Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment

INTRODUCTION: Stress, glucocorticoids and anti-depressant treatment have been found to modulate the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Recent research suggests that serum BDNF concentration is reduced in depression and that successful antidepressant treatment leads to an increase in serum BDNF concentration. METHODS: We studied depressed patients receiving a standardized antidepressant treatment with either 150 mg amitriptyline (n=20) or 40 mg paroxetine (n=20) for 36 days in a prospective design. Changes in the concentrations of serum neurotrophins and salivary cortisol in response to antidepressant treatment were assessed. RESULTS: Independent of clinical efficacy there was a significant 'treatment' by 'medication' interaction effect on BDNF serum concentrations that indicated a decline of BDNF by 12% in paroxetine-treated patients while there was an increase by 13% in amitriptyline-treated patients. Neither antidepressant altered NGF concentrations. The changes in cortisol and neurotrophin concentrations were not related. DISCUSSION: Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant instead of being a general characteristic of response to antidepressant treatment.     

Curcumin produces antidepressant effects via activating MAPK/ERK-dependent brain-derived neurotrophic factor expression in the amygdala of mice

The potential antidepressant effects of curcumin have been demonstrated in various animal models of depression, however, there is little information regarding the site and mechanisms of curcumin in promoting antidepressant effects. The present study attempts to explore the mechanisms underlying the antidepressant-like action of curcumin by measuring the contents of brain derived neurotrophic factor (BDNF) in the amygdala of animal model of depression. The results showed that treatment with curcumin (40mg/kg, i.p.) significantly reduced depressive-like behaviors of mice in the forced swim test. Chronic administration of curcumin (40mg/kg, i.p., 21 days) increased BDNF protein levels in the amygdala and this enhancement was suppressed by pretreatment with the extracellular signal-regulated kinase (ERK) inhibitor SL327. Additionally, the increased levels of ERK phosphoryation in the amygdala by curcumin were blocked by the ERK inhibitor, and inhibition of this kinase prevented the antidepressant effects of curcumin. All of these effects of curcumin, were essentially identical to that observed with the clinical antidepressant, fluoxetine. These results suggest that the antidepressant-like effects of curcumin in the forced swim test are mediated, at least in part, by an ERK-regulated increase of BDNF expression in the amygdala of mice.     

Epidermal growth factor influences the neurotrophic/differentiating action of nerve growth factor

Exposure of naive PC12 cells, sympathetic neurons from rat superior cervical ganglia, and brain-derived septal neurons to epidermal and nerve growth factors simultaneously resulted in some alteration of cellular events induced by nerve growth factor alone. A more pronounced decline of catecholamine content, no additional change in acetylcholinesterase activity, and additive stimulation of RNA and protein syntheses were found in PC12 cells. Earlier elevation of the enzyme activity was observed in sympathetic but not in septal neurons. Epidermal growth factor appeared to support independently the same level of acetylcholinesterase activity in septal neurons as revealed for nerve growth factor during the first week and cell survival throughout 2 weeks of observation. The data obtained indicate that epidermal growth factor augments temporarily some effects of nerve growth factor, thus supporting the idea of an important role of mitogenic growth factors in neural development as complementary and/or substitutive regulators of nerve cell differentiation and survival.     

Nerve growth factor and the neurotrophic factor hypothesis

The discovery of nerve growth factor (NGF) over 40 years ago led to the formulation of the “Neurotrophic Factor Hypothesis”. This hypothesis states that developing neurons compete with each other for a limited supply of a neurotrophic factor (NTF) provided by the target tissue. Successful competitors survive; unsuccessful ones die. Subsequent research on NTFs has shown that NTF expression and actions are considerably more complex and diverse than initially predicted. Even for NGF, different regulatory patterns are seen for different neuronal populations. As would be predicted by the “Neurotrophic Factor Hypothesis”, NGF levels critically regulate basal forebrain cholinergic neuron size and neurochemical differentiation. In contrast, the level of trkA, the NGF receptor, regulates these properties in caudate-putamen cholinergic neurons. Understanding NTF regulation and actions on neurons has led to their use in clinical trials of human neurological diseases. NTFs may emerge as important therapies to prevent neuronal dysfunction and death.     

