Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A soluble protein which binds basic fibroblast growth factor (FGF-2) has been detected in cerebral spinal fluid from normal individuals and patients with Alzheimer's disease and Parkinson's disease. This 70-85 kDa protein is recognized by an antibody to the extracellular domain of the high affinity FGF receptor and is not detected by an antibody to the intracellular domain of the FGF receptor, suggesting that it consists of a truncated portion of the extracellular domain of the high affinity FGF receptor. This FGF-BP appears to be identical to the two IgG-like loop form of FGFR-1 identified and purified from human and bovine blood. The possibility that this FGF-BP may play a role in transporting, sequestering, or even delivering the FGFs to target cells in the CNS is discussed.
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PMID:A fibroblast growth factor binding protein in human cerebral spinal fluid. 761 76

Fibroblast growth factor (FGF) is synthesized and stored by astroglial cells and regulates their proliferation and differentiation in vitro. Its implication in the transformation of quiescent astrocytes into reactive astroglia has been discussed. Using a mouse model of Parkinson's disease, in which FGF-2 has been shown to exert marked neuroprotection of nigrostriatal dopaminergic neurons, we have studied striatal levels of glial fibrillary acidic protein (GFAP), an established marker for astrocytes, and the distribution and morphologies of GFAP-immunoreactive cells following treatments with the neurotoxic drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the growth factor FGF-2, and the non-trophic control protein cytochrome C (cyt C). Systemic injections of MPTP (30 mg/kg) on 3 consecutive days, which we have previously shown to cause profound and long-lasting damage to the nigrostriatal system, induced an approximate 20% transient increase in striatal GFAP, determined by enzyme-linked immunosorbent assay (ELISA), 1 day after the final MPTP injection (= day 4), with subsequent normalization at day 7, which lasted until the end of the experiment (day 18). Morphologically, MPTP elicited a marked increase in number, size, arborization, and stainability of GFAP-immunoreactive cells at day 4 in a striatal area adjacent to the corpus callosum, which was evaluated throughout all experiments. Even on day 18, astrocytes were still apparently larger and more branched than in unlesioned controls. Administration of 4 micrograms of either FGF-2 or cyt C (soaked into a piece of Gelfoam unilaterally to the right striatum in either MPTP- or saline-injected controls) increased striatal GFAP levels bilaterally about 2- to 2.5-fold at 14 days, when FGF-2 showed marked protection of dopaminergic parameters. Likewise, GFAP immunocytochemistry revealed increased numbers of intensely immunoreactive astrocytes under any experimental situation. Differences in the morphologies of astrocytes in FGF-2- and cyt C-treated animals were very subtle and only noted at greater distances away from the site of application of the factors. We conclude that FGF-2, a potent neurotrophic factor for the neurotoxically lesioned nigrostriatal system, does not cause a marked astrogliotic reaction, which might be expected from previous in vitro and in vivo studies in other neural systems. This may limit concerns regarding potential applicability of FGF-2 to the parkinsonian striatum.
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PMID:FGF-2 in the MPTP model of Parkinson's disease: effects on astroglial cells. 807 Aug 94

Basic fibroblast growth factor (bFGF; FGF-2) has potent trophic effects on developing and toxically impaired midbrain dopaminergic (DAergic) neurons which are crucially affected in Parkinson's disease. The trophic effects of FGF-2 are largely indirect, both in vitro and in vivo, and possibly involve intermediate actions of astrocytes and other glial cells. To further investigate the cellular and molecular mechanisms underlying the restorative actions of FGF-2, and to analyse in more detail the changes within astroglial cells in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned striatum, we have studied striatal expression and regulation of connexin-43 (cx43), the principal gap junction protein of astroglial cells, along with the expression of glial fibrillary acidic protein (GFAP), FGF-2, and functional coupling. Our results show an immediate, yet transient increase in cx43 mRNA, and a sustained increase in FGF-2 mRNA, GFAP-positive cells, and cx43-immunoreactive punctata following the MPTP lesion, without any induction of functional coupling between astrocytes and other glial cells as revealed by dye coupling of patched cells. Unilateral administration of FGF-2 in a piece of gelfoam caused a further increase in cx43-positive punctata immediately adjacent to the implant, which was more pronounced than after application of a gelfoam containing the nontrophic control protein cytochrome C. These changes were parallelled by a small increase in cx43 protein determined by Western blot, but not by alterations in the coupling state of cells in the vicinity of the gelfoam implant. Although our data indicate that MPTP and exogenous FGF-2 may alter expression and protein levels of cx43, they do not support the notion that increases in cellular coupling may underly the trophic and widespread actions of FGF-2 in the MPTP-model of Parkinson's disease.
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PMID:Regulation of connexin-43, GFAP, and FGF-2 is not accompanied by changes in astroglial coupling in MPTP-lesioned, FGF-2-treated parkinsonian mice. 895 72

