transforming-growth-factor-beta and Parkinson-Disease

The adult midbrain contains 75% of all dopaminergic neurons in the CNS. Within the midbrain, these neurons are divided into three anatomically and functionally distinct clusters termed A8, A9 and A10. The A9 group plays a functionally non-redundant role in the control of voluntary movement, which is highlighted by the motor syndrome that results from their progressive degeneration in the neurodegenerative disorder, Parkinson's disease. Despite 50 years of investigation, treatment for Parkinson's disease remains symptomatic, but an intensive research effort has proposed delivering neurotrophic factors to the brain to protect the remaining dopaminergic neurons, or using these neurotrophic factors to differentiate dopaminergic neurons from stem cell sources for cell transplantation. Most neurotrophic factors studied in this context have been members of the transforming growth factor β (TGFβ) superfamily. In recent years, an intensive research effort has focused on understanding the function of these proteins in midbrain dopaminergic neuron development and their role in the molecular architecture that regulates the development of this brain region, with the goal of applying this knowledge to develop novel therapies for Parkinson's disease. In this review, the current evidence showing that TGFβ superfamily members play critical roles in the regulation of midbrain dopaminergic neuron induction, differentiation, target innervation and survival during embryonic and postnatal development is analysed, and the implications of these findings are discussed.

Topics: Animals; Cell Differentiation; Dopaminergic Neurons; Humans; Mesencephalon; Nerve Growth Factors; Parkinson Disease; Transforming Growth Factor beta

ransforming growth factor betas (TGF-betas) are multifunctional cytokines with widespread distribution.In the nervous system the biological effects of TGF-beta cover regulation of proliferation, migration, differentiation, survival and death. Specifically, the effects of TGF-(3 on mesencephalic DAergic neurons extend from induction and specification of the dopaminergic phenotype via promotion of survival to neuroprotection in animal models of parkinsonism. Experimental in vitro and in vivo models have contributed to a better understanding of the putative mechanisms underlying the effects of TGF-beta on DAergic neurons and unravelled synergisms between members of the TGF-beta superfamily. In this chapter, we will review the literature available with focus on TGF-beta proper and glial cell-line-derived neurotrophic factor (GDNF).

Topics: Animals; Cell Differentiation; Cell Survival; Cytoprotection; Dopamine; Glial Cell Line-Derived Neurotrophic Factor; Humans; Neurons; Parkinson Disease; Substantia Nigra; Transforming Growth Factor beta

Recent studies have indicated that proteins in the transforming growth factor-beta superfamily alter damage induced by various neuronal injuries. Of these proteins, glial cell line-derived neurotrophic factor (GDNF) and bone morphogenetic protein-7 (BMP-7) have unique protective and regenerative effects in stroke animals. Delivery of GDNF or BMP-7 to brain tissue reduced cerebral infarction and improved motor functions in stroke animals. Pretreatment with these factors reduced caspase-3 activity and DNA fragmentation in the ischemic brain region, suggesting that antiapoptotic effects are involved. Beside the protective effects, BMP-7 given after stroke improves locomotor function. These regenerative effects of BMP-7 may involve the enhancement of dendritic growth and remodeling. In this review, we illustrate the neuroprotective and neuroregenerative properties of GDNF and BMP-7 and emphasize their therapeutic potential for stroke.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Brain Ischemia; Cell Transplantation; Clinical Trials as Topic; Genetic Therapy; Glial Cell Line-Derived Neurotrophic Factor; Humans; Nerve Growth Factors; Neuroprotective Agents; Parkinson Disease; Stroke; Transforming Growth Factor beta

The Transforming Growth Factor-betas (TGF-beta) are a group of multifunctional proteins whose cellular sites of production and action are widely distributed throughout the body, including the central nervous system (CNS). Within the CNS, various isoforms of TGF-beta are produced by both glial and neural cells. When evaluated in either cell culture or in vivo models, the various isoforms of TGF-beta have been shown to have potent effects on the proliferation, function, or survival of both neurons and all three glial cell types, astrocytes, microglia and oligodendrocytes. TGF-beta has also been shown to play a role in several forms of acute CNS pathology including ischemia, excitotoxicity and several forms of neurodegenerative diseases including multiple sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease.

