Changes of insulin-like growth factor-Ⅱ and insulin-like growth factor binding protein-3 in cerebrospinal fluid of children with tuberculous meningitis

BACKGROUND: Recent studies have found that insulin-like growth factors (IGFs) and insulin-like growth factor binding protein-3 (IGFBP-3) have stronger neurotrophic and neuroprotective effects. But whether their levels in cerebrospinal fluid could be used as an auxiliary indicator in differentially diagnosing tuberculous meningitis and viral encephalitis is not yet clear. OBJECTIVE: To explore the changes of insulin-like growth factor-Ⅱ (IGF-Ⅱ) and IGFBP-3 in cerebrospinal fluid (CSF) of children with tuberculous meningitis and the significance of the changes. DESIGN: A non-randomized concurrent controlled study. SETTING: Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College. PARTICIPANTS: Thirty children with tuberculous meningitis (14 males and 16 females) were selected from the Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College from January 2005 to December 2006. Tuberculous meningitis was diagnosed according to their clinical manifestations, the history of close contact with tuberculosis, typical cerebrospinal fluid changes of tuberculous meningitis, positive tuberculosis antibody and effective antituberculosis treatment. There were 30 children (13 males and 17 females) with viral encephalitis, and viral encephalitis was diagnosed according to epidemiological history, clinical manifestations, conventional and biochemical changes of cerebrospinal fluid, and negative bacteriology judgment. Meanwhile, 30 children (13 males and 17 females) without infectious and central nervous system disease were selected as the control group. Informed consent was obtained from the parents of all the enrolled children. METHODS: ① The lumbar puncture operation was implemented immediately to obtain cerebrospinal fluid (3 mL). The contents of IGF-Ⅱ and IGFBP-3 were detected with immunoradiometric assay. The concentrations of glucose and protein in cerebrospinal fluid were determined with a dry-chemical method. The number of white blood cells was counted by Fushi Method. ② The Pearson correlation analysis was used to analyze the correlation of the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. MAIN OUTCOME MEASURES: The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid, and their correlation with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. RESULTS: ① Contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid: The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid in the tuberculous meningitis group were significantly higher than those in the encephalitis virus group and control group (P < 0.05). There was no significant difference in the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid between the viral encephalitis group and control group (P > 0.05). ② Correlation: The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid were positively correlated with the protein concentration in cerebrospinal fluid (r =0.821, 0.855, P < 0.01), but negatively with the glucose (r =0.742, –0.605, P < 0.01). CONCLUSION: ① IGFs and IGFBPs are involved in the pathophysiological process of tuberculous meningitis, as well as the glucose and protein metabolism in cerebrospinal fluid. ② The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid can be used as the auxiliary indicators to differentially diagnose tuberculous meningitis and viral encephalitis.     

Expression of insulin-like growth factor-1 and insulin-like growth factor binding proteins in the serum and cerebrospinal fluid of patients with Parkinson’s disease

Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra. Insulin like growth factor-1 (IGF-1) promotes the survival of dopaminergic neurons and protects them from toxin-induced damage in vitro. IGF-1 is produced by a wide variety of cells and is found in many physiological fluids, including cerebrospinal fluid (CSF). IGFs in physiological fluids are associated with insulin-like growth factor binding proteins (IGFBPs), which bind to them and modulate their bioactivity at the cellular level. Since the CSF is in contact with the extracellular space of the brain, biochemical brain modifications are, to some extent, reflected in the CSF, and peptides and growth factors in the CSF can be used as biomarkers of PD. The aim of this study was to determine the concentrations of IGF-1 and IGFBPs in the serum and CSF of patients with PD. Concentrations were measured in a total of 76 CSF samples from patients with PD (n = 38) and controls (n = 38). Serum and CSF IGF-1 and IGFBP concentrations were higher in patients with PD than in controls (p < 0.001). We conclude that IGF-1 and IGFBPs are always present in human serum and CSF, and may be involved in the pathophysiology of PD.     

