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Moreover, the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway was significantly enhanced in the hippocampus of Efr3a-deficient mice, as reflected by increased expression of BDNF, TrkB, and the downstream molecules, including phospho-MAPK and phospho-Akt. Furthermore, the number of TUNEL(+) cells was decreased in the subgranular zone of dentate gyrus in Efr3a-deficient mice compared with that of control mice. Our data suggest that brain-specific deletion of Efr3a could promote adult hippocampal neurogenesis, presumably by upregulating the expression of BDNF and its receptor, TrkB, and therefore provide new insight into the roles of Efr3 in the brain.-Qian, Q., Liu, Q., Zhou, D., Pan, H., Liu, Z., He, F., Ji, S., Wang, D., Bao, W., Liu, X., Liu, Z., Zhang, H., Zhang, X., Zhang, L., Wang, M., Xu, Y., Huang, F., Luo, B., Sun B. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

  18. Design of a Conformationally Defined and Proteolytically Stable Circular Mimetic of Brain-derived Neurotrophic Factor*S⃞

    PubMed Central

    Fletcher, Jordan M.; Morton, Craig J.; Zwar, Richard A.; Murray, Simon S.; O'Leary, Paul D.; Hughes, Richard A.

    2008-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of neurotrophic factors. BDNF has long been recognized to have potential for the treatment of a variety of human neurodegenerative diseases. However, clinical trials with recombinant BDNF have yet to yield success, leading to the suggestion that alternative means of harnessing BDNF actions for therapeutic use may be required. Here we describe an approach to create low molecular weight peptides that, like BDNF, promote neuronal survival. The peptides were designed to mimic a cationic tripeptide sequence in loop 4 of BDNF shown in previous studies to contribute to the binding of BDNF to the common neurotrophin receptor p75NTR. The best of these peptides, the cyclic pentapeptide 2 (cyclo(-d-Pro-Ala-Lys-Arg-)), despite being of low molecular weight (Mr 580), was found to be an effective promoter of the survival of embryonic chick dorsal root ganglion sensory neurons in vitro (maximal survival, 68 ± 3% of neurons supported by BDNF). Pentapeptide 2 did not affect the phosphorylation of either TrkB (the receptor tyrosine kinase for BDNF) or the downstream signaling molecule MAPK, indicating that its mechanism of neuronal survival action is independent of TrkB. NMR studies reveal that pentapeptide 2 adopts a well defined backbone conformation in solution. Furthermore, pentapeptide 2 was found to be effectively resistant to proteolysis when incubated in a solution of rat plasma in vitro. These properties of pentapeptide 2 (low molecular weight, appropriate pharmacological actions, a well defined solution conformation, and proteolytic stability) render it worthy of further investigation, either as a template for the further design of neuronal survival promoting agents or as a lead compound with therapeutic potential in its own right. PMID:18809686

  19. Microglia-Mediated Neuroinflammation and Neurotrophic Factor-Induced Protection in the MPTP Mouse Model of Parkinson’s Disease-Lessons from Transgenic Mice

    PubMed Central

    Machado, Venissa; Zöller, Tanja; Attaai, Abdelraheim; Spittau, Björn

    2016-01-01

    Parkinson’s disease (PD) is a neurodegenerative disease characterised by histopathological and biochemical manifestations such as loss of midbrain dopaminergic (DA) neurons and decrease in dopamine levels accompanied by a concomitant neuroinflammatory response in the affected brain regions. Over the past decades, the use of toxin-based animal models has been crucial to elucidate disease pathophysiology, and to develop therapeutic approaches aimed to alleviate its motor symptoms. Analyses of transgenic mice deficient for cytokines, chemokine as well as neurotrophic factors and their respective receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have broadened the current knowledge of neuroinflammation and neurotrophic support. Here, we provide a comprehensive review that summarises the contribution of microglia-mediated neuroinflammation in MPTP-induced neurodegeneration. Moreover, we highlight the contribution of neurotrophic factors as endogenous and/or exogenous molecules to slow the progression of midbrain dopaminergic (mDA) neurons and further discuss the potential of combined therapeutic approaches employing neuroinflammation modifying agents and neurotrophic factors. PMID:26821015

  20. Conserved Dopamine Neurotrophic Factor-Transduced Mesenchymal Stem Cells Promote Axon Regeneration and Functional Recovery of Injured Sciatic Nerve

    PubMed Central

    Liu, Yi; Nie, Lin; Zhao, Hua; Zhang, Wen; Zhang, Yuan-Qiang; Wang, Shuai-Shuai; Cheng, Lei

    2014-01-01

    Peripheral nerve injury (PNI) is a common disease that often results in axonal degeneration and the loss of neurons, ultimately leading to limited nerve regeneration and severe functional impairment. Currently, there are no effective treatments for PNI. In the present study, we transduced conserved dopamine neurotrophic factor (CDNF) into mesenchymal stem cells (MSCs) in collagen tubes to investigate their regenerative effects on rat peripheral nerves in an in vivo transection model. Scanning electron microscopy of the collagen tubes demonstrated their ability to be resorbed in vivo. We observed notable overexpression of the CDNF protein in the distal sciatic nerve after application of CDNF-MSCs. Quantitative analysis of neurofilament 200 (NF200) and S100 immunohistochemistry showed significant enhancement of axonal and Schwann cell regeneration in the group receiving CDNF-MSCs (CDNF-MSCs group) compared with the control groups. Myelination thickness, axon diameter and the axon-to fiber diameter ratio (G-ratio) were significantly higher in the CDNF-MSCs group at 8 and 12 weeks after nerve transection surgery. After surgery, the sciatic functional index, target muscle weight, wet weight ratio of gastrocnemius muscle and horseradish peroxidase (HRP) tracing demonstrated functional recovery. Light and electron microscopy confirmed successful regeneration of the sciatic nerve. The greater numbers of HRP-labeled neuron cell bodies and increased sciatic nerve index values (SFI) in the CDNF-MSCs group suggest that CDNF exerts neuroprotective effects in vivo. We also observed higher target muscle weights and a significant improvement in muscle atrophism in the CDNF-MSCs group. Collectively, these findings indicate that CDNF gene therapy delivered by MSCs is capable of promoting nerve regeneration and functional recovery, likely because of the significant neuroprotective and neurotrophic effects of CDNF and the superior environment offered by MSCs and collagen tubes. PMID

  1. Resveratrol induces the expression of interleukin-10 and brain-derived neurotrophic factor in BV2 microglia under hypoxia.

    PubMed

    Song, Juhyun; Cheon, So Yeong; Jung, Wonsug; Lee, Won Taek; Lee, Jong Eun

    2014-09-02

    Microglia are the resident macrophages of the central nervous system (CNS) and play an important role in neuronal recovery by scavenging damaged neurons. However, overactivation of microglia leads to neuronal death that is associated with CNS disorders. Therefore, regulation of microglial activation has been suggested to be an important target for treatment of CNS diseases. In the present study, we investigated the beneficial effect of resveratrol, a natural phenol with antioxidant effects, in the microglial cell line, BV2, in a model of hypoxia injury. Resveratrol suppressed the mRNA expression of the pro-inflammatory molecule, tumor necrosis factor-α, and promoted the mRNA expression of the anti-inflammatory molecule, interleukin-10, in BV2 microglia under hypoxic conditions. In addition, resveratrol inhibited the activation of the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), which is upstream in the control of inflammatory reactions in hypoxia-injured BV2 microglia. Moreover, resveratrol promoted the expression of brain-derived neurotrophic factor (BDNF) in BV2 microglia under hypoxic stress. Overall, resveratrol may promote the beneficial function of microglia in ischemic brain injury.

  2. Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: tropomyosin-related kinase B in hippocampus ofobesity-induced hypertensive rats.

    PubMed

    Kishi, Takuya; Hirooka, Yoshitaka; Nagayama, Tomomi; Isegawa, Kengo; Katsuki, Masato; Takesue, Ko; Sunagawa, Kenji

    2015-01-01

    In metabolic syndrome (MetS), previous studies have suggested that cognitive decline is worsened. Among the factors associated with cognition, decreased brain-derived neurotrophic factor (BDNF) in the hippocampus causes cognitive decline. We previously reported that exercise training with calorie restriction yielded protection against cognitive decline via BDNF in the hippocampus of hypertensive rats. The aim of the present study was to determine whether or not calorie restriction results in protection against cognitive decline via BDNF and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of MetS model rats. We divided dietary-induced obesity-prone and hypertensive rats (OP), as metabolic syndrome model rats, into three groups, fed with a high fat diet (HF), treated with calorie restriction (CR) plus vehicle, and treated with CR and ANA-12 (a TrkB antagonist) (CR+A). After treatment for 28 days, body weight, insulin, fasting blood glucose, adiponectin, systolic blood pressure, and oxidative stress in the hippocampus were significantly lower, and BDNF expression in the hippocampus was significantly higher in CR and CR+A than in HF. Cognitive performance determined by the Morris water maze test was significantly higher in CR than in HF, whereas the benefit was attenuated in CR+A. In conclusion, calorie restriction protects against cognitive decline via up-regulation of BDNF/TrkB through an antioxidant effect in the hippocampus of dietary-induced obesity rats.