Topics: AIDS Dementia Complex; Alzheimer Disease; Animals; Astrocytes; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Gene Expression; Humans; Ischemia; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Oligodendroglia; Parkinson Disease; Transforming Growth Factor beta

Dopaminergic neurons of the nigrostriatal system are important in the control of motor performance and degenerate in Parkinson's disease. Therefore, in order to design novel strategies for the treatment of Parkinson's disease, it is important for us to understand their development, function, trophic factor requirements, plasticity and susceptibility to toxic influences. A large and still increasing number of growth factors have been implicated in the regulation of the survival and differentiation of dopaminergic neurons. These factors may also protect against a variety of toxic influences. On the basis of their localization, putative sources and mechanisms of actions, such growth factors fall into several categories: (i) local factors within the midbrain influencing proliferation, transmitter phenotype, migration, positioning and neurite growth of stem cells and early neurons; (ii) factors acting retrogradely from the striatum, which are responsible for intrastriatal sprouting and navigation of newly arrived axons as well as life-long maintenance of the dopaminergic nigrostriatal connection; (iii) factors coming into play when the system is toxically impaired; (iv) factors directly acting on dopaminergic neurons; and (v) factors provided by cytokinestimulated astroglia, microglia and neurons affecting dopaminergic neurons anterogradely. This article reviews actions of growth factors on dopaminergic neurons in vitro and in vivo, with a focus on members of the transforming growth factor (TGF)-beta superfamily. TGF-beta s may be particularly relevant to dopaminergic neurons, since they are expressed in the nigrostriatal system from early embryonic stages to adulthood and are significantly up-regulated in response to lesions.

Topics: Animals; Dopamine Agents; Humans; Mesencephalon; Nerve Degeneration; Neurons; Parkinson Disease; Transforming Growth Factor beta

The beneficial effect of chromaffin cell grafts to the striatum in patients with Morbus Parkinson and in animal models of the disease may be due to liberated growth factors rather than to the relatively small amounts of dopamine released. This overview summarizes the current knowledge concerning synthesis, storage, and release of growth factors and neuropeptides with growth factor-like effects by chromaffin cells. Peptides of interest include several well-established neurotrophic factors, neuropeptides, and cytokines known to stimulate neurotrophic factor levels in a number of neural lesion paradigms, such as fibroblast growth factor-2, transforming growth factors-beta, interleukins, enkephalins, somatostatin, neurotensin, VIP, and biological activities resembling ciliary neurotrophic factor. Fibroblast growth factor-2 has been most extensively studied, and its ameliorative effects on pathological chemical and morphological parameters of the Parkinsonian brain will also be addressed.

Topics: Adrenal Glands; Adrenal Medulla; Animals; Brain; Chromaffin System; Chromogranins; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Growth Substances; Humans; Interleukins; Nerve Growth Factors; Nerve Tissue Proteins; Parkinson Disease; RNA, Messenger; Transforming Growth Factor beta

A large body of evidence underscore the regulatory role of TGF-β superfamily in the central nervous system. Components of the TGF-β superfamily modulate key events during embryonic brain development and adult brain tissue injury repair. With respect to Parkinson's disease (PD), TGF-ß signaling pathways are implicated in the differentiation, maintenance and synaptic function of the dopaminergic neurons, as well as in processes related to the activation state of astrocytes and microglia. In vitro and in vivo studies using toxin models, have interrogated on the dopaminotrophic and protective role of the TGF-β superfamily members. The evolution of genetic and animal models of PD that more closely recapitulate the disease condition has made possible the dissection of intracellular pathways in response to TGF-β treatment. Although the first clinical trials using GDNF did not meet their primary endpoints, substantial work has been carried out to reappraise the TGF-β superfamily's clinical benefit.

