Brain-derived neurotrophic factor selectively rescues mesencephalic dopaminergic neurons from 2,4,5-trihydroxyphenylalanine-induced injury

Brain-derived neurotrophic factor (BDNF) supports the survival of sensory neurons as well as retinal ganglion cells, basal forebrain cholinergic neurons, and mesencephalic dopaminergic neurons in vitro. Here we examined the ability of BDNF to confer protection on cultured dopaminergic neurons against the neurotoxic effects of 6-hydroxyDOPA (TOPA or 2,3,5,-trihydroxyphenylalanine), a metabolite of the dopamine pathway suggested to participate in the pathology of Parkinson's disease. Cells prepared from embryonic day 14–15 rat mesencephalon were maintained with 10–50 ng/ml BDNF for 7 days prior to addition of TOPA (10–30 μM) for 24 hr. In BDNF-treated cultures, the extensive loss ( >90%) of tyrosine hydroxylase immunopositive cells was virtually (<10%) eliminated, while the equally drastic loss (>90%) of the overall cell population was limited to only a 25–30% recovery. Furthermore, the monosialoganglioside GM1 (1–10 μM), although inactive alone, acted synergistically with subthreshold amounts of BDNF to rescue tyrosine hydroxylase-positive cells against TOPA neurotoxicity. These results add impetus to exploring the therapeutic potential of gangliosides and BDNF in Parkinson's disease. © 1993 Wiley-Liss, Inc.     

脑源性神经营养因子对海马神经元NMDA受体功能下调的逆转作用

应用全细胞膜片钳技术研究BDNF对培养养海马神经元NMDA受体的调控作用。结果发现,培养18d的海马神经元NMDA诱发电流小,BDNF可快速、可逆地增加NMDA诱发电流,而培养10,14d的海马神经元NMDA诱发电流大,BDNF增强NMDA诱发电流不明显。本文结果提示BDNF对功能低下的海马神经元NMDA受体具有上调作用。     

脑源性神经营养因子对海马神经元NMDA受体功能下调的逆转作用

应用全细胞膜片钳技术研究BDNF对培养海马神经元NMDA受体的调控作用.结果发现,培养18d的海马神经元NMDA诱发电流小,BDNF可快速、可逆地增加NMDA诱发电流,而培养10,14d的海马神经元NMDA诱发电流大,BDNF增强NMDA诱发电流不明显.本文结果提示BDNF对功能低下的海马神经元NMDA受体具有上调作用.     

Brain-derived neurotrophic factor rescues neuronal death induced by methamphetamine.

BACKGROUND: Methamphetamine (MA) induces degeneration of various regions of the brain, resulting in neuropsychiatric damage. Although the underlying mechanisms of MA-induced neurotoxicity have been studied, there are few reports to date regarding the factor(s) that can effectively prevent MA-induced neurotoxicity. Because brain-derived neurotrophic factor (BDNF) has been known to prevent many kinds of neuronal cell death, we investigated whether BDNF inhibits MA-induced neuronal death. METHODS: Using primary cortical neurons, we examined the effect of BDNF on MA-induced neuronal death. In addition, using pharmacologic and molecular biological tools, we elucidated which pathways are involved in this effect. RESULTS: Brain-derived neurotrophic factor dose-dependently blocked MA-induced neuronal death, and this effect was inhibited by phosphatidylinositol-3-kinase inhibitors. In addition, overexpression of activated Akt protects neurons against MA. Furthermore, expression of kinase-defective Akt blocked the effect of BDNF on MA-induced neuronal death. CONCLUSIONS: Brain-derived neurotrophic factor effectively blocks MA-induced neuronal death, and Akt activation is necessary and sufficient for this effect.     