MicroRNA-98 induces an Alzheimer’s disease-like disturbance by targeting insulin-like growth factor 1

Alzheimer ’s disease（ A D） is a progressive neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles.Many microRNAs（miRs） participate in regulating amyloid β（Aβ） formation and the metabolism of tau protein in the process of AD,and some are up-regulated in AD patients or transgenic models of AD.However,the role of miR-98 in AD remains unclear.Here,we showed that the expression of miR-98 was negatively correlated with the insulin-like growth factor 1（IGF-1） protein level in APP/PS1 mice.MiR-98 target sites in IGF-1 were confirmed by luciferase assay in HEK293 cells.Overexpression of miR-98 in N2a/APP cells down-regulated the IGF-1 protein level and promoted Aβ production,whereas inhibition of miR-98 in N2a/APP cells up-regulated the IGF-1 protein level and suppressed Aβ production.Furthermore,overexpression of miR-98 in N2a/WT cells increased the phosphorylation of tau,whereas inhibition of miR-98 reduced it.These results suggest that miR-98 increases Aβ formation and tau phosphorylation by inhibiting the translation of IGF-1,which might provide a therapeutic strategy for AD.     

Expression of basic fibroblast growth factor,nerve growth factor,platelet-derived growth factor and transforming growth factor-β in human brain abscess

We correlated the histopathological findings of six human brain abscesses with the expression of basic fibroblast growth factor (bFGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF). The clinical courses ranged from 1 month to 1 year and viridans streptoccus was the major pathogen. In early abscesses, we demonstrated strong bFGF and moderate NGF and PDGF immunoreactivities in neutrophils and monocytes/macrophages infiltrating the abscess wall and in the fibrin layer lining the abscess center. In the subacute cases, growth of capillaries and fibroblasts into the fibrin layer and deposition of collagen resulted in the formation of a mesodermal layer between the abscess center and the outer gliotic layer. The proliferative non-neural cells (endothelial cells, fibroblasts and glial cells) expressed mild to strong bFGF, NGF and PDGF immunoreactivities, while strong TGF staining was seen in the extracellular matrix. A loss of growth factor expression and increased fibrosis was seen in the chronic case. These findings suggest that bFGF, NGF, PDGF and TGF produced by the continued influx of leukocytes and by the proliferating non-neural cells may mediate various steps of defense mechanisms and wound healing such as angiogenesis, fibrogenesis and gliosis.Supported by NSC-82-0115-B-006-127 from the National Science Council, Republic of China     

Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes?

The neurodegeneration that occurs in sporadic Alzheimer's disease (AD) is consistently associated with a number of characteristic histopathological, molecular, and biochemical abnormalities, including cell loss, abundant neurofibrillary tangles and dystrophic neurites, amyloid-beta deposits, increased activation of pro-death genes and signaling pathways, impaired energy metabolism/mitochondrial function, and evidence of chronic oxidative stress. The general inability to convincingly link these phenomena has resulted in the emergence and propagation of various heavily debated theories that focus on the role of one particular element in the pathogenesis of all other abnormalities. However, the accumulating evidence that reduced glucose utilization and deficient energy metabolism occur early in the course of disease, suggests a role for impaired insulin signaling in the pathogenesis of AD. The present work demonstrates extensive abnormalities in insulin and insulin-like growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3beta activity and amyloid precursor protein mRNA expression. The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. Therefore, we propose the term, "Type 3 Diabetes" to reflect this newly identified pathogenic mechanism of neurodegeneration.     

Vascular endothelial growth factor in central nervous system injuries - a vascular growth factor getting nervous?

Vascular Endothelial Growth Factor (VEGF) is recognized as a central factor in growth, survival and permeability of blood vessels in both physiological and pathological conditions. It is as such of importance for vascular responses in various central nervous system (CNS) disorders. Accumulating evidence suggest that VEGF may also act as a neuroprotective and neurotrophic factor supporting neuronal survival and neuronal regeneration. Findings of neuropilins as shared co-receptors between molecules with such seemingly different functions as the axon guidance molecules semaphorins and VEGF has further boosted the interest in the role of VEGF in neural tissue injury and repair mechanisms. Thus, VEGF most likely act in parallel or concurrent on cells in both the vascular and nervous system. The present review gives a summary of known or potential aspects of the VEGF system in the healthy and diseased nervous system. The potential benefits but also problems and pitfalls in intervening in the actions of such a multifunctional factor as VEGF in the disordered CNS are also covered.     