Topics: Animals; Astrocytes; Dopaminergic Neurons; Parkinson Disease; Signal Transduction; Transforming Growth Factor beta

MicroRNAs are regulators of gene expression. A wide-spread, yet not validated, assumption is that the targetome of miRNAs is non-randomly distributed across the transcriptome and that targets share functional pathways. We developed a computational and experimental strategy termed high-throughput miRNA interaction reporter assay (HiTmIR) to facilitate the validation of target pathways. First, targets and target pathways are predicted and prioritized by computational means to increase the specificity and positive predictive value. Second, the novel webtool miRTaH facilitates guided designs of reporter assay constructs at scale. Third, automated and standardized reporter assays are performed. We evaluated HiTmIR using miR-34a-5p, for which TNF- and TGFB-signaling, and Parkinson's Disease (PD)-related categories were identified and repeated the pipeline for miR-7-5p. HiTmIR validated 58.9% of the target genes for miR-34a-5p and 46.7% for miR-7-5p. We confirmed the targeting by measuring the endogenous protein levels of targets in a neuronal cell model. The standardized positive and negative targets are collected in the new miRATBase database, representing a resource for training, or benchmarking new target predictors. Applied to 88 target predictors with different confidence scores, TargetScan 7.2 and miRanda outperformed other tools. Our experiments demonstrate the efficiency of HiTmIR and provide evidence for an orchestrated miRNA-gene targeting.

Topics: 1-Methyl-4-phenylpyridinium; 3' Untranslated Regions; Cell Line; Cell Line, Tumor; Gene Expression Regulation; Genes, Reporter; High-Throughput Screening Assays; Humans; Mesencephalon; MicroRNAs; Neuroblastoma; Neurons; Parkinson Disease; Predictive Value of Tests; Sensitivity and Specificity; Signal Transduction; Transcriptome; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Parkinson's disease (PD) is a long-term degenerative disease of the central nervous system (CNS) that primarily affects the motor system. So far there is no effective treatment for PD, only some drugs, surgery, and comprehensive treatment can alleviate the symptoms of PD. Stem cells derived from human exfoliated deciduous teeth (SHED), mesenchymal stem cells derived from dental pulp, may have promising potential in regenerative medicine. In this study, we examine the therapeutic effect of SHED-derived conditioned medium (SHED-CM) in a rotenone-induced PD rat model. Intravenous administration of SHED-CM generated by standardized procedures significantly improved the PD symptoms accompanied with increased tyrosine hydroxylase amounts in the striatum, and decreased α-synuclein levels in both the nigra and striatum, from rotenone-treated rats. In addition, this SHED-CM treatment decreased both Iba-1 and CD4 levels in these brain areas. Gene ontology analysis indicated that the biological process of genes affected by SHED-CM was primarily implicated in neurodevelopment and nerve regeneration. The major constituents of SHED-CM included insulin-like growth factor binding protein-6 (IGFBP-6), tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-1, and transforming growth factor 1 (TGF-1). RNA-sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) revealed that these factors may ameliorate PD symptoms through modulating the cholinergic synapses, calcium signaling pathways, serotoninergic synapses, and axon guidance. In conclusion, our data indicate that SHED-CM contains active constituents that may have promising efficacy to alleviate PD.

Topics: alpha-Synuclein; Animals; Cells, Cultured; Corpus Striatum; Culture Media, Conditioned; Female; Humans; Injections, Intravenous; Insulin-Like Growth Factor Binding Protein 6; Mesenchymal Stem Cells; Neuroprotective Agents; Parkinson Disease; Rats; Rats, Inbred Lew; Tissue Inhibitor of Metalloproteinases; Tooth, Deciduous; Transforming Growth Factor beta; Tyrosine 3-Monooxygenase