Brain-derived neurotrophic factor

Zusammenfassung Der brain-derived neurotrophic factor (BDNF) gehört zur Familie der Neurotrophine und spielt eine wichtige Rolle beim axonalen und dendritischen Wachstum von Neuronen und der Gehirnplastizität. Die Proform von BDNF (pro-BDNF) wird in den synaptischen Spalt ausgeschüttet und dort durch die Protease Plasmin zum maturen BDNF abgebaut. BDNF fördert die synaptische Plastizität und eine Langzeitpotenzierung. Neuere Untersuchungsergebnisse deuten auf eine Beteiligung von BDNF und dessen genetischer funktioneller Polymorphismen bei der Pathogenese verschiedener psychischer Erkrankungen wie z. B. Depression, Manie, Schizophrenie, Essstörungen, Demenz und Huntington-Erkrankung hin. Die BDNF-Konzentration im Gehirn, aber auch im Serum wird durch verschiedene Faktoren beeinflusst. Sie ist z. B. durch Stress vermindert und wird durch Lernprozesse, verschiedene antidepressive Therapiemodalitäten, körperliche Aktivität und Diät erhöht. Die Bestimmung der BDNF-Serumspiegel könnte diagnostische Bedeutung erlangen. Daneben könnte die gezielte Beeinflussung der BDNF-Verfügbarkeit durch verschiedene Maßnahmen eine Relevanz zur Therapie und möglicherweise auch zur Prävention oben genannter psychischer Krankheitsbilder gewinnen.     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson''s disease

BACKGROUND:Parkinson's disease (PD) is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor (BDNF) mRNA (20%) than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.     

Brain-derived neurotrophic factor mediates macrophage migration inhibitory factor to protect neurons against oxygen-glucose deprivation

Macrophage migration inhibitory factor(MIF)is a chemokine that plays an essential role in immune system function.Previous studies suggested that MIF protects neurons in ischemic conditions.However,few studies are reported on the role of MIF in neurological recovery after ischemic stroke.The purpose of this study is to identify the molecular mechanism of neuroprotection mediated by MIF.Human neuroblastoma cells were incubated in Dulbecco’s modified Eagle’s medium under oxygen-glucose deprivation(OGD)for 4 hours and then returned to normal aerobic environment for reperfusion(OGD/R).30 ng/mL MIF recombinant(30 ng/mL)or ISO-1(MIF antagonist;50μM)was administered to human neuroblastoma cells.Then cell cultures were assigned to one of four groups:control,OGD/R,OGD/R with MIF,OGD/R with ISO-1.Cell viability was analyzed using WST-1 assay.Expression levels of brain-derived neurotrophic factor(BDNF),microtubule-associated protein 2(MAP2),Caspase-3,Bcl2,and Bax were detected by western blot assay and immunocytochemistry in each group to measure apoptotic activity.WST-1 assay results revealed that compared to the OGD/R group,cell survival rate was significantly higher in the OGD/R with MIF group and lower in the OGD/R with ISO-1 group.Western blot assay and immunocytochemistry results revealed that expression levels of BDNF,Bcl2,and MAP2 were significantly higher,and expression levels of Caspase-3 and Bax were significantly lower in the MIF group than in the OGD/R group.Expression levels of BDNF,Bcl2,and MAP2 were significantly lower,and expression levels of Caspase-3 and Bax were significantly higher in the ISO-1 group than in the OGD/R group.MIF administration promoted neuronal cell survival and induced high expression levels of BDNF,MAP2,and Bcl2(anti-apoptosis)and low expression levels of Caspase-3 and Bax(pro-apoptosis)in an OGD/R model.These results suggest that MIF administration is effective for inducing expression of BDNF and leads to neuroprotection of neuronal cells against hypoxic injury.     

Brain-derived neurotrophic factor and post-stroke depression

Brain-derived neurotrophic factor (BDNF) is well known to play a critical role in cognition. Its role in mood disorders, including post stroke depression (PSD), is also recognized with more evidence surfacing. In patients with PSD, their serum BNDF level is lower than in those without depression. Furthermore, antidepressants could enhance BDNF expression in the brain, resulting in an alleviation of depression symptoms. Such therapeutic effect can be abolished in animals with the BDNF gene deleted. In PSD patients, the presence of stroke may contribute to the development of depression, including affecting the expression of BDNF. However, the mechanisms of BDNF in the development of PSD remain largely unknown. Lower BDNF levels may have existed in some patients before stroke onset, making them vulnerable to develop depressive symptoms. Meanwhile, the hypoxic environment induced by stroke could possibly downregulate BDNF expression in the brain. Current antidepressant treatments are not specific for PSD and there is a lack of treatments to address the linkage between stroke and PSD. This review summarizes the current knowledge of BDNF in PSD. By regulating BDNF expression, a synergistic effect may be achieved when such treatments are applied together with existing antidepressants.     