Brain-derived neurotrophic factor signaling modifies hippocampal gene expression during epileptogenesis in transgenic mice

Brain-derived neurotrophic factor (BDNF) regulates neuronal survival, differentiation and plasticity. It has been shown to promote epileptogenesis and transgenic mice with decreased and increased BDNF signaling show opposite alterations in epileptogenesis. However, the mechanisms of BDNF action are largely unknown. We studied the gene expression changes 12 days after kainic acid-induced status epilepticus in transgenic mice overexpressing either the functional BDNF receptor trkB or a dominant-negative truncated trkB. Epileptogenesis produced marked changes in expression of 27 of 1090 genes. Cluster analysis revealed BDNF signalling-mediated regulation of functional gene classes involved in cellular transport, DNA repair and cell death, including kinesin motor kinesin family member 3A involved in cellular transport. Furthermore, the expression of cytoskeletal and extracellular matrix components, such as tissue inhibitor of metalloproteinase 2 was altered, emphasizing the importance of intracellular transport and interplay between neurons and glia during epileptogenesis. Finally, mice overexpressing the dominant-negative trkB, which were previously shown to have reduced epileptogenesis, showed a decrease in mRNAs of several growth-associated genes, including growth-associated protein 43. Our data suggest that BDNF signaling may partly mediate the development of epilepsy and propose that regrowth or repair processes initiated by status epilepticus and promoted by BDNF signaling may not be as advantageous as previously thought.     

脑源性神经营养因子及其信号通路与抑郁症

抑郁症是以持续的心境低落为主要临床特征的一种精神疾病.抑郁症最严重的症状--自杀,使得抑郁症成为高病死率的疾病,已引起广泛重视.关于抑郁症的发病机制一直在研究中,但病因始终不明.     

Effects of antidepressant treatment on mice lacking brain‐derived neurotrophic factor expression through promoter IV

Brain‐derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depression; mice lacking BDNF expression through promoter IV (BDNF‐KIV) exhibit a depression‐like phenotype. We tested our hypothesis that deficits caused by promoter IV deficiency (depression‐like behavior, decreased levels of BDNF, and neurogenesis in the hippocampus) could be rescued by a 3‐week treatment with different types of antidepressants: fluoxetine, phenelzine, duloxetine, or imipramine. Each antidepressant reduced immobility time in the tail suspension test without affecting locomotor activity in the open field test in both BDNF‐KIV and control wild type mice, except that phenelzine increased locomotor activity in wild type mice and anxiety‐like behavior in BDNF‐KIV mice. The antidepressant treatments were insufficient to reverse decreased BDNF levels caused by promoter IV deficiency. No antidepressant treatment increased the hippocampal progenitors of either genotype, whereas phenelzine decreased the surviving progenitors in both genotypes. The antidepressant treatments differently affected the dendritic extension of hippocampal immature neurons: fluoxetine and imipramine increased extension in both genotypes, duloxetine increased it only in BDNF‐KIV mice, and phenelzine decreased it only in wild type mice. Interestingly, a saline‐only injection increased neurogenesis and dendrite extensions in both genotypes. Our results indicate that the behavioral effects in the tail suspension test by antidepressants do not require promoter IV‐driven BDNF expression and occur without a detectable increase in hippocampal BDNF levels and neurogenesis but may involve increased dendritic reorganisation of immature neurons. In conclusion, the antidepressant treatment demonstrated limited efficacy; it partially reversed the defective phenotypes caused by promoter IV deficiency but not hippocampal BDNF levels.     

Neonatal perturbation of neurotrophic signaling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development

Epidermal growth factor (EGF) and its structurally related proteins are implicated in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. There are EGF and EGF receptor abnormalities in both brain tissues and blood from schizophrenic patients. We administered EGF to neonatal rats to transiently perturb endogenous EGF receptor signaling and evaluated the neurobehavioral consequences. EGF-treatment-induced transient impairment in tyrosine hydroxylase expression. The animals grew normally, exhibited normal weight increase, glial growth, and gross brain structures, and later lost the tyrosine hydroxylase abnormality. During and after development, however, the rats began to display various behavioral abnormalities. Abnormal sensorimotor gating was apparent, as measured by deficits in prepulse inhibition of acoustic startle. Motor activity and social interaction scores of the EGF-treated animals were also impaired in adult rats, though not in earlier developmental stages. In parallel, there was a significant abnormality in dopamine metabolism in the brain stem of the adult animals. Gross learning ability appeared to be normal as measured by active avoidance. These behavioral alterations, which are often present in schizophrenic models, were ameliorated by subchronic treatment with clozapine. Although the molecular and/or physiologic background(s) of these behavioral abnormalities await further investigation, the results of the present experiment indicate that abnormal EGF receptor stimulation given during limited neonatal stages can result in severe and persistent cognitive/behavioral dysfunctions, which appear only in adulthood.     