  3. Theophylline Regulates Inflammatory and Neurotrophic factor Signals in Functional Recovery after C2-Hemisection in Adult Rats

    PubMed Central

    Singh, LP; Devi, TS; Nantwi, KD

    2012-01-01

    Recovery of respiratory activity in an upper cervical hemisection model (C2H) of spinal cord injury (SCI) can be induced by systemic theophylline administration 24–48 h after injury. The objectives in the present study are (1) to identify pro-inflammatory and neurotrophic factors expressed after C2H and (2) molecular signals involved in functional recovery. Four groups of adult female rats classified as (i) sham (SH) controls, (ii) subjected to a left C2 hemisection (C2H) only, (iii) C2H rats administered theophylline for 3 consecutive days 2 days after C2H (C2H-T Day 5) and (iv) C2H rats treated with theophylline for 3 consecutive days 2 days after C2H and then weaned for 12 days (C2H-T Day 17) prior to assessment of respiratory function and molecular analysis were employed. Corresponding Sham controls, C2H untreated (vehicle only controls) and C2H treated (theophylline) rats were sacrificed, C3-C6 spinal cord segments quickly dissected and left (ipsilateral) hemi spinal cord and right (contralateral) hemi spinal cord were separately harvested 2 days post surgery. SHAM operated and C2H untreated-controls corresponding to C2H-T Day 5 and C2H-T Day 17 rats, respectively, were prepared similarly. Messenger RNA levels for pro-inflammatory genes (TXNIP, IL-1β, TNF-α and iNOS) and neurotrophic and survival factors (BDNF, GDNF, and Bcl2) were analyzed by real time quantitative PCR. Gene expression pattern was unaltered in SH rats. TXNIP, iNOS, BDNF, GDNF and Bcl2 mRNA levels were significantly increased in the ipsilateral hemi spinal cord in C2H rats. BDNF, GDNF and Bcl2 levels remained elevated in the ipsilateral hemi spinal cord in C2H-T Day 5 rats. In this same group, there was further enhancement in TXNIP and IL-1β while iNOS returned to basal levels. Theophylline increased DNA binding activity of transcription factors - cyclic AMP responsive element (CRE) binding protein (CREB) and pro-inflammatory NF-κB. Messenger RNA levels for all genes returned to basal

  4. A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor.

    PubMed

    Wu, A; Molteni, R; Ying, Z; Gomez-Pinilla, F

    2003-01-01

    We have conducted studies to determine the potential of dietary factors to affect the capacity of the brain to compensate for insult. Rats were fed with a high-fat sucrose (HFS) diet, a popularly consumed diet in industrialized western societies, for 4 weeks before a mild fluid percussion injury (FPI) or sham surgery was performed. FPI impaired spatial learning capacity in the Morris water maze, and these effects were aggravated by previous exposure of the rats to the action of the HFS diet. Learning performance decreased according to levels of brain-derived neurotrophic factor (BDNF) in individual rats, such that rats with the worst learning efficacy showed the lowest levels of BDNF in the hippocampus. BDNF immunohistochemistry localized the decreases in BDNF to the CA3 and dentate gyrus of the hippocampal formation. BDNF has a strong effect on synaptic plasticity via the action of synapsin I and cAMP-response element-binding protein (CREB), therefore, we assessed changes in synapsin I and CREB in conjunction with BDNF. Levels of synapsin I and CREB decreased in relation to decreases in BDNF levels. The combination of FPI and the HFS diet had more dramatic effects on the active state (phosphorylated) of synapsin I and CREB. There were no signs of neurodegeneration in the hippocampus of any rat group assessed with Fluoro-Jade B staining. The results suggest that FPI and diet impose a risk factor to the molecular machinery in charge of maintaining neuronal function under homeostatic and challenging situations.

  5. Investigating the neurobiology of music: brain-derived neurotrophic factor modulation in the hippocampus of young adult mice.

    PubMed

    Angelucci, Francesco; Fiore, Marco; Ricci, Enzo; Padua, Luca; Sabino, Andrea; Tonali, Pietro Attilio

    2007-09-01

    It has been shown that music might be able to improve mood state in people affected by psychiatric disorders, ameliorate cognitive deficits in people with dementia and increase motor coordination in Parkinson patients. Robust experimental evidence explaining the central effects of music, however, is missing. This study was designed to investigate the effect of music on brain neurotrophin production and behavior in the mouse. We exposed young adult mice to music with a slow rhythm (6 h/day; mild sound pressure levels, between 50 and 60 db) for 21 consecutive days. At the end of the treatment, mice were tested for passive avoidance learning and then killed for analysis of brain-derived neurotrophic factor (BDNF) and nerve growth factor with enzyme-linked immunosorbent assay (ELISA) in selected brain regions. We found that music-exposed mice showed increased BDNF, but not nerve growth factor in the hippocampus. Furthermore, we observed that music exposure significantly enhanced learning performance, as measured by the passive avoidance test. Our results demonstrate that exposure to music can modulate the activity of the hippocampus by influencing BDNF production. Our findings also suggest that music exposure might be of help in several central nervous system pathologies.

  6. A Lack of Correlation between Brain-Derived Neurotrophic Factor Serum Level and Verbal Memory Performance in Healthy Polish Population

    PubMed Central

    Wilkosc, Monika; Markowska, Anita; Zajac-Lamparska, Ludmila; Skibinska, Maria; Szalkowska, Agnieszka; Araszkiewicz, Aleksander

    2016-01-01

    Brain derived neurotrophic factor (BDNF) is considered to be connected with memory and learning through the processes of long term synaptic potentiation and synaptic plasticity. The aim of the study was to examine the relationship between precursor BDNF (proBNDF) and mature BDNF (mBDNF) serum levels and performance on Rey Auditory-Verbal Learning Test (RAVLT) in 150 healthy volunteers. In addition, we have verified the relationships between serum concentration of both forms of BDNF and RAVLT with sociodemographic and lifestyle factors.We found no strong evidence for the correlation of proBDNF and mBDNF serum levels with performance on RAVLT in healthy Polish population in early and middle adulthood. We observed the mBDNF serum concentration to be higher in women compared with men. Moreover, we revealed higher mBDNF level to be connected with lower body mass index (BMI). In turn, the results of RAVLT correlated with sociodemographic and lifestyle factors, such as: age, education, gender, BMI and smoking. PMID:27242447

  7. Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats.

    PubMed

    Jiang, Y; Wei, N; Lu, T; Zhu, J; Xu, G; Liu, X

    2011-01-13

    Inflammation plays a vital role in the pathogenesis of ischemic stroke. Brain-derived neurotrophic factor (BDNF) may protect brain tissues from ischemic injury. In this study, we investigated whether intranasal BDNF exerted neuroprotection against ischemic insult by modulating the local inflammation in rats with ischemic stroke. Rats were subjected to temporary occlusion of the right middle cerebral artery (120 min) and intranasal BDNF or vehicle was adminstrated 2 h after reperfusion. Infarct volume and neuron injury were measured using triphenyltetrazolium chloride, Nissl staining and TUNEL assay, respectively. Microglia were detected by immunohistofluorescence. Tumor necrosis factor-α, interleukin10 and mRNAs were evaluated by enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction. DNA-binding activity of nuclear factor-kappa B was measured by electrophoretic mobility shift assay. BDNF level in brain tissues was markedly raised following intranasal administration. There were more Nissl positive and less TUNEL positive neurons in BDNF group than in control group while intranasal BDNF did not reduce the infarct volume significantly (n=6, 0.27±0.04 vs. 0.24±0.05, P>0.05). BDNF increased the number of activated microglia (OX-42 positive) and phagocytotic microglia (ED1 positive). BDNF suppressed tumor necrosis factor-α and mRNA expression while increasing the interleukin10 and mRNA expression. BDNF also increased DNA-binding activity of nuclear factor-kappa B (n=6, 49.78±1.23 vs. 52.89±1.64, P<0.05). Our data suggest intranasal BDNF might protect the brain against ischemic insult by modulating local inflammation via regulation of the levels of cellular, cytokine and transcription factor in the experimental stroke.

  8. An Association Study of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Amphetamine Response

    PubMed Central

    Flanagin, Brody A.; Cook, Edwin H.; de Wit, Harriet

    2008-01-01

    Although genetic factors are known to be important in addiction, no candidate genes have yet been consistently linked to drug use or abuse. Brain-derived neurotrophic factor (BDNF), which has been implicated in the behavioral response to psychomotor stimulants and potentiates neurotransmitters that are strongly linked to addiction, is a logical candidate gene to study. Using a drug challenge approach, we tested for association between BDNF G196A (val66met) genotype and subjective responses to amphetamine (AMPH). Healthy volunteers participated in a double-blind, crossover design in which they received placebo, 10 mg, and 20 mg oral d-amphetamine in random order. Subjective and physical responses to ingestion of AMPH were measured at thirty minute intervals after drug ingestion. Each subject was genotyped for the BDNF G196A polymorphism and grouped and analyzed accordingly. The effects of AMPH on ratings of arousal, energy, and heart rate were compared in subjects with the val/val genotype (N = 67) and the subjects with either the val/met or met/met genotypes (N = 32). AMPH produced less pronounced self-ratings of arousal and energy, yet higher increases in heart rate, in the val/met and met/met compared to the val/val group. These results suggest that BDNF is related to the subjective and physical response to low doses of AMPH. PMID:16823800

  9. Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke.

    PubMed

    Fouda, Abdelrahman Y; Alhusban, Ahmed; Ishrat, Tauheed; Pillai, Bindu; Eldahshan, Wael; Waller, Jennifer L; Ergul, Adviye; Fagan, Susan C

    2017-01-01

    Angiotensin type 1 receptor blockers (ARBs) have been shown to be neuroprotective and neurorestorative in experimental stroke. The mechanisms proposed include anti-inflammatory, antiapoptotic effects, as well as stimulation of endogenous trophic factors leading to angiogenesis and neuroplasticity. We aimed to investigate the involvement of the neurotrophin, brain-derived neurotrophic factor (BDNF), in ARB-mediated functional recovery after stroke. To achieve this aim, Wistar rats received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles or nontargeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-min middle cerebral artery occlusion (MCAO) and received the ARB, candesartan, 1 mg/kg, or saline IV at reperfusion (one dose), then followed for another 14 days using a battery of behavioral tests. BDNF protein expression was successfully reduced by about 70 % in both hemispheres at 14 days after bilateral shRNA lentiviral particle injection. The NTC group that received candesartan showed better functional outcome as well as increased vascular density and synaptogenesis as compared to saline treatment. BDNF knockdown abrogated the beneficial effects of candesartan on neurobehavioral outcome, vascular density, and synaptogenesis. In conclusion, BDNF is directly involved in candesartan-mediated functional recovery, angiogenesis, and synaptogenesis.