α-synuclein-induced degeneration of dopaminergic neurons has been proposed to be central to the early progression of Parkinson's disease. This highlights the need to identify factors that are neuroprotective or neuroregenerative against α-synuclein-induced degeneration. Due to their potent neurotrophic effects on nigrostriatal dopaminergic neurons, we hypothesized that members of the bone morphogenetic protein (BMP) family have potential to protect these cells against α-synuclein.. To identify the most relevant BMP ligands, we used unbiased gene co-expression analysis to identify all BMP family members having a significant positive correlation with five markers of dopaminergic neurons in the human substantia nigra (SN). We then tested the ability of lead BMPs to promote neurite growth in SH-SY5Y cells and in primary cultures of ventral mesencephalon (VM) dopaminergic neurons, treated with either 6-OHDA or MPP. Only the expression of BMP2 was found to be significantly correlated with multiple dopaminergic markers in the SN. We found that BMP2 treatment promoted neurite growth in SH-SY5Y cells and in dopaminergic neurons. Moreover, BMP2 treatment promoted neurite growth in both SH-SY5Y cells and VM neurons, treated with the neurotoxins 6-OHDA or MPP. These findings are important given that clinical trials of two neurotrophic factors, GDNF and neurturin, have failed to meet their primary endpoints. Our findings are a key first step in rationalising the further study of BMP2 as a potential neurotrophic factor in α-synuclein-based translational models of Parkinson's disease.

Topics: alpha-Synuclein; Animals; Bone Morphogenetic Protein 2; Dopaminergic Neurons; Gene Expression Profiling; Humans; Nerve Growth Factors; Neurites; Parkinson Disease; Rats; Recombinant Proteins; Substantia Nigra; Transforming Growth Factor beta

Alpha - synuclein (ASN) is the principal component of Lewy pathology and strongly influences on the pathogenesis of Parkinson's disease (PD). The increased level of ASN protein causes microglial response. The reactive microglial cells may actively participate in the damaging of dopaminergic neurons. The data suggests that ASN accumulation in astrocytes might damage these cells in the substantia nigra pars compacta (SN) and promotes degeneration of dopaminergic neurons in SN. We examined the potential role of recombinant ASN monomers as a major pathogenic factor causing the inflammatory response in the central nervous system.. Mice were bilaterally infused by human ASN monomers into the striatum (ST) or SN (single treatment was 4μg/structure, 8μg per brain) and decapitated after 1, 4 or 12 weeks post injection. The changes in the level of inflammatory factors in ST were evaluated using Real-Time PCR and Western Blot method. The analysis of morphological changes of glial cells was performed by immunohistochemical staining.. We observed a strong activation of microglia cells in ST and increased expression of striatal interleukin 1α, tumor necrosis factor alpha and interferon gamma after ASN injection into the ST. We noticed an increase in striatal glial fibrillary acidic protein mRNA level 4 weeks after ASN injection into the ST. Injection of ASN into the SN led to an increase of striatal transforming growth factor beta mRNA level and has no influence on striatal glial fibrillary acidic protein mRNA level.. Our results suggest that both the microglia activation and supressing astrocytes play a crucial role in ASN-related dopaminergic neurotoxicity.

Topics: alpha-Synuclein; Animals; Astrocytes; Brain; Dopamine; Dopaminergic Neurons; Gliosis; Humans; Interferon-gamma; Interleukin-1alpha; Male; Mice; Mice, Inbred C57BL; Microglia; Parkinson Disease; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Parkinson's disease (PD) is a common neurodegenerative disorder in middle-aged and elderly people. This study aimed to elucidate the role of mesenchymal stem cells (MSCs) in management of PD in ovariectomized rat model. MSCs were excised from adipose tissue of both the omentum and the inguinal fat pad of male rats, grown, and propagated in culture; then characterized morphologically; and by the detection of surface markers gene expression. In this study, 40 ovariectomized animals were classified into 5 groups; group 1 was ovariectomized control, groups 2 to 5 were subcutaneously administered with rotenone for 14 days after 1 month of ovariectomy for induction of PD. Group 2 was left untreated; groups 3, 4, and 5 were treated with Sinemet(®), Cerebrolysin(®), and a single dose of adipose tissue-derived MSCs (ADMSCs), respectively. Y-chromosome gene (sry) was assessed by polymerase chain reaction (PCR) in brain tissue of the female rats. Serum transforming growth factor β (TGF-β), monocyte chemoattractant protein 1 (MCP-1), and brain-derived neurotrophic factor (BDNF) levels were assayed using enzyme-linked immunosorbent assay technique. Brain dopamine level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) gene expression was detected by semiquantitative real-time PCR. The PD group showed significant increase in serum TGF-β and MCP-1 levels associated with significant decrease in serum BDNF, brain dopamine, and brain TH gene expression levels. In contrast, all treatments produce significant decrease in serum TGF-β and MCP-1 levels in concomitant with significant increase in serum BDNF, brain dopamine, and brain TH gene expression levels. In conclusion, the observed improvements in the studied biomarkers due to ADMSCs infusion might be attributed to their immunomodulatory, anti-inflammatory, and neurotrophic effects.