Chromaffin cells of the adrenal medulla and their tumor counterparts, the pheochromocytoma (PC12) cells, are well-established model systems in neurobiology. The development of sympathoadrenal progenitor cells to chromaffin cells can be studied with regard to developmental signals which trigger the differentiation. With regard to potential treatments of neurological disorders like Parkinson's disease chromaffin cell grafting can be used as one therapeutical approach. The beneficial effect of chromaffin cell grafts is possibly not only related to the release of dopamine but may also be linked to the release of growth factors. One of the growth factors that is synthesized by chromaffin and PC12 cells is basic fibroblast growth factor (FGF-2). The experimental data available so far, are in agreement with different functional roles of FGF-2. This article summarizes the putative physiological functions of FGF-2 in the adrenal medulla. Three differential functional roles of FGF-2 are discussed: (1) as a differentiation factor for sympathoadrenal progenitor cells; (2) as a target-derived neurotrophic factor for preganglionic sympathetic neurons which innervate adrenal medullary cells; (3) as an auto-/paracrine factor in the adrenal medulla.
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PMID:The multifunctionality of FGF-2 in the adrenal medulla. 904 80

The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the innumerous substances that originate from tobacco smoke, nicotine is by far the most widely studied, and the most likely candidate for a protective effect against neuronal degeneration in Parkinson's disease. Nicotine is a natural alkaloid that has considerable stimulatory effects on the central nervous system (CNS). Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChR, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)nicotine in two animal models of parkinsonism: the diethyldithiocarbamate (DDC)-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, and the methamphetamine-induced neurotoxicity in rats and mice. In parallel experiments, we found that (-)nicotine induces the basic fibroblast growth factor (FGF-2) and the brain-derived neurotrophic factor (BDNF) in rat striatum. As FGF-2 and BDNF have been reported to be neuroprotective for dopaminergic cells, our data indicate that the increase in neurotrophic factors is a possible mechanism by which (-)nicotine protects from experimental parkinsonisms. Moreover, they suggest that nAChR agonists could be of potential benefit in the progression of Parkinson's disease.
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PMID:Striatal increase of neurotrophic factors as a mechanism of nicotine protection in experimental parkinsonism. 950 63

The multiple combinations of nAChR subunits identified in central nervous structures possess distinct pharmacological and physiological properties. A growing number of data have shown that compounds interacting with neuronal nAChRs have, both in vivo and in vitro, the potential to be neuroprotective and that treatment with nAChR agonists elicit long-lasting improving of cognitive performance in a variety of behavioural tests in rats, monkeys and humans. Epidemiological and clinical studies suggested also a potential neuroprotective/trophic role of (-)-nicotine in neurodegenerative disease, such as Alzheimer's and Parkinson's disease. Taken together experimental and clinical data largely indicate a neuroprotective/trophic role of nAChR activation involving mainly alpha7 and alpha4beta2 nAChR subtypes, as evidenced using selective nAChR antagonists, and by potent nAChR agonists recently found displaying efficacy and/or larger selective affinities than (-)-nicotine for neuronal nAChR subtypes. A neurotrophic factor gene regulation by nAChR signalling has been taken into consideration as possible mechanism involved in neuroprotective/trophic effects by nAChR activation and has evidenced an involvement of the fibroblast growth factor (FGF-2) gene as a target of nAChR signalling. These findings suggested that FGF-2 could be involved, according to the FGF-2 neurotrophic functions, in nAChR mechanisms mediating the neuronal survival, trophism and plasticity.
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PMID:Central nicotinic receptors, neurotrophic factors and neuroprotection. 1094 29

A growing number of data have shown that compounds interacting with neuronal nicotinic acetylcholine receptors (nAChRs) have, both in vivo and in vitro, the potential to be neuroprotective and that treatment with nAChR agonists elicit long-lasting improvement of cognitive performance in a variety of behavioural tests in rats, monkeys and humans. Epidemiological and clinical studies suggested also a potential neuroprotective/trophic role of (-)-nicotine in neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease. This neuroprotective/trophic role of nAChR activation has been mainly mediated by alpha7 and alpha4beta2 nAChR subtypes, as evidenced using selective nAChR antagonists, and by potent nAChR agonists recently found displaying efficacy and/or larger selective affinities than (-)-nicotine for neuronal nAChR subtypes. A neurotrophic factor gene regulation by nAChR signalling has been taken into consideration as a possible mechanism involved in neuroprotective/trophic effects of nAChR activation and has given evidence that the fibroblast growth factor (FGF-2) gene is a target for nAChR signalling. These findings suggested that FGF-2 could be involved, in view of its neurotrophic functions, in nAChR mechanisms mediating neuronal survival, trophism and plasticity.
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PMID:Neurotrophic effects of central nicotinic receptor activation. 1120 43