脑源性神经营养因子Val66Met功能基因多态性与抗抑郁剂疗效

目的：探讨脑源性神经营养因子（BDNF）Val66Met功能基因多态性与抗抑郁剂临床疗效的相关性。方法：302例抑郁症患者给予抗抑郁剂治疗8周。于治疗前和治疗2、4、6、8周后采用汉密尔顿抑郁量表（HAMD）评定抑郁严重程度和疗效。以治疗后HAMD总分≤7分为临床痊愈,将302例患者分为痊愈组160例和未痊愈组142例,抽取患者静脉血,采用Illumina GoldenGate定制芯片分析BDNFVal66Met基因多态性并进行基因分型。结果：痊愈组基因型分布A/A31例（19.4%）、A/G92例（57.5%）和G/G37例（23.1%）,未痊愈组分别为28例（19.7%）、78例（54.9%）和36例（25.4%）（χ2=0.054,P=0.817）;痊愈组等位基因频率分布A154例（48.1%）和G166例（51.9%）,未痊愈组分别为134例（47.2%）和150例（52.8%）（χ2=0.247,P=0.884）。3种BDNFVal66Met基因型患者间在性别、年龄、受教育年限、病程、发病次数、有无精神疾病家族史、HAMD基线及减分率上差异均无统计学意义（P均〉0.05）。结论：BDNFVal66Met基因多态性不是影响抗抑郁剂治疗近期疗效的主要因素。     

Vascular endothelial growth factor (VEGF) and its role in the central nervous system: a new element in the neurotrophic hypothesis of antidepressant drug action

Vascular endothelial growth factor (VEGF) is a well-known cellular mitogen, and a vascular growth factor and permeability regulator. It participates in physiological and pathological processes of angiogenesis and in the development of lymphatic vessels. In addition to the proangiogenic activity, studies of recent years have revealed neurotrophic and neuroprotective potential of VEGF both in the peripheral and central nervous system. VEGF directly influences Schwann cells, neuronal progenitor cells, astrocytes and microglia. This factor plays an import role in developmental processes of the nervous tissue since it is implicated in neurogenesis and the regulation of neuronal development, and in the differentiation and formation of vessels in the brain. VEGF elicits its biological effect via an interaction with three VEGF receptor subtypes: VEGFR1, VEGFR2 and VEGFR3. In the nervous system, VEGFR2 signaling prevails. VEGF as a trophic factor, influencing both vascular endothelial cells and brain cells is a focus of the studies on neuropsychiatric disorders and psychotropic drug action. Antidepressant drugs were shown to induce hippocampal expression of VEGF. In addition, the experiments in animals models of depression have demonstrated that VEGFR2 signaling is indispensable for cellular and behavioral response to antidepressant drugs. Acquiring a deeper knowledge into the signaling pathways engaged in neurogenic and behavioral VEGF actions can unravel new targets for more efficient and quick acting antidepressant drugs.     

Traffic at the intersection of neurotrophic factor signaling and neurodegeneration

Advances in understanding the biology of neurotrophic factors and their signaling pathways have provided important insights into the normal growth, differentiation and maintenance of neurons. Stimulated by neuropathological observations and genetic discoveries, studies in cell and animal models of neurodegenerative disorders have begun to clarify pathogenetic mechanisms. We examine the intersection of these research themes and identify several potential mechanisms for linking failed neurotrophic factor signaling to neurodegeneration. Studies of nerve growth factor signaling in a mouse model of Down syndrome encourage the views that neuronal dysfunction and atrophy might be linked to failed neurotrophic support and that additional studies focused on this possibility would enhance our understanding of the mechanisms of neurodegenerative disorders and their treatment.     