  10. Effect of yoga on pain, brain-derived neurotrophic factor, and serotonin in premenopausal women with chronic low back pain.

    PubMed

    Lee, Moseon; Moon, Woongjoon; Kim, Jaehee

    2014-01-01

    Background. Serotonin and brain-derived neurotrophic factor (BDNF) are known to be modulators of nociception. However, pain-related connection between yoga and those neuromodulators has not been investigated. Therefore, we aimed to evaluate the effect of yoga on pain, BDNF, and serotonin. Methods. Premenopausal women with chronic low back pain practiced yoga three times a week for 12 weeks. At baseline and after 12 weeks, back pain intensity was measured using visual analogue scale (VAS), and serum BDNF and serotonin levels were evaluated. Additionally, back flexibility and level of depression were assessed. Results. After 12-week yoga, VAS decreased in the yoga group (P < 0.001), whereas it increased (P < 0.05) in the control group. Back flexibility was improved in the yoga group (P < 0.01). Serum BDNF increased in the yoga group (P < 0.01), whereas it tended to decrease in the control group (P = 0.05). Serum serotonin maintained in the yoga group, while it reduced (P < 0.01) in the control group. The depression level maintained in the yoga group, whereas it tended to increase in the control group (P = 0.07). Conclusions. We propose that BDNF may be one of the key factors mediating beneficial effects of yoga on chronic low back pain.

  11. Brain derived neurotrophic factor gene (BDNF) and personality traits: the modifying effect of season of birth and sex.

    PubMed

    Kazantseva, A; Gaysina, D; Kutlumbetova, Yu; Kanzafarova, R; Malykh, S; Lobaskova, M; Khusnutdinova, E

    2015-01-02

    Personality traits are complex phenotypes influenced by interactions of multiple genetic variants of small effect and environmental factors. It has been suggested that the brain derived neurotrophic factor gene (BDNF) is involved in personality traits. Season of birth (SOB) has also been shown to affect personality traits due to its influences on brain development during prenatal and early postnatal periods. The present study aimed to investigate the effects of BDNF on personality traits; and the modifying effects of SOB and sex on associations between BDNF and personality traits. A sample of 1018 young adults (68% women; age range 17-25years) of Caucasian origin from the Russian Federation was assessed on personality traits (Novelty Seeking, Harm Avoidance, Reward Dependence, Persistence, Self-directedness, Cooperativeness, Self-transcendence) with the Temperament and Character Inventory-125 (TCI-125). Associations between personality traits and 12 BDNF SNPs were tested using linear regression models. The present study demonstrated the effect of rs11030102 on Persistence in females only (PFDR=0.043; r(2)=1.3%). There were significant interaction effects between Val66Met (rs6265) and SOB (PFDR=0.048, r(2)=1.4%), and between rs2030323 and SOB (PFDR=0.042, r(2)=1.3%), on Harm Avoidance. Our findings provide evidence for the modifying effect of SOB on the association between BDNF and Harm Avoidance, and for the modifying effect of sex on the association between BDNF and Persistence.

  12. Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma.

    PubMed

    Xiong, Ye; Liu, Liyun; Zhu, Shuang; Zhang, Baole; Qin, Yuxia; Yao, Ruiqin; Zhou, Hao; Gao, Dian Shuai

    2017-02-12

    As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion.

  13. Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth.

    PubMed

    Rauskolb, Stefanie; Zagrebelsky, Marta; Dreznjak, Anita; Deogracias, Rubén; Matsumoto, Tomoya; Wiese, Stefan; Erne, Beat; Sendtner, Michael; Schaeren-Wiemers, Nicole; Korte, Martin; Barde, Yves-Alain

    2010-02-03

    Although brain-derived neurotrophic factor (BDNF) is linked with an increasing number of conditions causing brain dysfunction, its role in the postnatal CNS has remained difficult to assess. This is because the bdnf-null mutation causes the death of the animals before BDNF levels have reached adult levels. In addition, the anterograde axonal transport of BDNF complicates the interpretation of area-specific gene deletion. The present study describes the generation of a new conditional mouse mutant essentially lacking BDNF throughout the CNS. It shows that BDNF is not essential for prolonged postnatal survival, but that the behavior of such mutant animals is markedly altered. It also reveals that BDNF is not a major survival factor for most CNS neurons and for myelination of their axons. However, it is required for the postnatal growth of the striatum, and single-cell analyses revealed a marked decreased in dendritic complexity and spine density. In contrast, BDNF is dispensable for the growth of the hippocampus and only minimal changes were observed in the dendrites of CA1 pyramidal neurons in mutant animals. Spine density remained unchanged, whereas the proportion of the mushroom-type spine was moderately decreased. In line with these in vivo observations, we found that BDNF markedly promotes the growth of cultured striatal neurons and of their dendrites, but not of those of hippocampal neurons, suggesting that the differential responsiveness to BDNF is part of a neuron-intrinsic program.

  14. Estradiol increases expression of the brain-derived neurotrophic factor after acute administration of ethanol in the neonatal rat cerebellum.

    PubMed

    Firozan, Bita; Goudarzi, Iran; Elahdadi Salmani, Mahmoud; Lashkarbolouki, Taghi; Rezaei, Arezou; Abrari, Kataneh

    2014-06-05

    Recently it has been shown that estradiol prevents the toxicity of ethanol in developing cerebellum. The neuroprotective effect of estradiol is not due to a single phenomenon but rather encompasses a spectrum of independent proccesses. According to the specific timing of Purkinje cell vulnerability to ethanol and several protective mechanisms of estradiol, we considered the neurotrophin system, as a regulator of differentiation, maturation and survival of neurons during CNS development. Interactions between estrogen and Brain derived neurotrophic factor (BDNF, an essential factor in neuronal survival) lead us to investigate involvement of BDNF pathway in neuroprotective effects of estrogen against ethanol toxicity. In this study, 17β-estradiol (300-900μg/kg) was injected subcutaneously in postnatal day (PD) 4, 30min prior to intraperitoneal injection of ethanol (6g/kg) in rat pups. Eight hours after injection of ethanol, BDNF mRNA and protein levels were assayed. Behavioral studies, including rotarod and locomotor activity tests were performed in PD 21-23 and histological study was performed after completion of behavioral tests in PD 23. Our results indicated that estradiol increased BDNF mRNA and protein levels in the presence of ethanol. We also observed that pretreatment with estradiol significantly attenuated ethanol-induced motoric impairment. Histological analysis also demonstrated that estradiol prevented Purkinje cell loss following ethanol treatment. These results provide evidence on the possible mechanisms of estradiol neuroprotection against ethanol toxicity.

  15. Brain-derived neurotrophic factor signaling in the HVC is required for testosterone-induced song of female canaries.

    PubMed

    Hartog, Tessa E; Dittrich, Falk; Pieneman, Anton W; Jansen, René F; Frankl-Vilches, Carolina; Lessmann, Volkmar; Lilliehook, Christina; Goldman, Steven A; Gahr, Manfred

    2009-12-09

    Testosterone-induced singing in songbirds is thought to involve testosterone-dependent morphological changes that include angiogenesis and neuronal recruitment into the HVC, a central part of the song control circuit. Previous work showed that testosterone induces the production of vascular endothelial growth factor (VEGF) and its receptor (VEGFR2 tyrosine kinase), which in turn leads to an upregulation of brain-derived neurotrophic factor (BDNF) production in HVC endothelial cells. Here we report for the first time that systemic inhibition of the VEGFR2 tyrosine kinase is sufficient to block testosterone-induced song in adult female canaries, despite sustained androgen exposure and the persistence of the effects of testosterone on HVC morphology. Expression of exogenous BDNF in HVC, induced locally by in situ transfection, reversed the VEGFR2 inhibition-mediated blockade of song development, thereby restoring the behavioral phenotype associated with androgen-induced song. The VEGFR2-inhibited, BDNF-treated females developed elaborate male-like song that included large syllable repertoires and high syllable repetition rates, features known to attract females. Importantly, although functionally competent new neurons were recruited to HVC after testosterone treatment, the time course of neuronal addition appeared to follow BDNF-induced song development. These findings indicate that testosterone-associated VEGFR2 activity is required for androgen-induced song in adult songbirds and that the behavioral effects of VEGFR2 inhibition can be rescued by BDNF within the adult HVC.

  16. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease.

    PubMed

    Murer, M G; Yan, Q; Raisman-Vozari, R

    2001-01-01

    Brain-derived neurotrophic factor (BDNF) is a small dimeric protein, structurally related to nerve growth factor, which is abundantly and widely expressed in the adult mammalian brain. BDNF has been found to promote survival of all major neuronal types affected in Alzheimer's disease and Parkinson's disease, like hippocampal and neocortical neurons, cholinergic septal and basal forebrain neurons, and nigral dopaminergic neurons. In this article, we summarize recent work on the molecular and cellular biology of BDNF, including current ideas about its intracellular trafficking, regulated synthesis and release, and actions at the synaptic level, which have considerably expanded our conception of BDNF actions in the central nervous system. But our primary aim is to review the literature regarding BDNF distribution in the human brain, and the modifications of BDNF expression which occur in the brain of individuals with Alzheimer's disease and Parkinson's disease. Our knowledge concerning BDNF actions on the neuronal populations affected in these pathological states is also reviewed, with an aim at understanding its pathogenic and pathophysiological relevance.

  17. Epigenetic and epistatic interactions between serotonin transporter and brain-derived neurotrophic factor genetic polymorphism: insights in depression.