We have investigated the role of dopaminergic receptors in modulation of basic fibroblast growth factor (FGF-2) expression in rat prefrontal cortex and hippocampus, two brain regions important for cognition. We found that FGF-2 expression is upregulated by quinpirole, a D2 agonist, in prefrontal cortex and to a lesser extent in hippocampus. This modulation was specific for dopamine D2 receptors because no effect was observed when the dopamine D1 and D3 agonists, SKF38393 and 7-OH-DPAT, respectively, were administered. Our findings show that activation of dopaminergic D2 receptors modulates FGF-2 expression in rat prefrontal cortex and hippocampus. Our data highlight the complex modulation of FGF-2 expression in limbic areas pointing to this trophic molecule as a putative target of drugs used against acute and chronic neurodegenerative diseases such as Parkinson's disease.
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PMID:Dopaminergic D2 receptor activation modulates FGF-2 gene expression in rat prefrontal cortex and hippocampus. 1313 May 8

Dopaminergic (DA) micrografts were co-transplanted with Schwann cells (SC) overexpressing 18 kDa and 21/23 kDa FGF-2 into the caudate-putamen unit (CPu) of unilaterally 6-hydroxydopamine-lesioned rats. We report here that SC engineered to overexpress FGF-2 promoted DA-graft-induced restoration, whether co-transplanted at the same site or grafted at a second more distant site within the CPu. In addition, the 21/23 kDa FGF-2 isoforms resulted in a significantly better reinnervation and survival of dopaminergic micrografts when compared to the 18-kDa FGF-2 isoform. However, this effect was not that distinct on functional recovery due to, for example, ceiling effects. One main finding of this study was the influence of the gene promotor on DA survival, respectively, vector-mediated trophism. Therefore, comparisons in terms of survival between 18 kDa and higher molecular weight (HMW) FGF-2 are complicated in the mixed grafted experiments. Furthermore, the first demonstration of the presence of the 21/23 kDa FGF-2 isoforms in the nigrostriatal system and their potent neurotrophic in vivo activities, as shown in the present study, suggest (I) a physiological role of these proteins for dopaminergic neurons and (II) a restorative potential under normal as well as regenerative processes. However, FGF-2-mediated effects are more pronounced after co-transplantation with SC/DA cells mixed in one suspension at the same implantation side than in the side-by-side approach with a spatially and temporally separated transplantation of SC (day 1) and DA-cells (day 3). These findings indicate the necessity of direct contact between FGF-2 and DA-neurons, further elucidate the neurotrophic role of FGF-2 for DA-neurons and highlight the differential restorative potentials of its respective isoforms. We propose that administration of HMW FGF-2 may be used to improve function in the rat Parkinson's disease model.
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PMID:Enhanced survival, reinnervation, and functional recovery of intrastriatal dopamine grafts co-transplanted with Schwann cells overexpressing high molecular weight FGF-2 isoforms. 1508 94

Basic fibroblast growth factor (FGF-2) is a physiological relevant neurotrophic factor in the nigrostriatal system and hence a promising candidate for the establishment of alternative therapeutic strategies in Parkinson's disease. FGF-2 and its high-affinity receptors (FGFR) display an expression in the developing, postnatal, and adult substantia nigra (SN) and in the striatum. Exogenous application promoted survival, neurite outgrowth and protection from neurotoxin-induced death of dopaminergic (DA) neurons both in vitro and in vivo. In animal models of Parkinson's disease, co-transplantation of fetal DA cells with FGF-2 expressing cells increased survival and functional integration of the grafted DA neurons resulting in improved behavioral performance. Analyzing the physiological function of the endogenous FGF-2 system during development and after neurotoxin-induced lesion revealed for the DA neurons of the SNpc a dependence on FGFR3 signaling during development. In addition, in the absence of FGF-2 an increased number of DA neurons was found, whereas enhanced levels of FGF-2 resulted in a reduced DA cell density. Following neurotoxin-induced lesion of DA neurons, FGF-2-deleted mice displayed a higher extent of DA neuron death whereas in FGF-2 overexpressing mice more DA neurons were protected. According to the data, FGF-2 seems to promote DA neuron survival via FGFR3 during development, whereas absence of this ligand could be compensated by other members of the FGF family. In contrast, in the adult organism, FGF-2 cannot be compensated by other factors under lesion conditions suggesting a central role for this molecule in the nigrostriatal system.
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PMID:The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatal system. 1722 67


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