Topics: Adipose Tissue; Amino Acids; Animals; Antigens, CD; Brain; Brain-Derived Neurotrophic Factor; Carbidopa; Cell Differentiation; Cells, Cultured; Chemokine CCL2; Disease Models, Animal; Drug Combinations; Female; Gene Expression; Genes, sry; Levodopa; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Ovariectomy; Parkinson Disease; Rats, Sprague-Dawley; Rotenone; Transforming Growth Factor beta; Tyrosine 3-Monooxygenase

Parkinson's disease (PD), a neurodegenerative disorder, has been reported to be associated with brain neuroinflammation in its pathogenesis. Herein, changes in peripheral immune system were determined to better understand PD pathogenesis and provide possible target for treatment of PD through improvement of immune disorder.. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was intraperitoneally injected into mice to prepare PD model. Expression levels of pro-inflammatory and anti-inflammatory cytokines and transcription factors of CD4+ T lymphocyte subsets in spleen and mesenteric lymph nodes and concentrations of the cytokines in serum were examined on day 7 after MPTP injection. Percentages of CD4+ T lymphocyte subsets were measured by flow cytometry.. MPTP induced PD-like changes such as motor and behavioral deficits and nigrostriatal impairment. Expression levels of the pro-inflammatory cytokines including interferon (IFN)-γ, interleukin (IL)-2, IL-17 and IL-22, in spleen and mesenteric lymph nodes were upregulated and their concentrations in serum were elevated in PD progression. But, the concentrations of the anti-inflammatory cytokines including IL-4, IL-10 and transforming growth factor (TGF)-β were not altered in the two lymphoid tissues or serum of PD mice. In addition, expression of T-box in T cells (T-bet), the specific transcription factor of helper T (Th) 1 cells, was downregulated, but expression of transcription factor forkhead box p3 (Foxp3), the transcription factor of regulatory T (Treg) cells, was upregulated. In support of the results, the numbers of IFN-γ-producing CD4+ cells (Th1 cells) were reduced but CD4+CD25+ cells (Treg cells) were elevated in both the lymphoid tissues of PD mice.. PD has a dysfunction of peripheral immune system. It manifests enhancement of proinflammatory response and CD4+ T cell differentiation bias towards Treg cells away from Th1 cells.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cytokines; Disease Models, Animal; Flow Cytometry; Forkhead Transcription Factors; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-22; Interleukin-4; Interleukins; Lymph Nodes; Lymphocyte Activation; Mice; Parkinson Disease; Spleen; T-Box Domain Proteins; T-Lymphocytes, Regulatory; Th1 Cells; Transforming Growth Factor beta

An inflammatory response has been hypothesised to be involved in the pathogenesis of primary dementias, above all Alzheimer's disease (AD). This study was aimed at evaluating interleukin (IL)-12 and a panel of related cytokine levels in paired CSF and sera of demented patients. IL-12 (p70 heterodimer and total IL-12 p40 chain), interferon (IFN)-gamma, IL-10 and transforming growth factor (TGF)-beta1 levels were measured in 30 patients with probable Alzheimer's disease (PrAD), 57 patients with other dementing disorders, including probable vascular dementia (PrVD), Parkinson's disease (PD) and normal pressure hydrocephalus (NPH), and 25 cognitively normal control subjects. In the presence of unchanged concentrations of IL-12, IFN-gamma and IL-10, the mean CSF level of TGF-beta1 and the correspondent TGF-beta1 index, but not the serum level, were significantly increased in PrAD compared to controls and PrVD, whereas no difference was found vs. NPH and PD. Our results support the pathophysiological role of TGF-beta1 system in AD.