    PubMed

    Ignácio, Z M; Réus, G Z; Abelaira, H M; Quevedo, J

    2014-09-05

    Epidemiological studies have shown significant results in the interaction between the functions of brain-derived neurotrophic factor (BDNF) and 5-HT in mood disorders, such as major depressive disorder (MDD). The latest research has provided convincing evidence that gene transcription of these molecules is a target for epigenetic changes, triggered by stressful stimuli that starts in early childhood and continues throughout life, which are subsequently translated into structural and functional phenotypes culminating in depressive disorders. The short variants of 5-HTTLPR and BDNF-Met are seen as forms which are predisposed to epigenetic aberrations, which leads individuals to a susceptibility to environmental adversities, especially when subjected to stress in early life. Moreover, the polymorphic variants also feature epistatic interactions in directing the functional mechanisms elicited by stress and underlying the onset of depressive disorders. Also emphasized are works which show some mediators between stress and epigenetic changes of the 5-HTT and BDNF genes, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cAMP response element-binding protein (CREB), which is a cellular transcription factor. Both the HPA axis and CREB are also involved in epistatic interactions between polymorphic variants of 5-HTTLPR and Val66Met. This review highlights some research studying changes in the epigenetic patterns intrinsic to genes of 5-HTT and BDNF, which are related to lifelong environmental adversities, which in turn increases the risks of developing MDD.

  18. Genomic organization and chromosomal localization of the human and mouse genes encoding the alpha receptor component for ciliary neurotrophic factor.

    PubMed

    Valenzuela, D M; Rojas, E; Le Beau, M M; Espinosa, R; Brannan, C I; McClain, J; Masiakowski, P; Ip, N Y; Copeland, N G; Jenkins, N A

    1995-01-01

    Ciliary neurotrophic factor (CNTF) has recently been found to share receptor components with, and to be structurally related to, a family of broadly acting cytokines, including interleukin-6, leukemia inhibitory factor, and oncostatin M. However, the CNTF receptor complex also includes a CNTF-specific component known as CNTF receptor alpha (CNTFR alpha). Here we describe the molecular cloning of the human and mouse genes encoding CNTFR. We report that the human and mouse genes have an identical intron-exon structure that correlates well with the domain structure of CNTFR alpha. That is, the signal peptide and the immunoglobulin-like domain are each encoded by single exons, the cytokine receptor-like domain is distributed among 4 exons, and the C-terminal glycosyl phosphatidylinositol recognition domain is encoded by the final coding exon. The position of the introns within the cytokine receptor-like domain corresponds to those found in other members of the cytokine receptor superfamily. Confirming a recent study using radiation hybrids, we have also mapped the human CNTFR gene to chromosome band 9p13 and the mouse gene to a syntenic region of chromosome 4.

  19. Dose-Dependent Differential Effect of Neurotrophic Factors on In Vitro and In Vivo Regeneration of Motor and Sensory Neurons

    PubMed Central

    Santos, Daniel; Gonzalez-Perez, Francisco; Navarro, Xavier

    2016-01-01

    Although peripheral axons can regenerate after nerve transection and repair, functional recovery is usually poor due to inaccurate reinnervation. Neurotrophic factors promote directional guidance to regenerating axons and their selective application may help to improve functional recovery. Hence, we have characterized in organotypic cultures of spinal cord and dorsal root ganglia the effect of GDNF, FGF-2, NGF, NT-3, and BDNF at different concentrations on motor and sensory neurite outgrowth. In vitro results show that GDNF and FGF-2 enhanced both motor and sensory neurite outgrowth, NGF and NT-3 were the most selective to enhance sensory neurite outgrowth, and high doses of BDNF selectively enhanced motor neurite outgrowth. Then, NGF, NT-3, and BDNF (as the most selective factors) were delivered in a collagen matrix within a silicone tube to repair the severed sciatic nerve of rats. Quantification of Fluorogold retrolabeled neurons showed that NGF and NT-3 did not show preferential effect on sensory regeneration whereas BDNF preferentially promoted motor axons regeneration. Therefore, the selective effects of NGF and NT-3 shown in vitro are lost when they are applied in vivo, but a high dose of BDNF is able to selectively enhance motor neuron regeneration both in vitro and in vivo. PMID:27867665

  20. Effect of Yoga on Pain, Brain-Derived Neurotrophic Factor, and Serotonin in Premenopausal Women with Chronic Low Back Pain

    PubMed Central

    Lee, Moseon

    2014-01-01

    Background. Serotonin and brain-derived neurotrophic factor (BDNF) are known to be modulators of nociception. However, pain-related connection between yoga and those neuromodulators has not been investigated. Therefore, we aimed to evaluate the effect of yoga on pain, BDNF, and serotonin. Methods. Premenopausal women with chronic low back pain practiced yoga three times a week for 12 weeks. At baseline and after 12 weeks, back pain intensity was measured using visual analogue scale (VAS), and serum BDNF and serotonin levels were evaluated. Additionally, back flexibility and level of depression were assessed. Results. After 12-week yoga, VAS decreased in the yoga group (P < 0.001), whereas it increased (P < 0.05) in the control group. Back flexibility was improved in the yoga group (P < 0.01). Serum BDNF increased in the yoga group (P < 0.01), whereas it tended to decrease in the control group (P = 0.05). Serum serotonin maintained in the yoga group, while it reduced (P < 0.01) in the control group. The depression level maintained in the yoga group, whereas it tended to increase in the control group (P = 0.07). Conclusions. We propose that BDNF may be one of the key factors mediating beneficial effects of yoga on chronic low back pain. PMID:25120574

  1. The Role of Brain-Derived Neurotrophic Factor in Comorbid Depression: Possible Linkage with Steroid Hormones, Cytokines, and Nutrition

    PubMed Central

    Numakawa, Tadahiro; Richards, Misty; Nakajima, Shingo; Adachi, Naoki; Furuta, Miyako; Odaka, Haruki; Kunugi, Hiroshi

    2014-01-01

    Increasing evidence demonstrates a connection between growth factor function (including brain-derived neurotrophic factor, BDNF), glucocorticoid levels (one of the steroid hormones), and the pathophysiology of depressive disorders. Because both BDNF and glucocorticoids regulate synaptic function in the central nervous system, their functional interaction is of major concern. Interestingly, alterations in levels of estrogen, another steroid hormone, may play a role in depressive-like behavior in postpartum females with fluctuations of BDNF-related molecules in the brain. BDNF and cytokines, which are protein regulators of inflammation, stimulate multiple intracellular signaling cascades involved in neuropsychiatric illness. Pro-inflammatory cytokines may increase vulnerability to depressive symptoms, such as the increased risk observed in patients with cancer and/or autoimmune diseases. In this review, we discuss the possible relationship between inflammation and depression, in addition to the cross-talk among cytokines, BDNF, and steroids. Further, since nutritional status has been shown to affect critical pathways involved in depression through both BDNF function and the monoamine system, we also review current evidence surrounding diet and supplementation (e.g., flavonoids) on BDNF-mediated brain functions. PMID:25309465

  2. Pro-brain-derived neurotrophic factor inhibits GABAergic neurotransmission by activating endocytosis and repression of GABAA receptors.

    PubMed

    Riffault, Baptiste; Medina, Igor; Dumon, Camille; Thalman, Carine; Ferrand, Nadine; Friedel, Perrine; Gaiarsa, Jean-Luc; Porcher, Christophe

    2014-10-01

    GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABAARs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABAAR trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABAAR, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK-STAT-ICER pathway leading to the repression of GABAARs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF-p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABAARs at inhibitory synapses.

  3. In-depth quantitative proteomic analysis of de novo protein synthesis induced by brain-derived neurotrophic factor.

    PubMed

    Zhang, Guoan; Bowling, Heather; Hom, Nancy; Kirshenbaum, Kent; Klann, Eric; Chao, Moses V; Neubert, Thomas A

    2014-12-05

    Measuring the synthesis of new proteins in the context of a much greater number of pre-existing proteins can be difficult. To overcome this obstacle, bioorthogonal noncanonical amino acid tagging (BONCAT) can be combined with stable isotope labeling by amino acid in cell culture (SILAC) for comparative proteomic analysis of de novo protein synthesis (BONLAC). In the present study, we show that alkyne resin-based isolation of l-azidohomoalanine (AHA)-labeled proteins using azide/alkyne cycloaddition minimizes contamination from pre-existing proteins. Using this approach, we isolated and identified 7414 BONCAT-labeled proteins. The nascent proteome isolated by BONCAT was very similar to the steady-state proteome, although transcription factors were highly enriched by BONCAT. About 30% of the methionine residues were replaced by AHA in our BONCAT samples, which allowed for identification of methionine-containing peptides. There was no bias against low-methionine proteins by BONCAT at the proteome level. When we applied the BONLAC approach to screen for brain-derived neurotrophic factor (BDNF)-induced protein synthesis, 53 proteins were found to be significantly changed 2 h after BDNF stimulation. Our study demonstrated that the newly synthesized proteome, even after a short period of stimulation, can be efficiently isolated by BONCAT and analyzed to a depth that is similar to that of the steady-state proteome.

  4. Spatial memory training modifies the expression of brain-derived neurotrophic factor tyrosine kinase receptors in young and aged rats.

    PubMed

    Silhol, M; Arancibia, S; Maurice, T; Tapia-Arancibia, L

    2007-05-25

    Aging leads to alterations in the function of the hippocampus, a brain structure largely involved in learning processes. This study aimed at examining the basal levels and the impact of a learning-associated task on brain-derived neurotrophic factor (BDNF), on BDNF full-length catalytic receptor (TrkB.FL) and on the truncated forms (TrkB.T1 and TrkB.T2) receptor expression (mRNA and protein) in the hippocampus of young (2-month-old) and aged (24-month-old) Wistar rats. Spatial memory was evaluated using a water-maze procedure involving visible and invisible platform location learning. Aged rats showed higher latencies during the first two training days but rapidly exhibited learning performances similar to patterns observed with young rats. Real-time PCR measurements showed that aged rats had significantly higher levels of trkB.FL mRNAs than young rats under basal conditions. In situ hybridization analysis indicated that the highest level of trkB.FL mRNA (mRNA encoding for TrkB.FL receptor) was noted in the dentate gyrus, and in the CA2 and CA3 hippocampal layers. In contrast, there was no marked difference in trkB.T1 signal in any hippocampal region. Training induced a significant reduction in trkB.FL mRNA levels solely in aged rats. In contrast, in young and aged rats, trkB.T2 mRNA levels were significantly increased after training. Measurements of proteins revealed that learning significantly increased TrkB.FL content in aged rats. Untrained aged rats presented higher levels of BDNF and brain-derived neurotrophic factor precursor (proBDNF) proteins than young rats. Training strongly increased precursor BDNF metabolism in young and aged rats, resulting in increased levels of proBDNF in the two groups but in old rats the mature BDNF level did not change. This study shows that Wistar rats present age-related differences in the levels of BDNF and TrkB isoforms and that spatial learning differentially modifies some of these parameters in the hippocampus.