Brain-derived neurotrophic factor in Huntington disease

Trophic factors, administered systemically or delivered via genetically-modified cells grafted into target regions, have been proposed as putative therapeutic agents in human neurodegenerative disorders. In parallel to the study of the beneficial effects in experimental models of particular diseases, a crucial aspect of the study of trophic factors is the gathering of information about the actual trophic factor expression in human diseased states. Brain-derived neurotrophic factor (BDNF) promotes survival and growth of various nerve cell populations during normal development and following various insults in the developing and adult brain. In particular, BDNF prevents cell death of certain striatal populations in excitotoxic models of Huntington disease (HD) following intrastriatal injection of quinolinic acid to the adult rodent brain. The present study examines BDNF expression, by gel electrophoresis and Western blotting, and immunohistochemistry, in the brains of patients who had suffered from HD. Reduced BDNF expression, ranging from 53 to 82%, has been found in the caudate and putamen in HD when compared with age-matched controls. No modifications in BDNF expression levels have been seen in the parietal cortex, temporal cortex and hippocampus. Furthermore, immunohistochemistry has shown reduced BDNF immunoreactivity in caudate neurons, but not in cortical neurons in HD when compared with controls. These data demonstrate selective BDNF decay in regions that are vulnerable to HD, and suggest, in combination with results in experimental models, that a BDNF surplus may have beneficial effects in the treatment of HD.     

Brain-derived neurotrophic factor upregulates and maintains AMPA receptor currents in neocortical GABAergic neurons

The regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors is implicated in synaptic plasticity. Although we have found that brain-derived neurotrophic factor (BDNF) triggers surface translocation of AMPA receptor proteins, the physiological significance of the BDNF effect remained to be determined. The present immunohistochemical studies revealed that cortical GABAergic neurons exhibited the most striking response to BDNF. Accordingly, we monitored AMPA-triggered currents through GABAergic neurons: Chronic BDNF treatment increased the AMPA-triggered currents but not NMDA-triggered currents in culture. In parallel, the amplitude, but not frequency, of spontaneous miniature excitatory postsynaptic currents (mEPSCs) was elevated in GABAergic neurons. In agreement, BDNF enhanced GABA release triggered by AMPA compared to the amount triggered by high potassium. Conversely, there was a significant decrease in the mEPSC amplitude of GABAergic neurons in heterozygous BDNF-knockout mice. These findings indicate that the neurotrophin enhances the input sensitivity of GABAergic neurons to facilitate their inhibitory function in the neocortex.     

Brain-derived neurotrophic factor/glial cell line-derived neurotrophic factor survival effects on auditory neurons are not limited by dexamethasone

Cochlear implant performance depends on the number of surviving excitable auditory neurons and prevention of degradation of nerve-electrode interaction caused by adverse tissue reactions. Glucocorticoids and neurotrophic factors are promising options for a possible therapeutic intervention. Neurons dissociated from the spiral ganglion of rats (3-5 days old) were cultivated with addition of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and the corticosteroid dexamethasone in various concentrations (25, 50, 100 ng/ml) and in combination with each other (100 ng/ml). The results suggest that a combination of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor does not enhance spiral ganglion cell survival significantly when compared with single brain-derived neurotrophic factor treatment (100 ng/ml). In addition, dexamethasone application did not interfere with the survival-promoting effects of brain-derived neurotrophic factor or glial cell line-derived neurotrophic factor.     

Brain-derived neurotrophic factor regulation of N-methyl-D-aspartate receptor-mediated synaptic currents in suprachiasmatic nucleus neurons

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells. Previous work raises the possibility that brain-derived neurotrophic factor (BDNF) and its high-affinity receptor TrkB may be important as modulators of this excitatory input into the SCN. To test this possibility, we used whole-cell patch-clamp methods to measure excitatory currents in rat SCN neurons. These currents were evoked by electrical stimulation of the optic nerve. We found that the amplitude of the N-methyl-D-aspartate (NMDA) component of the evoked excitatory postsynaptic currents (NMDA-EPSC) was increased by application of BDNF. The neurotrophin also increased the magnitude of NMDA-evoked currents in SCN neurons. The BDNF enhancement of the NMDA-EPSC was blocked by treatment with the neurotrophin receptor antagonist K252a as well as treatment with the soluble form of the TrkB receptor engineered as an immunoadhesin (TrkB IgG). Finally, the BDNF enhancement was lost in brain slices treated with the NR2B antagonist ifenprodil. The results demonstrate that BDNF and TrkB receptors are important regulators of retinal glutamatergic synaptic transmission within the SCN.     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson’s disease☆

Parkinson＇s disease （PD） is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor （BDNF） mRNA （20%） than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.     