IκB kinase/nuclear factor κB-dependent insulin-like growth factor 2 (Igf2) expression regulates synapse formation and spine maturation via Igf2 receptor signaling

Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF-κB) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IκB kinase (IKK)/NF-κB-related synapse-to-nucleus signaling. There is, however, little information on the molecular requirements and mechanisms regulating this IKK/NF-κB-dependent synapse development and remodeling. Here, we report that the NF-κB inducing IKK kinase complex is localized at the postsynaptic density (PSD) and activated under basal conditions in the adult mouse brain. Using different models of conditional genetic inactivation of IKK2 function in mouse principal neurons, we show that IKK/NF-κB signaling is critically involved in synapse formation and spine maturation in the adult brain. IKK/NF-κB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins PSD95, SAP97, GluA1, AMPAR-mediated basal synaptic transmission and a spatial learning impairment. Synaptic deficits can be restored in adult animals within 1 week by IKK/NF-κB reactivation, indicating a highly dynamic IKK/NF-κB-dependent regulation process. We further identified the insulin-like growth factor 2 gene (Igf2) as a novel IKK/NF-κB target. Exogenous Igf2 was able to restore synapse density and promoted spine maturation in IKK/NF-κB signaling-deficient neurons within 24 h. This process depends on Igf2/Igf2R-mediated MEK/ERK activation. Our findings illustrate a fundamental role of IKK/NF-κB-Igf2-Igf2R signaling in synapse formation and maturation in adult mice, thus providing an intriguing link between the molecular actions of IKK/NF-κB in neurons and the memory enhancement factor Igf2.     

Vascular endothelial growth factor induces brain erythropoietin expression?

To investigate whether the formation of vascular endothelial growth factor (VEGF) influences erythropoietin (EPO) expression in physiological conditions, we injected into the left lateral cerebral ventricle of the Mongolian gerbil an adeno-associated virus (AAV) vector capable of expressing the 165-amino-acid isoform of VEGF (VEGF165). Twelve and 18 days after AAV vector injection, the experimental animals were sacrificed and expression of EPO was evaluated through immunohistochemical analysis of both the hippocampus and the frontal cortex. We observed that VEGF165 induces EPO expression in the hippocampal pyramidal layers and in the frontal cortex of the gerbil, particularly after the 18th day following treatment with the vector, which suggests that VEGF165 could act as a hypoxic-like signal for EPO production. This finding could help to clarify the functional role of EPO and the molecular mechanisms by which VEGF might mediate its effects in the brain.     

Placental growth factor: a tissue modelling factor with therapeutic potentials in neurology?

Placental growth factor (PlGF) is an angiogenic factor that belongs to the vascular endothelial growth factor (VEGF) family. Besides its well known capacity to potentiate the angiogenic action of VEGF, PlGF also participates in inflammatory processes by attracting and activating monocytes; it plays therefore more specifically a role in pathological conditions. PIGF and its two receptors, VEGFR-1 and neuropilins (NRPs), are expressed in the brain and increase after experimental stroke, but their precise functions in the nervous system remain underexplored. In this review article, we summarize present knowledge on the role of PlGF in various nervous system disease processes. Given the available data, P1GF has neuroprotective and neurotrophic properties that make it an actor of considerable interest in the pathophysiology and potentially in the therapy of degenerative and traumatic brain or spinal cord diseases.     

Tumor necrosis factor(alpha) and insulin-like growth factor-I in the brain: is the whole greater than the sum of its parts?

The cytokine tumor necrosis factor(alpha) (TNFalpha) and the hormone insulin-like growth factor-I (IGF-I) have both been shown to regulate inflammatory events in the central nervous system (CNS). This review summarizes the seemingly independent roles of TNFalpha and IGF-I in promoting and inhibiting neurodegenerative diseases. We then offer evidence that the combined effects of IGF-I and TNFalpha on neuronal survival can be vastly different when both receptors are stimulated simultaneously, as is likely to occur in vivo. We propose the framework of a molecular model of hormone-cytokine receptor cross talk in which disparate cell surface receptors share intracellular substrates that regulate neuronal survival.     

Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor-β (PDGFR-β) in human gliomas

The growth of solid tumors is highly dependent on vascular proliferation. Vascular endothelial growth factor (VEGF), the main mediator of angiogenesis, and platelet-derived growth factor receptor-β (PDGFR-β), receptor for the potent mitogen PDGF, are two indicators of the angiogenic potential of human gliomas. We studied a series of 57 surgical biopsies of astrocytic neoplasms by immunohistochemistry to elucidate the relationship between tumor proliferation, quantified as Ki67-LI, and the expression of these two proteins. Ki67-LI increases throughout histological malignancy, although staining in endothelial cells has rarely been recorded. Elevated amounts of VEGF-positive tumor cells (VEGF-LI) were found in anaplastic astrocytomas and glioblastomas, mainly around areas of necrosis, cysts, or edema. Endothelium of blood vessels was consistently stained. PDGFR-β positivity was found in glomeruloid formations and in tumor cells, excluding pilocytic astrocytomas. Multinucleated giant cells and perivascular tumor cells were positive in glioblastomas. In addition, peritumoral microglia-like cells were also stained in some cases. Statistical correlation was only found between PDGFR-β and Ki67 LIs. In conclusion, VEGF as permeability factor is involved in the development of secondary neoplastic changes, whereas PDGFR-β is directly correlated to proliferation indexes. Strong expression of VEGF and PDGFR-β found in endothelium and tumor cells would seem to support a combined role in tumoral neoangiogenesis     