  5. Effects of brain-derived neurotrophic factor (BDNF) and electrical stimulation on survival and function of cochlear spiral ganglion neurons in deafened, developing cats.

    PubMed

    Leake, Patricia A; Stakhovskaya, Olga; Hetherington, Alexander; Rebscher, Stephen J; Bonham, Ben

    2013-04-01

    Both neurotrophic support and neural activity are required for normal postnatal development and survival of cochlear spiral ganglion (SG) neurons. Previous studies in neonatally deafened cats demonstrated that electrical stimulation (ES) from a cochlear implant can promote improved SG survival but does not completely prevent progressive neural degeneration. Neurotrophic agents combined with an implant may further improve neural survival. Short-term studies in rodents have shown that brain-derived neurotrophic factor (BDNF) promotes SG survival after deafness and may be additive to trophic effects of stimulation. Our recent study in neonatally deafened cats provided the first evidence of BDNF neurotrophic effects in the developing auditory system over a prolonged duration Leake et al. (J Comp Neurol 519:1526-1545, 2011). Ten weeks of intracochlear BDNF infusion starting at 4 weeks of age elicited significant improvement in SG survival and larger soma size compared to contralateral. In the present study, the same deafening and BDNF infusion procedures were combined with several months of ES from an implant. After combined BDNF + ES, a highly significant increase in SG numerical density (>50 % improvement re: contralateral) was observed, which was significantly greater than the neurotrophic effect seen with ES-only over comparable durations. Combined BDNF + ES also resulted in a higher density of myelinated radial nerve fibers within the osseous spiral lamina. However, substantial ectopic and disorganized sprouting of these fibers into the scala tympani also occurred, which may be deleterious to implant function. EABR thresholds improved (re: initial thresholds at time of implantation) on the chronically stimulated channels of the implant. Terminal electrophysiological studies recording in the inferior colliculus (IC) revealed that the basic cochleotopic organization was intact in the midbrain in all studied groups. In deafened controls or after ES-only, lower IC

  6. Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats: therapeutic potential of brain-derived neurotrophic factor for dopaminergic amacrine cells.

    PubMed

    Seki, Masaaki; Tanaka, Takayuki; Nawa, Hiroyuki; Usui, Tomoaki; Fukuchi, Takeo; Ikeda, Kazuhito; Abe, Haruki; Takei, Nobuyuki

    2004-09-01

    Although neurotrophins have been assessed as candidate therapeutic agents for neural complications of diabetes, their involvement in diabetic retinopathy has not been fully characterized. We found that the protein and mRNA levels of brain-derived neurotrophic factor (BDNF) in streptozotocin-induced diabetic rat retinas were reduced to 49% (P < 0.005) and 74% (P < 0.05), respectively, of those of normal control animals. In addition, dopaminergic amacrine cells appeared to be degenerating in the diabetic rat retinas, as revealed by tyrosine hydroxylase (TH) immunoreactivity. Overall TH protein levels in the retina were decreased to one-half that of controls (P < 0.01), reflecting reductions in the density of dopaminergic amacrine cells and the intensity of TH immunoreactivity within them. To confirm the neuropathological implications of BDNF reduction, we administered BDNF protein into the vitreous cavities of diabetic rats. Intraocular administration of BDNF rescued dopaminergic amacrine cells from neurodegeneration and counteracted the downregulation of TH expression, demonstrating its therapeutic potential. These findings suggest that the early retinal neuropathy of diabetes involves the reduced expression of BDNF and can be ameliorated by an exogenous supply of this neurotrophin.

  7. Altered maternal micronutrients (folic acid, vitamin B(12)) and omega 3 fatty acids through oxidative stress may reduce neurotrophic factors in preterm pregnancy.

    PubMed

    Dhobale, Madhavi; Joshi, Sadhana

    2012-04-01

    Preterm pregnancies account for approximately 10% of the total pregnancies and are associated with low birth weight (LBW) babies. Recent studies have shown that LBW babies are at an increased risk of developing brain disorders such as cognitive dysfunction and psychiatric disorders. Maternal nutrition, particularly, micronutrients involved in one-carbon metabolism (folic acid, vitamin B(12), and docosahexaenoic acid (DHA)) have a major role during pregnancy for developing fetus and are important determinants of epigenesis. A series of our studies in pregnancy complications have well established the importance of omega 3 fatty acids especially DHA. DHA regulates levels of neurotrophins like brain-derived neurotrophic factor and nerve growth factor, which are required for normal neurological development. We have recently described that in one carbon metabolic pathway, membrane phospholipids are major methyl group acceptors and reduced DHA levels may result in diversion of methyl groups toward deoxyribonucleic acid (DNA) ultimately resulting in DNA methylation. In this review, we propose that altered maternal micronutrients (folic acid, vitamin B(12)), increased homocysteine, and oxidative stress levels that cause epigenetic modifications may be one of the mechanisms that contribute to preterm birth and poor fetal outcome, increasing risk for behavioural disorders in children.

  8. Effects of alcohol on brain-derived neurotrophic factor mRNA expression in discrete regions of the rat hippocampus and hypothalamus.

    PubMed

    Tapia-Arancibia, L; Rage, F; Givalois, L; Dingeon, P; Arancibia, S; Beaugé, F

    2001-01-15

    Chronic alcohol consumption has adverse effects on the central nervous system, affecting some hippocampal and hypothalamic functions. In this study we tempted to demonstrate that some of these modifications could involve impairment of neurotrophic factors. Three experimental groups of male Sprague Dawley rats were studied: one control group, one chronically treated with alcohol vapor according to a well-established model that induces behavioral dependence, and a third group treated similarly but killed 12 hr after alcohol withdrawal. In all groups, changes in brain-derived neurotrophic factor mRNA expression occurring in the hippocampus and supraoptic nucleus were first analyzed by reverse transcription-polymerase chain reaction and then by in situ hybridization. In parallel, we used ribonuclease protection assay to measure mRNA levels encoding trkB in the two central nervous system regions. We showed that chronic alcohol intoxication decreases brain-derived neurotrophic factor mRNA expression in discrete regions of the rat hippocampus (CA1 region and dentate gyrus) and in the supraoptic nucleus of the hypothalamus. We also showed a global up-regulation of trkB mRNA expression encoding the high-affinity brain-derived neurotrophic factor receptor (TrkB), after applying the same treatment. Following 12 hr of alcohol withdrawal, a significant increase in BDNF mRNA expression was observed in the dentate gyrus and CA3 region of hippocampus and in the hypothalamic supraoptic nucleus. These findings suggest that chronic alcohol intake may modify hippocampal and hypothalamic neuronal functions through modifications in growth factors and its receptors.

  9. Brain-derived neurotrophic factor-modified umbilical cord mesenchymal stem cell transplantation improves neurological deficits in rats with traumatic brain injury.

    PubMed

    Yuan, Yuan; Pan, Shumao; Sun, Zhaoming; Dan, Qiqin; Liu, Jia

    2014-07-01

    This study explored the effect of brain-derived neurotrophic factor (BDNF) gene-modified umbilical cord mesenchymal stem cell (UCMSC) transplantation on neurological functional improvement in rats after brain trauma. A rat model of cerebral contusion in the motor-sensory cortex was established by the weight hammer-falling method. UCMSCs were cultured and transferred with BDNF gene. After determining BDNF expression and activity, the BDNF gene-modified UCMSCs were implanted into brains of rats receiving the brain injury. The neurological function was evaluated 1 and 2 weeks after brain injury. BDNF expression was then determined by immunohistochemistry. Severe neurological dysfunction was observed in animals subjected to contusion brain injury (10.50 ± 0.53). A significant improvement in neurological function was found in the UCMSC transplantation animals (7.75 ± 0.71) compared with the brain injury only group (p < 0.01). Rats with BDNF gene-modified UCMSCs showed the highest improvement in behavior (5.50 ± 0.76; p < 0.01). BDNF gene-modified UCMSCs can survive and migrate in rat cerebral tissues. The transplantation of these UCMSCs can improve the neurological functions of rats with traumatic brain injury.

  10. Heptamethoxyflavone, a citrus flavonoid, enhances brain-derived neurotrophic factor production and neurogenesis in the hippocampus following cerebral global ischemia in mice.

    PubMed

    Okuyama, Satoshi; Shimada, Naoko; Kaji, Miki; Morita, Mayu; Miyoshi, Kazuhiro; Minami, Sona; Amakura, Yoshiaki; Yoshimura, Morio; Yoshida, Takashi; Watanabe, Sono; Nakajima, Mitsunari; Furukawa, Yoshiko

    2012-10-24

    In the present study using a transient global ischemia mouse model, we showed that (1) a citrus flavonoid 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) in the hippocampus after ischemia; (2) HMF increased the expression of brain-derived neurotrophic factor (BDNF), a representative neurotrophic factor in the central nervous system, in the hippocampal dentate gyrus, and most BDNF-positive cells were also stained with anti-glial fibrillary acidic protein (one of the major intermediate filament proteins of mature astrocytes) and (3) HMF increased doublecortin positive neuronal precursor cells in the dentate gyrus subventricular zone or subgranular zone. These results suggest that HMF has the ability to induce BDNF production in astrocytes and enhance neurogenesis after brain ischemia, which may be mediated by activation of ERK1/2 and CREB.

  11. The cytokines cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF) and ciliary neurotrophic factor (CNTF) differ in their receptor specificities.