Topics: Aged; Alzheimer Disease; Biomarkers; Brain; Cerebrospinal Fluid; Dementia, Vascular; Disease Progression; Encephalitis; Female; Humans; Hydrocephalus, Normal Pressure; Interferon-gamma; Interleukin-10; Interleukin-12; Male; Middle Aged; Parkinson Disease; Predictive Value of Tests; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Alzheimer's disease (AD) is a progressive neurodegenerative illness and the most frequent cause of dementia in the elderly. The identification of activated microglia within neuritic plaques, coupled with the presence of numerous inflammatory proteins, suggests that inflammation is an integral part of the pathogenetic process in AD. In the present paper we have investigated the levels of circulating inflammatory mediators as potential AD biomarkers concentrating essentially on (a) soluble CD40 (sCD40), a member of the tumor necrosis factor receptor superfamily lacking the membrane-associated endodomain by alternative splicing, and (b) transforming growth factor (TGF)-beta 1, a cytokine deeply involved in AD and playing a protective role on CNS. Decrease of TGF-beta1 in AD patients could enhance the effects of pro-inflammatory cytokines produced by activated microglia as well as the expression of factors, such as the CD40/CD40 ligand complex, by microglia and astrocytes. Total venous blood samples were obtained from 33 patients with clinical diagnosis of possible late-onset AD, 40 healthy age-matched and 11 healthy young individuals. A significant increase of sCD40 levels plasma of AD patients versus healthy controls was measured, concomitantly with a decrease in TGF-beta1 concentration. These variations, however, showed no correlation with the expression of ApoE epsilon 4 allele, which was determined in order to assess the different frequency of this risk factor between AD and control groups. Since no comparable modifications were detected in patients affected by Parkinson's disease or non-AD-based dementia, we propose that sCD40 and TGF-beta1 plasma levels might represent possible differential biomarkers of AD, and be useful pre-mortem to support the clinical diagnosis of late-onset AD.

Topics: Adult; Aged; Alzheimer Disease; Apolipoproteins E; Biomarkers; CD40 Antigens; Diagnosis, Differential; Female; Genetic Predisposition to Disease; Genotype; Humans; Middle Aged; Parkinson Disease; Risk Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the changes in the expression of basic fibroblast growth factor (bFGF) and transforming growth factor beta 2 (TGFbeta2) in glomus cell grafts of carotid body in the rat model of 6-hydroxydopamine-induced Parkinson disease, immunohistochemical staining of bFGF and TGFbeta2 in the sections of striate body was done on the 2nd, 4th and 12th week after transplantation. The results showed that on the 2nd week after transplantation, bFGF and TGFbeta2 were not detectable in the glumous cell grafts. On the 4th week after graft, bFGF and TGFbeta2 immunoreactivity was increased within the grafts and at the graft-host interface but was restricted only to astrocytes. In the striatum surrounding the graft, bFGF was expressed persistently, while TGFbeta2 showed transient expression. It was suggested that the transient expression of TGFbeta2 was likely due more to the trauma imposed by the graft procedure than to an intrinsic. The deficiency in astrocytic bFGF early after graft may be responsible for the poor survival of grafted glomus cells of carotid body.

Topics: Animals; Carotid Body; Female; Fibroblast Growth Factor 2; Hydroxydopamines; Parkinson Disease; Rats; Transforming Growth Factor beta; Transforming Growth Factor beta2; Transplantation, Homologous

Growth/differentiation factor 5 is a member of the transforming growth factor beta superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinson's disease, and compare them with those of glial cell line-derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line-derived neurotrophic factor prior to transplantation into the left striatum of rats with 6-hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft-induced compensation of amphetamine-stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft-induced recovery of striatal binding of [11C]RTI-121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line-derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinson's disease.