RhoA/ROCK-I信号通路与增生性瘢痕成纤维细胞结缔组织生长因子的表达

背景：前期实验表明增生性瘢痕中RhoA和ROCK-I基因表达较正常皮肤高,提示RhoA/ROCK-I信号通路可能参与了增生性瘢痕的发生,但其在病理性瘢痕中的作用尚不清楚。 目的：研究RhoA/ROCK-I信号通路在增生性瘢痕成纤维细胞结缔组织生长因子(connective tissue growth factor,CTGF)表达调控中的作用。 方法：分离培养人增生性瘢痕组织来源的成纤维细胞,应用转化生长因子β1及Rho激酶的特异抑制剂Y-27632对细胞进行干预实验。采用实时荧光定量PCR及免疫荧光细胞化学方法检测瘢痕成纤维细胞中RhoA,ROCK-I及CTGF mRNA与蛋白的表达。 结果与结论：给予转化生长因子β1后,增生性瘢痕成纤维细胞中RhoA,ROCK-I及CTGF mRNA与蛋白表达明显增多(P < 0.01);而Y-27632能阻碍转化生长因子β1的作用;但单独给予Y-27632并不引起瘢痕成纤维细胞中RhoA,ROCK-I及CTGF的mRNA与蛋白表达改变。说明转化生长因子β1可通过RhoA/ROCK-I信号通路调控CTGF mRNA与蛋白的表达,即RhoA/ROCK-I信号通路参与了瘢痕成纤维细胞CTGF的表达调控,阻断RhoA下游通路是增生性瘢痕治疗靶点之一。     

Nerve growth factor and brain-derived neurotrophic factor in human paediatric hemimegalencephaly

Paediatric hemimegalencephaly (HME) is a congenital central nervous system (CNS) disorder, characterized by monolateral cerebral hemisphere enlargement, intractable seizures starting in the post-neonatal period, and mental retardation associated with neuropathological anomalies (mainly cortical thickness and lack of lamination). Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two neurotrophic factors produced in the mammalian CNS that are involved in the survival, development, and function of a variety of brain cells. In the present study, we found increased cerebral tissue levels of NGF and BDNF in 4 infants with HME; these changes appear to be also associated with abnormal NGF-receptor expression in subcortical blood vessels. Moreover, the marked reduction of cortical choline acetyltransferase immunoreactivity is strongly suggestive of a dysregulation in the NGF differentiative activity in this site that could lead to the pathogenesis of HME.     

Differential expression of brain-derived neurotrophic factor,neurotrophin-3, and low-affinity nerve growth factor receptor during the postnatal development of the rat cerebellar system

The spatio-temporal pattern of expression of neurotrophin-3 (NT3), brain-derived neurotrophic factor (BDNF) and low-affinity nerve growth factor receptor (LNGFR) genes was analyzed in the postnatal developing cerebellar system of the rat by in situ hybridization histochemistry. Different ontogenetic patterns of expression were observed for these three genes. In agreement with previously published results (Neuron, 5 (1990) 501–509; Dev. Brain Res., 55 (1990) 288–292) we found that NT3 and LNGFR mRNA peaked early, during the first 2 postnatal weeks, whereas BDNF mRNA peaked later, around postnatal day 20, in the cerebellar cortex. High levels of NT3 mRNA were found in the internal granule cell layer as early as postnatal day 5. NT3 mRNA was also present in the external-premigratory granule cell layer at postnatal day 10. From postnatal day 5 on, LNGFR mRNA was present in the proliferative area of the external granule cell layer and in the Purkinje cells. NT3 mRNA level decreased and BDNF mRNA increased in granule cells concomitantly with their migration and maturation, suggesting a sequential stimulation of these two genes during this developmental process. LNGFR mRNA levels decreased along the same period. Although practically undetectable in the cerebellar granule cell layer in the first two postnatal weeks, BDNF mRNA was transiently expressed in the deep cerebellar nuclei during this time and it was very abundant in the inferior olivary system from postnatal day 5 on. LNGFR mRNA was transiently expressed in the inferior olivary system, in the first postnatal week. These data are discussed in relation to the coordinated postnatal maturation of the different cells of the cerebellar system. Our results are compatible with a local delivery and role of NT3 in the early postnatal development of the cerebellar cortex. Its presence may be involved in the process of granule cell migration and/or the establishment of early synaptic contacts. BDNF, on the contrary, could play a role at a later stage, perhaps as a maintenance factor.     