Can amino-functionalized carbon nanotubes carry functional nerve growth factor？

Carbon nanotubes can carry protein into cells to induce biological effects. Amino-functionalized carbon nanotubes are soluble and biocompatible, have high reactivity and low toxicity, and can help promote nerve cell growth. In this study, amino-functionalized ethylenediamine-treated multi-walled carbon nanotubes were used to prepare carbon nanotubes-nerve growth factor complexes by non-covalent grafting. The physicochemical properties, cytotoxicity to PC12 and chick embryo dorsal root ganglion, and biological activity of the carbon nanotubes-nerve growth factor complexes were investigated. The results showed that amino functionalization improved carbon nanotubes-nerve growth factor complex dispersibility, reduced their toxicity to PC12 cells, and promoted PC 12 cell differentiation and chick embryo dorsal root ganglion.     

Effect on peripheral nerve vivo with human insulin-like regeneration by transgene in growth factor-1

BACKGROUND: Human insulin-like growth factor (hIGF-1) has been successful in treating peripheral nerve injury, but it is still unclear whether hIGF-1 after transgene in vivo has the effect on promoting the regeneration of peripheral nerve. OBJECTIVE: To observe the effect of hIGF-1 on the regeneration of peripheral nerve by transgene in vivo with electrophysiology, histological morphology and ultromicro morphology. DESIGN: A univariate design. SETTINGS: Jilin Institute of Surgery, China-Japan Friendship Hospital Affiliated to Jilin University; School of Basic Medical Sciences, Jilin University. MATERIALS: Thirty male adult Wistar rats of grade Ⅱ, weighing 200-250 g, were provided by the Animal Experimental Center of Jilin University [certification number: SCXK-(Ji)20030001]. The rats were raised in the environment at the temperature of 25 ℃ and humidity of 70%. All the rats were randomly divided into hIGF-1-treated group, treatment control group and blank control group, 10 rats in each group. Positive liposomes (mass concentration of 2 g/L) and pcDNA3.1 (mass concentration of 1 g/L) were purchased from Beijing Yuanpinghao Company; pcDNAhIGF-1 (mass concentration of 1 g/L) was provided by Dr. Shen from the School of Public Health of Jilin University. The liposomes were mixed with plasmids with the mass ratio of 1.5 to 10.Operative microscope was made by Jiangsu Zhenjiang Microsurgical Instrument Factory; EMB-5304K electromyogram (EMG) evoked potential meter by Nihon Kohden Corporation. HPIAS-1 000 high-acuity color pathological imaging analytical system (Japan) and JEM-1200EX transmission electron microscope (Japan) were also used. METHODS: The experiments were carried out in Jilin Institute of Surgery from April to June in 2004. ① All the rats were anesthetized, and the right sciatic nerve was exposed, and it was clipped with a clip at 5 mm below the piriform muscle for 3 times, 10 s for each time. The pressed width was 3 mm, and formed as membrane under operating microscope (×6). Rats in the hIGF-1-treated group were subepineurially injected with the mixture of pcDNAhIGF-1 and positive liposomes (10 μL) immediately, those in the treatment control group were injected with the mixture of pcDNA3.1, positive liposomes and distilled water (10 μL), and those in the blank control group were not given any injection. ② The sciatic nerve functional indexes (SFI) were measured within 56 days postoperatively according to the methods used by Shen et al. ISFI=0 was taken as normal, and ISFI=-100 as completely damaged. EMG evoked potential meter was used to record the electrophysiological changes of the regenerated nerve fibers. The indexes of histological morphology in 5 randomly selected sights were determined with the color pathological imaging analytical system, and the ultrostructures of the regenerated nerve fibers were also observed. MAIN OUTCOME MEASURES: ① Comparison of the SFI within 56 days postoperatively; ② Comparison of the electrophysiology, histological morphology and ultrastructure of the regenerated nerve fibers 56 days postoperatively. RESULTS: All the 30 Wistar rats were involved in the analysis of results. ① SFI: The SFI values were gradually increased as time prolonged in all the three groups, and the changes were more obvious after 24 days, the SFI values recovered better at each time point in the hIGF-1-treated group than in the other two groups. ② Eelectrophysiological results of right sciatic nerve: The latency of motor evoked potential (MEP) was close between the treatment control group and the blank control group [(2.55±0.36), (2.65±0.55) ms, P > 0.05], but higher in the hIGF-1-treated group [(2.14±0.22) ms] than in the blank control group (P < 0.01). The amplitude and conduction velocity of MEP in the treatment control group [(6.67±0.69) mV, (29.57±4.06) m/s] were close to those in the blank control group [(6.60±0.59) mV, (29.22±3.20) m/s, P > 0.05], but those in the hIGF-1-treated group [(7.81±0.84) mV, (36.91±4.37) m/s] were larger or faster than those in the blank control group (P < 0.01). ③ Results of the pathological image analysis of the regenerated nerve fibers: The axonal diameter, thickness of myelin sheath of the regenerated nerve fiber and the number of myelinated nerve fiber in the treatment control group [(2.28±0.33) μm, (1.08±0.18) μm2, (71.80±8.25) fibers] were close to those in the blank control group [(2.18±0.29) μm, (1.03±0.15) μm2, (68.60±8.55) fibers] (P > 0.05), and those in the hIGF-1-treated group [(3.03±0.35) μm, (1.65±0.24) μm2, (88.20±8.82) fibers] were obviously larger or more than those in the blank control group (P < 0.01). ④ Ultrastructure of the regenerated nerve fibers of sciatic nerve: In the hIGF-1-treated group, the regenerated fibers of sciatic nerve were more and mature, manifested by thicker nerve fibers, thicker and evener myelin sheath, which were better than those in the other two groups. CONCLUSION: The results of the quantitative parameters of the electrophysiology, gross histological morphology and ultrostructural changes in the process of repairing damaged peripheral nerve indicate that transgene in vivo with hIGF-1 can promote the neural regeneration after peripheral nerve injury.     