Topics: Animals; Behavior, Animal; Bone Morphogenetic Proteins; Brain Tissue Transplantation; Cell Count; Cell Survival; Corpus Striatum; Disease Models, Animal; Dopamine; Glial Cell Line-Derived Neurotrophic Factor; Graft Survival; Growth Differentiation Factor 5; Growth Substances; Immunohistochemistry; Male; Nerve Growth Factors; Nerve Tissue Proteins; Parkinson Disease; Rats; Rats, Sprague-Dawley; Rotation; Tomography, Emission-Computed; Transforming Growth Factor beta; Tyrosine 3-Monooxygenase

Transforming growth factor (TGF)beta plays a role in injury repair in sites surrounding brain injury. The present study tested the hypothesis that TGFbeta1 and TGFbeta2 levels in the postmortem CSF of patients with neurodegenerative disorders would be elevated compared to those in normal subjects. Free TGFbeta1 and total TGFbeta2 were measured by ELISA in postmortem ventricular cerebrospinal fluid (vCSF) of patients with Parkinson's disease (n = 30), Alzheimer's disease (n = 30), multiple sclerosis (n = 15), and schizophrenia (n = 12) and of normal controls (n = 16). In addition, albumin, IgG, and total protein in vCSF were measured. Both TGFbeta1 and TGFbeta2 were significantly different between groups (P < 0.002 and P < 0.001, respectively). Parkinson's disease vCSF showed significant increases in both TGFbeta1 (P = 0.015) and TGFbeta2 (P = 0.012) compared to normal controls. There was a trend for TGFbeta2 to be elevated in Alzheimer's disease and multiple sclerosis vCSFs, which failed to achieve significance. There were no differences between controls and schizophrenics in TGFbeta1 or TGFbeta2. Alzheimer's disease vCSF showed a significant decrease in protein compared to all other groups, which was not related to blood-brain barrier permeability, age, or autolysis differences. Evidence is presented suggesting that some TGFbeta1 may leak into the vCSF from plasma. Autopsy vCSF levels of TGFbeta isoforms were found to be distinctly different from those reported for human serum, especially for TGFbeta2, which is undetectable in plasma. These results indicate that further in vivo studies of TGFbeta2 in the CSF of Parkinson's disease patients are warranted to determine the relationship between clinical status, medication, and TGFbeta2 concentrations.

Topics: Age Factors; Aged; Aged, 80 and over; Albumins; Alzheimer Disease; Blood-Brain Barrier; Cerebral Ventricles; Cerebrospinal Fluid Proteins; Cross Reactions; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Male; Middle Aged; Multiple Sclerosis; Parkinson Disease; Schizophrenia; Sex Factors; Transforming Growth Factor beta

Transforming growth factor (TGF)-beta 1 content was measured for the first time in the brain (caudate nucleus, putamen, and cerebral cortex) and in ventricular cerebrospinal fluid (VCSF) from control and parkinsonian patients by a sandwich enzyme immunoassay. The concentrations of TGF-beta 1 were significantly higher in the dopaminergic striatal regions in parkinsonian patients than those in controls, but were not significantly different in the cerebral cortex between parkinsonian and control patients. Furthermore, the concentrations of TGF-beta 1 in VCSF were significantly higher in parkinsonian patients than those in non-parkinsonian control patients. Since TGF-beta 1 has potent regulatory activity on cell growth, these results suggest that TGF-beta 1 may have some significant modulatory role in the process of neurodegeneration in Parkinson's disease.

Topics: Aged; Aged, 80 and over; Cerebral Ventricles; Female; Growth Inhibitors; Growth Substances; Humans; Male; Middle Aged; Neostriatum; Parkinson Disease; Substantia Nigra; Transforming Growth Factor beta