A role for brain-derived neurotrophic factor in B cell development

In the present study, we demonstrated a significant reduction of B lymphocytes in the blood, spleen and bone marrow of BDNF deficient mice. The observed developmental block in bone marrow B cell development was linked specifically to the Pre-BII stage. B lymphocytes express the BDNF receptors p75NTR and TrkB(gp95), while no BDNF expression was found. However, a strong BDNF expression was demonstrated in bone marrow stromal cells. An increase of intracellular free calcium [Ca2+]i in B lymphocytes after BDNF application confirms a direct responsiveness of B lymphocytes to BDNF. In conclusion, these results suggest a role of BDNF for normal B lymphocyte development through paracrine effects in the bone marrow.     

Brain-derived neurotrophic factor and its intracellular signaling pathways in cocaine addiction

Cocaine addiction is one of the severest health problems faced by western countries, where there is an increasing prevalence of lifelong abuse. The most challenging aspects in the treatment of cocaine addiction are craving and relapse, especially in view of the fact that, at present, there is a lack of effective pharmacological treatment for the disorder. What is required are new pharmacological approaches based on our current understanding of the neurobiological bases of drug addiction. Within the context of the behavioral and neurochemical actions of cocaine, this paper considers the contribution of brain-derived neurotrophic factor (BDNF) and its main intracellular signaling mechanisms, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K), in psychostimulant addiction. Repeated cocaine administration leads to an increase in BDNF levels and enhanced activity in the intracellular pathways (PI3K and MAPK/ERK) in the reward-related brain areas, which applies especially several days following withdrawal. It has been hypothesized that these neurochemical changes contribute to the enduring synaptic plasticity that underlies sensitized responses to psychostimulants and drug-conditioned memories leading to compulsive drug use and frequent relapse after withdrawal. Nevertheless, increased BDNF levels could also have a role as a protection factor in addiction. The inhibition of the intracellular pathways, ERK and PI3K, leads to a disruption in sensitized responses and conditioned memories associated with cocaine addiction and suggests new, potential therapeutic strategies to explore in the dependence on psychostimulants.     

Verification of functional AAV-mediated neurotrophic and anti-apoptotic factor expression

The use of viral vectors for gene delivery offer many advantages for both basic research and therapeutic application through the continuous expression of a gene product within a target region. It is vital however that any gene product is correctly expressed in a biologically active form, and this should be confirmed prior to large scale in vivo studies. Using adeno-associated viral (AAV) vectors to direct the expression of either a neurotrophic factor or an anti-apoptotic protein, we have developed a range of in vitro assays to verify functional transgenic protein expression. Brain-derived neurotropic factor (BDNF) activity was confirmed by demonstrating enhanced generation of GABAergic neurons in embryonic (E15) striatal cultures and AAV-mediated glial-derived neurotrophic factor (GDNF) function using an assay for dopaminergic differentiation of embryonic (E14) ventral mesencephalic cultures. To assess functional anti-apoptotic factor expression we designed cell-survival assays, using embryonic cortical cultures to confirm Bcl-x(L) activity and the HT1080 cell-line for X-linked inhibitor of apoptosis protein (XIAP) activity following AAV-mediated expression. This study demonstrates that the use of functional assays provides valuable confirmation of desired biotherapeutic expression prior to extensive investigation with new gene delivery vectors.     

Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) support the viability and function of many types of neurons, and are likely mediators of activity-dependent changes in the CNS. We examined BDNF and NGF mRNA levels in several brain areas of adult male rats following 0, 2, 4, or 7 nights with ad libitum access to running wheels. BDNF mRNA was significantly increased in several brain areas, most notably in the hippocampus and caudal13 of cerebral cortex following 2, 4, and 7 nights with exercise. Significant elevations in BDNF mRNA were localized in Ammon's horn areas 1 (CAI) and 4 (CA4) of the hippocampus, and layers II–III of the caudal neocortex and retrosplenial cortex. NGF mRNA was also significantly elevated in the hippocampus and caudal13 of the cortex, affecting primarily the dentate gyrus granular layer (DG) and CA4 of the hippocampus and layers II–III in caudal neocortex.