Effect on peripheral nerve regeneration by transgene in vivo with human insulin-like growth factor-1

INTRODUCTION In 1950s, the development of microsurgery have greatly improved the quality in repairing peripheral nerve injury. Especially that more than 10 neurotrophic factors (NTFs) have been known in recent 30 years with the continuous exploration of t…     

Insulin-like growth factor I and Alzheimer's disease: therapeutic prospects?

The search for a cure of Alzheimer's dementia is restless. In recent years, unexpected epidemiological data showing a protective effect of anti-inflammatory and cholesterol-lowering drugs gave way to clinical trials with these compounds. Now, a newly described mechanism indicating that brain amyloid clearance is modulated by serum insulin-like growth factor I may also lead to new trials with this growth factor. Insulin-like growth factor I is an abundant circulating hormone with potent central actions whose levels in serum appear to be altered in Alzheimer's patients. Amyloid clearance, a potential therapeutic target in Alzheimer's disease was mostly neglected until recent antiamyloid therapies proved to involve a peripheral amyloid sink. Although more work in animal models are required, the evidence available strongly indicates that insulin-like growth factor I therapy in Alzheimer's dementia may be addressing pathogenic processes.     

Transforming growth factor β1 inhibits cytokine-induced CNS endothelial cell activation

Postcapillary endothelium at the sites of inflammation undergoes a series of changes collectively termed endothelial cell activation. Activated endothelium expresses immunologically relevant surface proteins that include MHC class II antigens (Ags) and adhesion proteins, as well as exhibits a number of functional changes. Endothelial activation has not been thoroughly studied in CNS endothelium. We have examined cytokine-mediated endothelial activation in isolated rat CNS microvessels. Freshly isolated rat CNS microvessels are viable in culture for at least 72 h. Untreated microvessels express no endothelial activation antigens, but do exhibit constitutive expression of the transferrin receptor (tfR). INFγ induces a dose-dependent increase in both MHC class II antigens and tfR measured by immunofluorescent staining and quantitated by laser cytometry. IFNγ-mediated endothelial cell activation could be inhibited with as little as 2 ng/mL TGF-β1, although 100% inhibition was seen with 10 ng/mL TGF-β1. Cytokinepreactivated endothelial expression of class II Ag and tfR could also be inhibited by TGF-β1. TGF-β1-treated microvessels become anergic to IFNγ stimulation. Results suggest that TGF-β1 may have a regulatory role in endothelial activation.