    PubMed

    Tormo, Aurélie Jeanne; Letellier, Marie-Claude; Lissilaa, Rami; Batraville, Laurie-Anne; Sharma, Mukut; Ferlin, Walter; Elson, Greg; Crabé, Sandrine; Gauchat, Jean-François

    2012-12-01

    Ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC) are two cytokines with neurotrophic and immunomodulatory activities. CNTF is a cytoplasmic factor believed to be released upon cellular damage, while CLC requires interaction with a soluble cytokine receptor, cytokine-like factor 1 (CLF), to be efficiently secreted. Both cytokines activate a receptor complex comprising the cytokine binding CNTF receptor α (CNTFRα) and two signaling chains namely, leukemia inhibitory factor receptor β (LIFRβ) and gp130. Human CNTF can recruit and activate an alternative receptor in which CNTFRα is substituted by IL-6Rα. As both CNTF and CLC have immune-regulatory activities in mice, we compared their ability to recruit mouse receptors comprising both gp130 and LIFRβ signaling chains and either IL-6Rα or IL-11Rα which, unlike CNTFRα, are expressed by immune cells. Our results indicate that 1) mouse CNTF, like its human homologue, can activate cells expressing gp130/LIFRβ with either CNTFRα or IL-6Rα and, 2) CLC/CLF is more restricted in its specificity in that it activates only the tripartite CNTFR. Several gp130 signaling cytokines influence T helper cell differentiation. We therefore investigated the effect of CNTF on CD4 T cell cytokine production. We observed that CNTF increased the number of IFN-γ producing CD4 T cells. As IFN-γ is considered a mediator of the therapeutic effect of IFN-β in multiple sclerosis, induction of IFN-γ by CNTF may contribute to the beneficial immunomodulatory effect of CNTF in mouse multiple sclerosis models. Together, our results indicate that CNTF activates the same tripartite receptors in mouse and human cells and further validate rodent models for pre-clinical investigation of CNTF and CNTF derivatives. Furthermore, CNTF and CLC/CLF differ in their receptor specificities. The receptor α chain involved in the immunomodulatory effects of CLC/CLF remains to be identified.

  12. Involvement of brain-derived neurotrophic factor and sonic hedgehog in the spinal cord plasticity after neurotoxic partial removal of lumbar motoneurons.

    PubMed

    Gulino, Rosario; Gulisano, Massimo

    2012-07-01

    Adult mammals could spontaneously achieve a partial sensory-motor recovery after spinal cord injury, by mechanisms including synaptic plasticity. We previously showed that this recovery is associated to the expression of synapsin-I, and that sonic hedgehog and Notch-1 could be also involved in plasticity. The role of brain-derived neurotrophic factor and glutamate receptors in regulating synaptic efficacy has been explored in the last decade but, although these mechanisms are now well-defined in the brain, the molecular mechanisms underlying the so called "spinal learning" are still less clear. Here, we measured the expression levels of choline acetyltransferase, synapsin-I, sonic hedgehog, Notch-1, glutamate receptor subunits (GluR1, GluR2, GluR4, NMDAR1) and brain-derived neurotrophic factor, in a motoneuron-depleted mouse spinal lesion model obtained by intramuscular injection of cholera toxin-B saporin. The lesion caused the down-regulation of the majority of analysed proteins. Moreover, we found that in lesioned but not in control spinal tissue, synapsin-I expression is associated to that of both brain-derived neurotrophic factor and sonic hedgehog, whereas GluR2 expression is linked to that of Shh. These results suggest that brain-derived neurotrophic factor and sonic hedgehog could collaborate in modulating synaptic plasticity after the removal of motoneurons, by a mechanism involving both pre- and post-synaptic processes. Interestingly, the involvement of sonic hedgehog showed here is novel, and offers new routes to address spinal cord plasticity and repair.

  13. Brain-derived neurotrophic factor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures.

    PubMed

    Pringle, A K; Sundstrom, L E; Wilde, G J; Williams, L R; Iannotti, F

    1996-06-28

    We have investigated the neuroprotective actions of neurotrophins in a model of ischaemia using slice cultures. Ischaemia was induced in organotypic hippocampal cultures by simultaneous oxygen and glucose deprivation. Cell death was assessed 24 h later by propidium iodide fluorescence. Pre- but not post-ischaemic addition of brain-derived neurotrophic factor (BDNF) produced a concentration-dependent reduction in neuronal damage. Neurotrophin-3 was not neuroprotective. These data suggest that BDNF may form part of an endogenous neuroprotective mechanism.

  14. Cholinergic neurons regulate secretion of glial cell line-derived neurotrophic factor by skeletal muscle cells in culture.

    PubMed

    Vianney, John-Mary; Spitsbergen, John M

    2011-05-16

    Glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent survival factor for both central and peripheral neurons. GDNF has been shown to be a potent survival factor for motor neurons during programmed cell death and continuous treatment with GDNF maintains hyperinnervation of skeletal muscle in adulthood. However, little is known about factors regulating normal production of endogenous GDNF in skeletal muscle. This study aimed to examine the role that motor neurons play in regulating GDNF secretion by skeletal muscle. A co-culture of skeletal muscle cells (C2C12) and cholinergic neurons, glioma×neuroblastoma hybrid cells (NG108-15) were used to create nerve-muscle interactions in vitro. Acetylcholine receptors (AChRs) on nerve-myotube co-cultures were blocked with alpha-bungarotoxin (α-BTX). GDNF protein content in cells and in culture medium was analyzed by enzyme-linked immunosorbant assay (ELISA) and western blotting. GDNF localization was examined by immunocytochemistry. The nerve-muscle co-culture study indicated that the addition of motor neurons to skeletal muscle cells reduced the secretion of GDNF by skeletal muscle. The results also showed that blocking AChRs with α-BTX reversed the action of neural cells on GDNF secretion by skeletal muscle. Although ELISA results showed no GDNF in differentiated NG108-15 cells grown alone, immunocytochemical analysis showed that GDNF was localized in NG108-15 cells co-cultured with C2C12 myotubes. These results suggest that motor neurons may be regulating their own supply of GDNF secreted by skeletal muscle and that activation of AChRs may be involved in this process.

  15. Correlations between cognitive impairment and brain‑derived neurotrophic factor expression in the hippocampus of post-stroke depression rats.

    PubMed

    Zhang, Zhao-Hui; Wu, Li-Na; Song, Jing-Gui; Li, Wen-Qiang

    2012-10-01

    The aim of this study was to investigate the correlation between brain-derived neurotrophic factor (BDNF) expression and cognitive impairment in post‑stroke depression (PSD) rats and to explore the mechanism(s) involved in the process of cognitive impairment. A rat model of focal cerebral ischemia was established by occluding the middle cerebral artery (MCA). Rats were subjected to isolation-housing combined with chronic unexpected mild stress (CUMS) to establish a PSD rat model. The learning and memory abilities of the PSD rat model were evaluated by passive avoidance tests. Real‑time PCR and immunohistochemical methods were used to detect changes in BDNF mRNA and protein expression in the hippocampus. Passive avoidance defects were revealed in the PSD and depression groups. Passive avoidance defects were more evident in the PSD group compared with the depression group and the difference was statistically significant (P<0.05). BDNF expression in the hippocampus was significantly lower in the PSD and depression groups compared with that in the normal control group (P<0.01). No significant difference in BDNF expression was identified between the normal control and stroke groups (P>0.05) or between the PSD and the depression groups (P>0.05). The decrease in BDNF expression in the hippocampus of PSD rats may aggravate cognitive impairment, however, the degree of cognitive impairment cannot be reflected by the expression levels of BDNF in the hippocampus.

  16. Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health.

    PubMed

    Rothman, Sarah M; Griffioen, Kathleen J; Wan, Ruiqian; Mattson, Mark P

    2012-08-01

    Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes, and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer's and Parkinson's diseases) neurological disorders. The findings described later, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this paper provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders.

  17. Functional recovery after transplantation of neural stem cells modified by brain-derived neurotrophic factor in rats with cerebral ischaemia.

    PubMed

    Zhu, J M; Zhao, Y Y; Chen, S D; Zhang, W H; Lou, L; Jin, X

    2011-01-01

    Functional recovery after transplantation of brain-derived neurotrophic factor (BDNF)-modified neural stem cells (NSCs) was evaluated in a rat model of cerebral ischaemia damage induced by temporary middle cerebral artery occlusion (tMCAO). Western blotting and enzyme-linked immunosorbent assay demonstrated upregulated BDNF protein expression by rat embryonic NSCs transfected with the human BDNF gene (BDNF-NSCs). BDNF-NSCs stimulated neurite outgrowth in cocultured dorsal root ganglion neurons, suggesting that BDNF increased neurogenesis in vitro. In vivo, BDNF promoted recovery of tMCAO. Phosphate-buffered saline, untransformed NSCs or BDNF-NSCs were introduced into the penumbra zone of the right striatum of tMCAO rats and neurological function deficit was assessed for up to 12 weeks using the neurological severity score (NSS). The NSS was significantly lower in the BDNF-NSC transfected transplant group than in all the other groups from week 10. BDNF-NSCs recovered 1 week after transplantation expressed BDNF protein. Transplanted NSCs had differentiated into mature neurons 12 weeks after transplantation. Transgenic NSCs have potential as a therapeutic agent for brain ischaemia.

  18. Post-stroke recovery: the role of activity-dependent release of brain-derived neurotrophic factor.

    PubMed

    Berretta, Antonio; Tzeng, Yu-Chieh; Clarkson, Andrew N

    2014-11-01

    Stroke remains the leading cause of long-term disability with no pharmacological approaches available to limit the degree of damage or aid in recovery. Considerable effort has been made to minimize neuronal damage using neuroprotective compounds. However, attempts have so far failed to translate into the clinic. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase type B are actively produced throughout the brain and are involved in regulating neuronal activity and normal day-to-day function. Further, BDNF has been shown to play a role in both protection and recovery of functions after stroke. This review focuses on the endogenous release of BDNF as well as activity-induced (pharmacological and physical) elevation in BDNF, and the role this plays during both acute (hours to days) and subacute (days to weeks) periods after stroke. Exogenous administration has previously been shown not to cross the blood-brain barrier; therefore, we have focused this review on approaches that allow us to directly stimulate, using pharmacological therapies and mimetics, physical activity and potential drug delivery systems that can be used to administer BDNF. Finally, we also discuss the role of BDNF polymorphisms and the influence of epigenetic regulation of BDNF on post-stroke recovery.