Brain-derived neurotrophic factor in amygdala-dependent learning.

The neurotrophin brain-derived neurotrophic factor (BDNF) has recently emerged as a possible molecular mediator of activity-dependent synaptic plasticity underlying learning and memory. Long-term potentiation (LTP) within the hippocampus and hippocampally dependent behaviors has been the primary model for examining the role of BDNF in learning and memory. However, these studies are limited by an incomplete understanding of the complex behavioral function of hippocampal circuitry, making it difficult to unravel the molecular machinery responsible for the formation and storage of these memories. In contrast, the amygdala and its role in Pavlovian fear conditioning promise to provide us with new insights into the mechanisms of BDNF-mediated synaptic plasticity during the learning and memory process. This article reviews the different levels of research on BDNF in learning and memory. The focus is primarily on the use of Pavlovian fear conditioning as a learning model that allows for the examination of the role of BDNF in the amygdala, following a single learning session and within a well-understood neural circuit.     

Brain-derived neurotrophic factor in experimental autoimmune neuritis

Long-term disability in Guillain-Barré syndrome (GBS) is associated with axonal, and some neuronal, degeneration. Brain-derived neurotrophic factor (BDNF) can prevent neuronal death following damage to motor axons and we have therefore examined the ability of BDNF to ameliorate the effects of experimental autoimmune neuritis (EAN), a model of GBS. Treatment of Lewis rats with BDNF (10 mg/kg/day) did not significantly affect the neurological deficit, nor significantly improve survival, motor function or motor innervation. The weight of the urinary bladder was significantly increased in control animals with EAN, but remained similar to normal in animals treated with BDNF. With the exception of a possibly protective effect indicated by bladder weight, this study suggests that BDNF may not provide an effective therapy for GBS, at least in the acute phase of the disease.     

Brain-derived neurotrophic factor increases activity of NR2B-containing N-methyl-D-aspartate receptors in excised patches from hippocampal neurons

Growth factors, including members of the neurotrophin gene family, play a central role in the regulation of neuronal survival and differentiation during development. In addition to these relatively long-term actions of neurotrophins, recent studies have shown that these factors also rapidly modulate synaptic transmission. Brain-derived neurotrophic factor (BDNF), in particular, regulates both pre- and postsynaptic aspects of hippocampal synaptic transmission. The postsynaptic effects include an increase in glutamate responsiveness, mediated by the N-methyl-D-aspartate (NMDA) glutamate receptor subtype. It is not clear, however, where BDNF-trkB signal transduction is initiated, because trkB receptors are located in both pre- and postsynaptic membranes. In the present study, we used excised membrane patches from cultured hippocampal neurons to determine whether BDNF directly modulates postsynaptic NMDA receptor activity. The results indicate that acute exposure to BDNF increases NMDA single channel open probability via postsynaptic trkB receptors and that this effect is dependent on the presence of the NR2B subunit of the NMDA receptor.     

Brain-derived neurotrophic factor spares choline acetyltransferase mRNA following axotomy of motor neurons in vivo

Choline acetyltransferase (ChAT) is a functional and specific marker gene for neurons such as primary motor neurons that synthesize and release acetylcholine as a neurotransmitter. In adult mammals, transection of the peripheral nerve results in a loss of immunoreactivity for ChAT in the injured motor neurons without affecting their cell number. Using a quantitative RNase protection assay, we have investigated dynamic changes in ChAT mRNA levels following axotomy of motor neurons in the brainstem of adult rats. One week after transection of the left hypoglossal nerve, levels of ChAT mRNA in the ipsilateral side of the hypoglossal motor nucleus decreased dramatically to around 10% when compared to the uninjured contralateral side. When cut axons were chronically exposed to brain-derived neurotrophic factor (BDNF) for 1 week, ChAT mRNA levels were maintained at 63% of control levels. Thus, BDNF can abrogate the injury-induced loss of ChAT mRNA in mature motor neurons in vivo. In contrast, neither neurotrophin 4/5 nor nerve growth factor could prevent the decrease in message. This effect of BDNF on ChAT mRNA levels following peripheral injury to motor neurons demonstrates the existence of regulatory pathways responsive to neurotrophic factors that can “rescue” or “protect” cholinergic gene expression. J. Neurosci. Res. 47:134–143, 1997. © 1997 Wiley-Liss, Inc.     

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.