BDNF Production Research Articles

Effect of glatiramer acetate (Copaxone ®) on the immunophenotypic and cytokine profile and BDNF production in multiple sclerosis: A longitudinal study

We assessed the effect of glatiramer acetate (GA) on the immunophenotypic and cytokine profile and the BDNF production by peripheral blood mononuclear cells, and their association with the clinical response in 19 naïve-treated MS patients prospectively followed-up after GA therapy. Two patients withdrew the therapy. After a median follow-up of 21 months, twelve were considered responders and five as non-responders. Non-responder patients had significant longer disease duration and a higher EDSS score at baseline. In the responder group, a significant decrease in the percentage of INF-γ producing total lymphocytes, CD4 + and CD8 + T cells, and reduced percentage of IL-2 producing CD4 + and CD8 + T cells were observed at 12, 18 and 24 months. These changes were associated with a significant increase in the percentage of CD3 +, CD4 + and CD4 +CD45RA + T cells, and BDNF production from month 6 that remained significant throughout the study. We did not observe significant changes in the nonresponder group for any of the parameters studied. Our data suggest that GA treatment induces a downmodulation of proinflammatory cytokines associated with the regulation of the peripheral T cell compartment and with increased production of BDNF that might be related to the clinical response.

P3-342: Abeta upregulates BDNF production from astrocytes: Rescue of neurons from abeta-related synaptic impairment

P3-342: Abeta upregulates BDNF production from astrocytes: Rescue of neurons from abeta-related synaptic impairment

Sa.35. BDNF Production by Immune Cells of Relapsing Remitting Multiple Sclerosis Is Reduced and Is Not Responsive to Cd40 Stimulation

Sa.35. BDNF Production by Immune Cells of Relapsing Remitting Multiple Sclerosis Is Reduced and Is Not Responsive to Cd40 Stimulation

Neurotrophic factors in relapsing remitting and secondary progressive multiple sclerosis patients during interferon beta therapy

Although interferon (IFN) beta is a widely used disease-modifying therapy in multiple sclerosis (MS), the mechanisms responsible for its effects are not fully understood. Some studies demonstrated that IFNbeta induces nerve growth factor (NGF) secretion by astrocytes and by brain endothelial cells. In this study, we determined the production of various neurotrophins (brain-derived neurotrophic factor, BDNF; NGF; glial cell line-derived neurotrophic factor; neurotrophin 3; neurotrophin 4) by peripheral blood mononuclear cells (PBMCs) in relapsing–remitting (RR) and secondary progressive (SP) MS patients during IFNbeta treatment. There were no main variations in neurotrophin production either among all MS patients globally considered or in the group of SPMS subjects. Instead, in the group of RRMS patients who did not present clinical exacerbation of disease up to the end of the study, we found a significant increase in BDNF production as from 6 months after starting therapy.

Epithelial NGF and BDNF production induce prolonged survival of eosinophils during allergic airway inflammation

Epithelial NGF and BDNF production induce prolonged survival of eosinophils during allergic airway inflammation

BDNF Gene-Modified Mesenchymal Stem Cells Promote Functional Recovery and Reduce Infarct Size in the Rat Middle Cerebral Artery Occlusion Model

Examination of the clinical therapeutic efficacy of using bone marrow stromal cells, including mesenchymal stem cells (MSC), has recently been the focus of much investigation. MSC were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we transfected telomerized human MSC with the BDNF gene using a fiber-mutant F/RGD adenovirus vector and investigated whether these cells contributed to improved functional recovery in a rat transient middle cerebral artery occlusion (MCAO) model. BDNF production by MSC-BDNF cells was 23-fold greater than that seen in uninfected MSC. Rats that received MSC-BDNF showed significantly more functional recovery than did control rats following MCAO. Specifically, MRI analysis revealed that the rats in the MSC-BDNF group exhibited more significant recovery from ischemia after 7 and 14 days. The number of TUNEL-positive cells in the ischemic boundary zone was significantly smaller in animals treated with MSC-BDNF compared to animals in the control group. These data suggest that MSC transfected with the BDNF gene may be useful in the treatment of cerebral ischemia and may represent a new strategy for the treatment of stroke.

P.3.08 Effect of different neurochemicals on peripheral BDNF production

P.3.08 Effect of different neurochemicals on peripheral BDNF production

Glatiramer acetate-reactive T cells produce brain-derived neurotrophic factor

Experimental and MRI evidence suggest that glatiramer acetate's (Copaxone) therapeutic effect in multiple sclerosis (MS) could be mediated by anti-inflammatory GA-reactive Th2 cells that enter the brain, cross-react with myelin antigens, and produce bystander suppression. Furthermore, a neuroprotective effect, possibly mediated by neurotrophic factors such as BDNF, has been suggested based on experimental evidence in animal models, and the observation that inflammatory cells can elaborate BDNF. Therefore, we examined BDNF production in 73 GA, 13 MBP, and 22 TT-reactive short-term T-cell lines from 12 MS patients treated with GA. Ten of 73 GA-TCL (14%), 1 of the MBP-TCL (3%), and 2 of the TT-TCL (9%) produced BDNF levels two standard deviations above the mean levels produced by resting TCL. RT-PCR analysis confirmed BDNF expression in some GA- and MBP-reactive TCL. The mean BDNF level produced by GA-TCL was significantly higher than that for MBP-TCL, or TT-TCL when lines originating from the same patients were compared ( P=0.033). All 10 high BDNF-producing GA-reactive TCL were Th2-biased as determined by the IL-5/IFN-γ levels ratio. A positive correlation was observed between BDNF and IL-5 (Th2 indicator) ( P=0.006) but not with IFN-γ Th1 indicator) levels in GA-TCL derived from MS patients during but not pre-treatment. We conclude that while BDNF production by T cells is not antigen-specific, GA-reactive TCL are more likely to produce BDNF, and to be Th2-biased.

Neuroprotection of Vestibular Sensory Cells from Gentamicin Ototoxicity Obtained Using Nitric Oxide Synthase Inhibitors, Reactive Oxygen Species Scavengers, Brain-derived Neurotrophic Factors and Calpain Inhibitors

Objective--In order to devise a new treatment for inner ear disorders, the efficacy of a nitric oxide synthase inhibitor (L-NG-nitroarginine methylester [L-NAME]), a radical scavenger (D-methionine), a neurotrophin (brain-derived neurotrophic factor [BDNF]) and a calpain inhibitor (leupeptin) for protection from hair cell damage was investigated. Material and methods--The effects of these drugs on gentamicin-induced production of nitric oxide (NO) and reactive oxygen species (ROS) were studied by means of the fluorescence indicators 4,5-diaminofluorescein diacetate and dihydrotetramethylrosamine. The effect on gentamicin-induced vestibular hair cell damage was examined by using an in vitro LIVE/DEAD system. Results--L-NAME inhibited the production of NO, D-methionine and BDNF restricted the production of ROS and leupeptin inhibited neither NO nor ROS. All the drugs used limited the vestibular hair cell damage caused by gentamicin. The combinations L-NAME+BDNF, L-NAME+leupeptin and D-methionine+BDNF had a significantly stronger preventive effect on hair cell damage. Conclusion--It is suggested that combined treatment with a radical inhibitor and either a neurotrophin or calpain inhibitor may help to treat inner ear disorders more effectively.

Brain-derived neurotrophic factor in patients with multiple sclerosis

The aim of the present research was to verify the production of BDNF by peripheral blood mononuclear cells (PBMCs), unstimulated and stimulated with phytohemagglutinin (PHA), anti-OKT3 Ab and myelin basic protein (MBP), in 35 patients affected by multiple sclerosis (MS), 20 with relapsing–remitting (R-R) MS and 15 with secondary progressive (SP) MS. Seven R-R MS patients were assessed during the attack, in the subsequent recovery phase and also 3 months after relapse. The production of BDNF by PBMCs was also evaluated in 20 age- and sex-matched control subjects. Levels of BDNF were also determined in CSF of both patient groups and 20 control subjects. Results: Levels of BDNF (pg/ml) in the supernatants of unstimulated and PHA-, anti-OKT3 Ab- and MBP-stimulated PBMCs in patients with R-R MS were significantly higher during relapse and in the recovery phase compared with values detected in the stable phase of the disease. Significantly lower BDNF values were found in unstimulated and stimulated PBMC supernatants of patients with SP MS compared to control subjects. This reduction was greater in patients with a 1-point increase in the EDSS score in the last 6 months compared with that in patients without a progression of the disability score. Reduction in the levels of BDNF was also confirmed in the CSF of SP MS patients compared with R-R MS patients assessed during a stable phase of the disease and control subjects. Discussion: On the basis of recent experimental findings, a neuroprotective effect of BDNF produced by inflammatory cells can be hypothesized during relapses in MS. This can favor remyelination. The reduced production of BDNF by PBMCs of patients with SP MS can contribute to the progression of demyelinating disease and axonal loss in this form.

Biomedicine. Huntingtin--profit and loss.

Huntington9s disease (HD) is a neurodegenerative disease caused by an expanded run of glutamine repeats in the huntingtin protein. How this glutamine expansion results in the selective loss of striatal neurons characteristic of HD is not known. In a Perspective, Trottier and Mandel discuss new findings demonstrating that loss of the beneficial effects of the wild-type huntingtin protein, including production of BDNF, results in the demise of striatal neurons, which depend on BDNF for their survival.

Transgenic Mice Overexpressing Truncated trkB Neurotrophin Receptors in Neurons Show Increased Susceptibility to Cortical Injury after Focal Cerebral Ischemia

It has been suggested that the increased production of endogenous BDNF after brain insults supports the survival of injured neurons and limits the spread of the damage. In order to test this hypothesis experimentally, we have produced transgenic mouse lines that overexpress the dominant-negative truncated splice variant of BDNF receptor trkB (trkB.T1) in postnatal cortical and hippocampal neurons. When these mice were exposed to transient focal cerebral ischemia by occluding the middle cerebral artery for 45 min and the damage was assessed 24 h later, transgenic mice had a significantly larger damage than wild-type littermates in the cerebral cortex (204 ± 32% of wild-type, P = 0.02), but not in striatum, where the transgene is not expressed. Our results support the notion that endogenously expressed BDNF is neuroprotective and that BDNF signaling may have an important role in preventing brain damage after transient ischemia.

BDNF gene transfer to the mammalian brain using CNS-derived neural precursors.

Neural stem cell lines represent a homogeneous source of cells for genetic, developmental, and gene transfer and repair studies in the nervous system. Since both gene transfer of neurotrophic factors and cell replacement strategies are of immediate interest for therapeutical purposes, we have generated BDNF-secreting neural stem cell lines and investigated to what extent different endogenous levels of BDNF expression affect in vitro survival, proliferation and differentiation of these cells. Also, we have investigated the in vivo effects of such BDNF gene transfer procedure in the rat neostriatum. Hippocampus- and cerebellum-derived cell lines reacted differently to manipulations aimed at varying their levels of BDNF production. Over-expression of BDNF enhanced survival of both cell types, in a serum-deprivation assay. Conversely, and ruling out unspecific effects, expression of an antisense version of BDNF resulted in compromised survival of cerebellum-derived cells, and in a lethal phenotype in hippocampal progenitors. These data indicate that endogenous BDNF level strongly influences the in vitro survival of these cells. These effects are more pronounced for hippocampus- than for cerebellum-derived progenitors. Hippocampus-derived BDNF overproducers showed no major change in their capacity to differentiate towards a neuronal phenotype in vitro. In contrast, cerebellar progenitors overproducing BDNF did not differentiate into neurons, whereas cells expressing the antisense BDNF construct generated cells with morphological features of neurons and expressing immunological neuronal markers. Taken together, these results provide evidence that BDNF controls both the in vitro survival and differentiation of neural stem cells. After in vivo transplantation of BDNF-overproducing cells to the rat neostriatum, these survived better than the control ones, and induced the expected neurotrophic effects on cholinergic neurons. However, long-term (3 months) administration of BDNF resulted in detrimental effects, at this location. These findings may be of importance for the understanding of brain development, for the design of therapeutic neuro-regenerative strategies, and for cell replacement and gene therapy studies.

Enhancement of BDNF production by co-cultivation of human neuroblastoma and fibroblast cells

It has been proved that co-cultivation of human neuroblastoma cells and human fibrolast cells can enhance nerve cell growth and the production of BDNF in perfusion cultivation. In batch co-cultivation, maximum cell density was increased up to 1.76×106 viable cells/mL from 9×105 viable cells/mL of only neuroblastoma cell culture. The growth of neuroblastoma cells was greatly improved by culturing both nerve and fibroblast cells in a perfusion process, maintaining 1.5×106 viable cells/mL, which was much higher than that from fed-batch cultivation. The nerve cell growth was greatly enhanced in both fed-batch and perfusion cultivations while the growth of fibroblast cells was not. It strongly implies that the factors secreted from, human fibroblast cells and/or the environments of co-culture system can enhance both cell growth and BDNF secretion. Specific BDNF production rate was not enhanced in co-cultures; however, the production period was increased as the cell growth was lengthened in the co-culture case. Competitive growth between nerve cells and fibroblast cells was not observed in all cases, showing no changes of fibroblast cell growth and only enhancement of the neuroblastoma cell growth and overall BDNF production. It was also found that the perfusion cultivation was the most appropriate process for cultivating two cell lines simultaneously in a bioreactor.

Paracrine Interactions of BDNF Involving NGF-Dependent Embryonic Sensory Neurons

The expression of BDNF mRNA by a proportion of embryonic dorsal root ganglion neurons has led to the proposal that BDNF acts by an autocrine loop on these neurons. To clarify the role of BDNF expression in developing sensory neurons, we measured the level of BDNF mRNA in purified populations of cranial sensory neurons that depend on either NGF or BDNF for survival. When neuronal death is taking place, the highest levels of BDNF mRNA were detected in NGF-dependent cutaneous sensory neurons. BDNF mRNA was expressed at lower levels in BDNF-dependent cutaneous sensory neurons and was undetectable in BDNF-dependent proprioceptive neurons. In coculture, NGF-dependent neurons promoted the survival of BDNF-dependent neurons by the production and release of BDNF. Depolarizing levels of KCl increased the expression of BDNF mRNA in cultured sensory neurons and this effect was partially inhibited by calcium channel antagonists. Our results suggest that during the phase of naturally occurring neuronal death, BDNF acts by a paracrine mechanism in sensory neurons and that BDNF expression is regulated by neural activity.

Activity‐dependent and hormonal regulation of neurotrophin mRNA levels in brain–implications for neuronal plasticity

The neurotrophins exhibit neurotrophic effects on specific, partially overlapping populations of neurons both in the peripheral and the central nervous system (CNS). In the periphery, they are synthesized by a variety of nonneuronal cells, and their synthesis seems to be independent of the neuronal input. In contrast, in the CNS all neurotrophins are expressed under physiological conditions primarily by neurons. The production of NGF and BDNF is controlled by neuronal activity: up-regulation by glutamate and acetylcholine, down-regulation by gamma-aminobutyric acid. In contrast, NT-3 regulation is independent of neuronal activity, but it is up-regulated by thyroid hormones and BDNF. The latter observation suggests that NT-3 might be controlled indirectly by neuronal activity via BDNF. In peripheral nonneuronal tissues, glucocorticoid hormones down-regulate NGF mRNA levels both in vitro and in vivo. In contrast, in the CNS, neuronal production of NGF is enhanced by glucocorticoids. The rapid regulation of NGF and BDNF by subtle physiological stimuli together with the recent demonstration that the neurotrophins release neurotransmitters such as acetylcholine opens up interesting perspectives for the function of neurotrophins as mediators of neuronal plasticity.