  19. [Whole sequence analysis of brain-derived neurotrophic factor gene in Asiatic Black Bear through faecal sampling].

    PubMed

    Zhang, Zhi-Min; Wang, Hui-Juan; Liu, Zhong-Lai; Xiong, Guo-Mei

    2006-06-01

    Using our lab's improved protocol for faecal DNA extraction, the entire 753-bp DNA coding sequence of the nuclear brain-derived neurotrophic factor (BDNF) gene was cloned for the first time from Asiatic Black Bear Selenarctos thibetanus faecal samples with primers based on the reported sequence of the Malayan Bear BDNF gene. Hair was used as a positive control and the experiments were repeated several times to obtain reliable and identical results. Sequence analysis showed that the BDNF gene of Asiatic Black Bear was highly conserved compared to those of human and giant panda, with an identity of 94.5% and 98.9%, respectively. The deduced amino acid sequence of the mature protein was found to be identical to those of all the reported mammalians. According to gene sequence alignment, the giant panda appeared to be phylogenetically closer to Asiatic Black Bear than the lesser panda. This study represents the first time that a non-invasive method such as faecal sampling was used to analyze a functional nuclear BDNF gene of Asiatic Black Bear. It will not only provide important reference for the conservation and breeding of Asiatic Black Bear and open up new avenues of non-invasive sampling in the study of endangered wildlife, but also provide another molecular evidence for the study of relationship of Asiatic Black Bear and its related species.

  20. Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets

    PubMed Central

    Zhang, Ji-chun; Yao, Wei; Hashimoto, Kenji

    2016-01-01

    Depression is the most prevalent and among the most debilitating of psychiatric disorders. The precise neurobiology of this illness is unknown. Several lines of evidence suggest that peripheral and central inflammation plays a role in depressive symptoms, and that anti-inflammatory drugs can improve depressive symptoms in patients with inflammation-related depression. Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants. A recent paper showed that lipopolysaccharide (LPS)-induced inflammation gave rise to depression-like phenotype by altering BDNF-TrkB signaling in the prefrontal cortex, hippocampus, and nucleus accumbens, areas thought to be involved in the antidepressant effects of TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist, ANA-12. Here we provide an overview of the tryptophan-kynurenine pathway and BDNF-TrkB signaling in the pathophysiology of inflammation-induced depression, and propose mechanistic actions for potential therapeutic agents. Additionally, the authors discuss the putative role of TrkB agonists and antagonists as novel therapeutic drugs for inflammation-related depression. PMID:26786147

  1. Modulatory effect of coffee fruit extract on plasma levels of brain-derived neurotrophic factor in healthy subjects.

    PubMed

    Reyes-Izquierdo, Tania; Nemzer, Boris; Shu, Cynthia; Huynh, Lan; Argumedo, Ruby; Keller, Robert; Pietrzkowski, Zb

    2013-08-28

    The present single-dose study was performed to assess the effect of whole coffee fruit concentrate powder (WCFC), green coffee caffeine powder (N677), grape seed extract powder (N31) and green coffee bean extract powder (N625) on blood levels of brain-derived neurotrophic factor (BDNF). Randomly assorted groups of fasted subjects consumed a single, 100mg dose of each material. Plasma samples were collected at time zero (T0) and at 30 min intervals afterwards, up to 120 min. A total of two control groups were included: subjects treated with silica dioxide (as placebo) or with no treatment. The collected data revealed that treatments with N31 and N677 increased levels of plasma BDNF by about 31% under these experimental conditions, whereas treatment with WCFC increased it by 143% (n 10), compared with baseline. These results indicate that WCFC could be used for modulation of BDNF-dependent health conditions. However, larger clinical studies are needed to support this possibility.

  2. Functional Multipotency of Stem Cells: A Conceptual Review of Neurotrophic Factor-Based Evidence and Its Role in Translational Research

    PubMed Central

    Teng, Yang D; Yu, Dou; Ropper, Alexander E; Li, Jianxue; Kabatas, Serdar; Wakeman, Dustin R; Wang, Junmei; Sullivan, Maryrose P; Redmond, D. Eugene; Langer, Robert; Snyder, Evan Y; Sidman, Richard L

    2011-01-01

    We here propose an updated concept of stem cells (SCs), with an emphasis on neural stem cells (NSCs). The conventional view, which has touched principally on the essential property of lineage multipotency (e.g., the ability of NSCs to differentiate into all neural cells), should be broadened to include the emerging recognition of biofunctional multipotency of SCs to mediate systemic homeostasis, evidenced in NSCs in particular by the secretion of neurotrophic factors. Under this new conceptual context and taking the NSC as a leading example, one may begin to appreciate and seek the “logic” behind the wide range of molecular tactics the NSC appears to serve at successive developmental stages as it integrates into and prepares, modifies, and guides the surrounding CNS micro- and macro-environment towards the formation and self-maintenance of a functioning adult nervous system. We suggest that embracing this view of the “multipotency” of the SCs is pivotal for correctly, efficiently, and optimally exploiting stem cell biology for therapeutic applications, including reconstitution of a dysfunctional CNS. PMID:22654717

  3. Effects of music aerobic exercise on depression and brain-derived neurotrophic factor levels in community dwelling women.

    PubMed

    Yeh, Shu-Hui; Lin, Li-Wei; Chuang, Yu Kuan; Liu, Cheng-Ling; Tsai, Lu-Jen; Tsuei, Feng-Shiou; Lee, Ming-Tsung; Hsiao, Chiu-Yueh; Yang, Kuender D

    2015-01-01

    A randomized clinical trial was utilized to compare the improvement of depression and brain-derived neurotrophic factor (BDNF) levels between community women with and without music aerobic exercise (MAE) for 12 weeks. The MAE group involved 47 eligible participants, whereas the comparison group had 59 participants. No significant differences were recorded in the demographic characteristics between the participants in the MAE group and the comparison group. Forty-one participants in the MAE group and 26 in the comparison group completed a pre- and posttest. The MAE group displayed significant improvement in depression scores (p = 0.016), decreased depression symptoms in crying (p = 0.03), appetite (p = 0.006), and fatigue (p = 0.011). The BDNF levels of the participants significantly increased after the 12-week MAE (p = 0.042). The parallel comparison group revealed no significant changes in depression scores or BDNF levels. In summary, the 12-week MAE had a significant impact on the enhancement of BDNF levels and improvement of depression symptoms. Middle-aged community women are encouraged to exercise moderately to improve their depression symptoms and BDNF levels.

  4. Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor.

    PubMed

    Rendeiro, Catarina; Vauzour, David; Rattray, Marcus; Waffo-Téguo, Pierre; Mérillon, Jean Michel; Butler, Laurie T; Williams, Claire M; Spencer, Jeremy P E

    2013-01-01

    Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w), results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively), to a similar extent to that following blueberry supplementation (p = 0.002). These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, p<0.01), suggesting a common mechanism for the enhancement of memory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods.

  5. Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health

    PubMed Central

    Rothman, Sarah M; Griffioen, Kathleen J; Wan, Ruiqian; Mattson, Mark P

    2012-01-01

    Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes, and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer's and Parkinson's diseases) neurological disorders. The findings described later, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this paper provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders. PMID:22548651

  6. A new derivatizing agent, trimethylammoniopropyl methanethiosulphonate, is efficient for preparation of recombinant brain-derived neurotrophic factor from inclusion bodies.

    PubMed

    Inoue, M; Akimaru, J; Nishikawa, T; Seki, N; Yamada, H

    1998-12-01

    Derivatization with trimethylammoniopropyl methanethiosulphonate (TAPS-sulphonate) enabled brain-derived neurotrophic factor (BDNF) to be prepared efficiently from Escherichia coli inclusion bodies. Reduced BDNF obtained from inclusion bodies solubilized by urea and reduced by dithiothreitol was suggested to form a complex with itself or with other compounds such as lipids. It could hardly be adsorbed on to cation-exchange resin for partial purification prior to a refolding reaction. Reversible derivatization of cysteine residues was tested as a method of dissociating BDNF from such complexes. However, even if a methyl or aminoethyl group was introduced, BDNF could not be dissociated readily. Derivatization with TAPS-sulphonate brought about good dissociation of BDNF, and more than 50% adsorbed on to the cation-exchange resin. BDNF derivatized with TAPS-sulphonate refolded well, and the refolded samples showed the same biological activity as purified BDNF. Derivatization with TAPS-sulphonate would increase the intermolecular repulsion of BDNF, due to the positively charged character of the quaternized amine, and inhibit complex formation. Thus, TAPS-sulphonate is effective for the preparation of BDNF under denatured conditions.

  7. Mesenchymal stem cells expressing brain-derived neurotrophic factor enhance endogenous neurogenesis in an ischemic stroke model.

    PubMed

    Jeong, Chang Hyun; Kim, Seong Muk; Lim, Jung Yeon; Ryu, Chung Heon; Jun, Jin Ae; Jeun, Sin-Soo

    2014-01-01

    Numerous studies have reported that mesenchymal stem cells (MSCs) can ameliorate neurological deficits in ischemic stroke models. Among the various hypotheses that have been suggested to explain the therapeutic mechanism underlying these observations, neurogenesis is thought to be critical. To enhance the therapeutic benefits of human bone marrow-derived MSCs (hBM-MSCs), we efficiently modified hBM-MSCs by introduction of the brain-derived neurotrophic factor (BDNF) gene via adenoviral transduction mediated by cell-permeable peptides and investigated whether BDNF-modified hBM-MSCs (MSCs-BDNF) contributed to functional recovery and endogenous neurogenesis in a rat model of middle cerebral artery occlusion (MCAO). Transplantation of MSCs induced the proliferation of 5-bromo-2'-deoxyuridine (BrdU-) positive cells in the subventricular zone. Transplantation of MSCs-BDNF enhanced the proliferation of endogenous neural stem cells more significantly, while suppressing cell death. Newborn cells differentiated into doublecortin (DCX-) positive neuroblasts and Neuronal Nuclei (NeuN-) positive mature neurons in the subventricular zone and ischemic boundary at higher rates in animals with MSCs-BDNF compared with treatment using solely phosphate buffered saline (PBS) or MSCs. Triphenyltetrazolium chloride staining and behavioral analysis revealed greater functional recovery in animals with MSCs-BDNF compared with the other groups. MSCs-BDNF exhibited effective therapeutic potential by protecting cell from apoptotic death and enhancing endogenous neurogenesis.

  8. Overexpression of Brain-Derived Neurotrophic Factor Protects Large Retinal Ganglion Cells After Optic Nerve Crush in Mice

    PubMed Central

    Chen, Hui; Liang, Peiji; Troy, John B.

    2017-01-01

    Abstract Brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neuron survival and function, plays an important role in neuroprotection during neurodegenerative diseases. In this study, we examined whether a modest increase of retinal BDNF promotes retinal ganglion cell (RGC) survival after acute injury of the optic nerve in mice. We adopted an inducible Cre-recombinase transgenic system to up-regulate BDNF in the mouse retina and then examined RGC survival after optic nerve crush by in vivo imaging. We focused on one subtype of RGC with large soma expressing yellow fluorescent protein transgene that accounts for ∼11% of the total SMI-32–positive RGCs. The median survival time of this subgroup of SMI-32 cells was 1 week after nerve injury in control mice but 2 weeks when BDNF was up-regulated. Interestingly, we found that the survival time for RGCs taken as a whole was 2 weeks, suggesting that these large-soma RGCs are especially vulnerable to optic nerve crush injury. We also studied changes in axon number using confocal imaging, confirming first the progressive loss reported previously for wild-type mice and demonstrating that BDNF up-regulation extended axon survival. Together, our results demonstrate that the time course of RGC loss induced by optic nerve injury is type specific and that overexpression of BDNF prolongs the survival of one subgroup of SMI-32–positive RGCs. PMID:28101532

  9. An Antioxidant Dietary Supplement Improves Brain-Derived Neurotrophic Factor Levels in Serum of Aged Dogs: Preliminary Results

    PubMed Central

    Sechi, Sara; Chiavolelli, Francesca; Spissu, Nicoletta; Di Cerbo, Alessandro; Canello, Sergio; Guidetti, Gianandrea; Fiore, Filippo; Cocco, Raffaella

    2015-01-01

    Biological aging is characterized by a progressive accumulation of oxidative damage and decreased endogenous antioxidant defense mechanisms. The production of oxidants by normal metabolism damages proteins, lipids, and nucleotides, which may contribute to cognitive impairment. In this study 36 dogs were randomly divided into four groups and fed croquettes of different compositions for 6 months. We monitored derivatives of reactive oxygen metabolites (dROMs) and biological antioxidant potential (BAP) levels in dogs' plasma samples as well as brain-derived neurotrophic factor (BDNF) serum levels at the beginning and at the end of the dietary regime. Our results showed that a dietary regime, enriched with antioxidants, induced a significant decrease of plasma levels of dROMs (p < 0.005) and a significant increase in BDNF serum levels (p < 0.005) after six months. Thus, we hypothesized a possible role of the diet in modulating pro- and antioxidant species as well as BDNF levels in plasma and serum, respectively. In conclusion the proposed diet enriched with antioxidants might be considered a valid alternative and a valuable strategy to counteract aging-related cognitive decline in elderly dogs. PMID:26464952

  10. Brain-derived neurotrophic factor (BDNF) gene delivery into the CNS using bone marrow cells as vehicles in mice.

    PubMed

    Makar, T K; Trisler, D; Eglitis, M A; Mouradian, M M; Dhib-Jalbut, S

    2004-02-19

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is protective in animal models of neurodegenerative diseases. However, BDNF has a short half-life and its efficacy in the CNS when delivered peripherally is limited due to the blood-brain barrier. In the present study, bone marrow cells were used as vehicles to deliver the BDNF gene into the CNS. Marrow cells obtained from 6 to 8 week-old SJL/J mice were transduced with BDNF expressing pro-virus. RT-PCR analysis revealed that BDNF mRNA was expressed in transduced but not in non-transduced marrow cells. Additionally, virus transduced marrow cells expressed the BDNF protein (296+/-1.2 unit/ml). BDNF-transduced marrow cells were then transplanted into irradiated mice through the tail vein. Three months post-transplantation, significant increases in BDNF as well as glutamic acid decarboxylase (GAD(67)) mRNA were detected in the brains of BDNF transplanted mice compared to untransplanted animals, indicating biological activity of the BDNF transgene. Thus, bone marrow cells can be used as vehicles to deliver the BDNF gene into the brain with implications for the treatment of neurological diseases.

  11. Attention-deficit hyperactivity disorder and intellectual disability: a study of association with brain-derived neurotrophic factor gene polymorphisms.

    PubMed

    Aureli, A; Del Beato, T; Sebastiani, P; Marimpietri, A; Melillo, C V; Sechi, E; Di Loreto, S

    2010-01-01

    Symptoms of attention-deficit hyperactivity disorder (ADHD) have been found in several studies of children with intellectual disabilities (ID) but the two diseases are not always associated. Several lines of evidence implicate the involvement of brain-derived neurotrophic factor (BDNF) in ADHD, and it may also be relevant in ID due to its known involvement in the development of the central nervous system (CNS) and in learning/memory functions. We genotyped paediatric patients with ADHD and ID for the Val66Met and 270 C/T polymorphisms in BDNF. Diagnosis of ADHD and ID was confirmed by the clinicians in accordance with DSM-IV criteria. The G/A genotype of the Val66Met SNP was associated with both ADHD and ID, and the G allele was significantly associated with ADHD. The C/C genotype of the C270T SNP was significantly overrepresented in both ADHD and ID groups compared with the controls. Data suggest that both BDNF polymorphisms could play a role in the etiology of ADHD. In addition, we present the first results suggesting that these BDNF SNPs are significantly associated with ID.

  12. Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain.

    PubMed

    Schnydrig, Sabine; Korner, Lukas; Landweer, Svenja; Ernst, Beat; Walker, Gaby; Otten, Uwe; Kunz, Dieter

    2007-12-11

    Peripheral inflammation induced by intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS) is known to cause functional impairments in the brain affecting memory and learning. One of mechanisms may be the interference with neurotrophin (NT) expression and function. In the current study we administered a single, high dose of LPS (3mg/kg, i.p.) into mice and investigated changes in brain-derived neurotrophic factor (BDNF) gene expression within 1-6 days after LPS injection. Crude synaptosomes were isolated from brain tissue and subjected to Western-blot analyses. We found transient reductions in synaptosomal proBDNF- and BDNF protein expression, with a maximal decrease at day 3 as compared to saline injected controls. The time course of reduction of BDNF mRNA in whole brain extracts parallels the decrease in protein levels in synaptosomes. LPS effects in the central nervous system (CNS) are known to crucially involve the activation of the hypothalamic-pituitary-adrenal (HPA) axis. We analysed the time course of corticotropin releasing hormone (CRH)- and proopiomelanocortin (POMC) mRNA expression. As observed for BDNF-, CRH- and POMC mRNA levels are also significantly reduced on day 3 indicating a comparable time course. These results suggest that peripheral inflammation causes a reduction of trophic supply in the brain, including BDNF at synaptic sites. The mechanisms involved could be a negative feedback of the activated HPA axis.

  13. Construction of a plasmid for human brain-derived neurotrophic factor and its effect on retinal pigment epithelial cell viability

    PubMed Central

    Yan, Bo-jing; Wu, Zhi-zhong; Chong, Wei-hua; Li, Gen-lin

    2016-01-01

    Several studies have investigated the protective functions of brain-derived neurotrophic factor (BDNF) in retinitis pigmentosa. However, a BDNF-based therapy for retinitis pigmentosa is not yet available. To develop an efficient treatment for fundus disease, an eukaryotic expression plasmid was generated and used to transfect human 293T cells to assess the expression and bioactivity of BDNF on acute retinal pigment epithelial-19 (ARPE-19) cells, a human retinal epithelial cell line. After 96 hours of co-culture in a Transwell chamber, ARPE-19 cells exposed to BDNF secreted by 293T cells were more viable than ARPE-19 cells not exposed to secreted BDNF. Western blot assay showed that Bax levels were downregulated and that Bcl-2 levels were upregulated in human ARPE-19 cells exposed to BDNF. Furthermore, 293T cells transfected with the BDNF gene steadily secreted the protein. The powerful anti-apoptotic function of this BDNF may be useful for the treatment of retinitis pigmentosa and other retinal degenerative diseases. PMID:28197196

  14. Ciliary Neurotrophic Factor (CNTF) for Macular Telangiectasia Type 2 (MacTel): Results from a phase I safety trial

    PubMed Central

    Chew, Emily Y.; Clemons, Traci E.; Peto, Tunde; Sallo, Ferenc B.; Ingerman, Avner; Tao, Weng; Singerman, Lawrence; Schwartz, Steven D.; Peachey, Neal S.; Bird, Alan C.

    2015-01-01

    PURPOSE To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. DESIGN An open-labeled safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. METHODS The participant’s more severely affected eye (worse baseline visual acuity) received the high dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. RESULTS The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. CONCLUSIONS The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy. PMID:25528956

  15. Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury

    PubMed Central

    Wurzelmann, Mary; Romeika, Jennifer; Sun, Dong

    2017-01-01

    Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects,