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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In reactive gliosis, astrocytes undergo morphological and biochemical changes which can be mimicked in vitro by treatment with bFGF (basic fibroblast growth factor) or cAMP. To investigate the influence of activated cortical astrocytes on central nervous system (CNSD) neurons, we studied the effect of the supernatant from bFGF-treated astrocytes on the development of dopaminergic neurons from rat mesencephalon. Conditioned medium of untreated astrocytes stimulated dopamine uptake of mesencephalic cultures. After activation of astrocytes with bFGF this effect was greatly enhanced. It was significantly more potent than stimulating effects of other neurotrophic factors. The supernatant of these astrocytes increased the biochemical differentiation but not the survival of dopaminergic neurons in our cell culture system. Trypsin digestion and gel chromatography revealed that the activity was due to one or several proteins with molecular mass above 5 kDa. We excluded the participation of several factors known to be produced by astrocytes or that are neurotrophic for substantia nigra cultures. In particular, we provide evidence that bFGF, BDNF, NT-3, Il-1, Il-6, S100 beta and alpha 2-macroglobulin were not involved in the effect of the conditioned medium. In vitro stimulation of astrocytes therefore triggers the expression of currently uncharacterized factors which influence the biochemical differentiation of mesencephalic dopaminergic neurons, the cells that degenerate in Parkinson's disease.
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PMID:Cortical astrocytes activated by basic fibroblast growth factor secrete molecules that stimulate differentiation of mesencephalic dopaminergic neurons. 127 4

In 1979, we presented the first evidence that grafts of fetal brain tissue to the adult central nervous system could counteract an experimentally induced neurological deficit. Using the unilaterally dopamine-denervated rat model of Parkinson's disease, it was first shown that fetal substantia nigra grafts were effective and, later, that adult adrenal medullary chromaffin tissue might be used as a possible substitute for fetal brain tissue. These observations led to the first clinical trials with chromaffin autografting in severe cases of Parkinson's disease, which were initiated at the Karolinska Hospital in 1982, and several years later to clinical trials with grafts of fetal dopamine neuroblasts obtained after early elective abortions. In parallel with the ongoing intense basic research aimed at optimizing grafting procedures and finding new possible clinical applications, there are now worldwide clinical trials of grafting procedures involving a large number of neurosurgical centers and a large number of patients. Here, I shall review our recent studies of grafts and growth factors as they relate to possible new therapeutic principles applicable not only to Parkinson's disease, but also to Alzheimer's senile dementia and possibly to spinal cord injury and other afflictions. Recent evidence suggests that cholinergic neurons in the brain, known to degenerate in Alzheimer's disease, depend on nerve growth factor. In one approach we have grafted genetically modified cell lines, designed to secrete large amounts of nerve growth factor, and demonstrated that they can rescue lesioned cholinergic neurons that would otherwise die. Nerve growth factor can also serve to enhance survival of, and promote fiber formation by, chromaffin grafts in experimental parkinsonism. Interestingly, a series of other growth factors, such as IGF-1, bFGF, aFGF, BDNF, TGF's, as well as their receptors, are now being cloned and in several cases shown to have interesting temporal and regional distributions as well as effects in the central nervous system. Our own studies using intraocular grafts suggest potent effects on fetal brain tissue growth of truncated IGF-1, bFGF, and aFGF. It thus appears as if neurosurgery is on the verge of entering a new era in which repair in the adult brain and spinal cord, once thought impossible in mammals, will become possible using growth factors and grafts.
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PMID:Grafts and growth factors in CNS. Basic science with clinical promise. 208 Mar 39

Fibroblast growth factors (FGFs) are a family consisting of at least seven members, and the FGF family will continue to expand. The best studied members of this family are acidic and basic FGF (aFGF and bFGF). They are richly concentrated in brain, and have potent trophic effects for neurons and glia. I now report that expressions of aFGF and bFGF are altered in several neurodegenerative disorders such as Alzheimer disease (AD), Huntington disease (HD) and Parkinson disease (PD). In AD aFGF was upregulated in reactive astrocytes in severely affected areas. The bFGF-positive astrocytes were also increased. In addition, bFGF was detected in senile plaques, neurofibrillary tangles and neuropil threads. In AD, aFGF and bFGF showed a similar alteration pattern. A large number of aFGF- or bFGF-positive astrocytes were observed in the striatum. Some remaining neurons were strongly stained for aFGF or bFGF. In PD, marked loss of bFGF was observed on midbrain dopaminergic neurons, The depletion of bFGF preceded the loss of tyrosine hydroxylase. Since bFGF has a potent trophic effect on midbrain dopaminergic neurons, this depletion may be related to the disease process.
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PMID:[Fibroblast growth factors (FGFs) in neurodegenerative disorders]. 817 23

Embryonic substantia nigra cells when transplanted into the striatum can reverse many of the defects of Parkinson's disease. The efficacy of such grafts is compromised by the poor survival of grafted dopaminergic neurones; typically, 3-10% survive transplantation. We used three tissue culture models to identify stages in the procedure for the preparation and insertion of grafts which might be responsible for this cell death and to identify environments in which survival is optimised. (1) The ventral mesencephalon was dissected from the donor brain, then placed immediately into culture contained in a collagen gel. (2) The dissected tissue fragments were enzymatically dissociated, then the cells placed into monolayer culture. (3) Enzymatically dissociated tissue was packed into 0.5-mm-diameter porous tubes, to simulate the compaction of cells into a graft deposit in the host brain. Dissociation of the tissue by itself caused the death of approximately 30% of dopaminergic neurones, as judged by the difference in cell counts between the intact embryonic day 14 (E14) mesencephalon, and cells dissociated then packed into tubes. Of the dissociated neurones approximately 60% died during the first 24 h and 87% during the first 3 days in monolayer culture, while only 7% of dopaminergic neurones in three-dimensional cultures and 11% of neurones in explant cultures died over the first 3 days. Embryonic dopaminergic neurones are clearly very vulnerable to adverse conditions during the first days after their removal from the donor brain. The excellent survival of neurones in three-dimensional and explant cultures indicates that close association with other cells, which may provide greatly improved access to trophic factors, can enable the cells to survive this period of vulnerability. In contrast to its effects in monolayer cultures, bFGF had no effect on dopaminergic neuronal survival in either explant or three-dimensional cultures.
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PMID:Dopaminergic neuronal survival and the effects of bFGF in explant, three dimensional and monolayer cultures of embryonic rat ventral mesencephalon. 856 92

We have studied how stimulation of protein kinase C and cAMP-dependent protein kinases affect the development of mesencephalic dopaminergic neurons in vitro. IGF-I and bFGF did not activate either second messenger system nor affect the survival of dopaminergic neurons but stimulated dopamine uptake per neuron. Phorbol esters, which stimulate protein kinase C, had no effect on dopamine uptake. Dibutyryl-cAMP caused an increase in dopamine uptake, which was blocked with (Rp)-cAMPS, a specific inhibitor of cAMP-dependent protein kinases. Treating cells with specific phosphodiesterase type IV inhibitors elevated the forskolin-induced increase in dopamine uptake. Furthermore, cAMP, but neither bFGF nor activation dependent astrocyte factor (ADAF), was able to prevent the degeneration of dopaminergic neurons induced by MPP+. These results suggest that increased intracellular cAMP protects dopaminergic neurons in situations of stress and therefore reveal novel possibilities for the treatment of Parkinson's disease.
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PMID:Cyclic AMP promotes the survival of dopaminergic neurons in vitro and protects them from the toxic effects of MPP+. 882 Oct 58

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

The success of embryonic neural transplants as a treatment for patients with Parkinson's disease has been limited by poor survival of transplanted dopamine neurons. To see if a new partially intact tissue preparation method improves survival, we have developed a technique for extruding embryonic tissue into strands. We expected this method to reduce cell damage and improve transplant survival as well as provide improved tissue delivery. We have compared transplants of tissue strands with mechanically dispersed suspensions of embryonic day 15 rat ventral mesencephalon. Tissue from ventral mesencephalon was transplanted into a single site in dopamine denervated striatum of unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. To evaluate the effects of striatal cografts and growth factors on dopamine cell survival, dispersed mesencephalic cells were cotransplanted with dispersed striatal cells. Another group had dispersed mesencephalic cells cotransplanted with striatal cells incubated in the cold for 2 h with glial cell line-derived neurotrophic factor (GDNF, 100 ng/ml), insulin-like growth factor-I (IGF-I, 1500 ng/ml), and basic fibroblast growth factor (bFGF, 150 ng/ml). Behavioral improvement was assessed monthly by changes in methamphetamine-induced rotational behavior. Animals were sacrificed after 3 months, and dopamine neurons were identified by tyrosine hydroxylase (TH) immunohistochemistry. Transplants of tissue strands produced better dopamine neuron survival and led to more robust behavioral restoration than did cell suspensions even when suspensions were supported with cografts of striatal cells or pretreatment with growth factors.
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PMID:Strands of embryonic mesencephalic tissue show greater dopamine neuron survival and better behavioral improvement than cell suspensions after transplantation in parkinsonian rats. 973 8

Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intraparenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF results in widespread retrograde transport throughout the CNS. BDNF has also been shown to be transported anterogradely within the CNS. Infusion of GDNF into the CNS results in retrograde transport limited to the nigrostriatal pathway. Hippocampal injections of NT-3 retrogradely label mainly basal forebrain neurons. Retrograde transport of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve. Following intraventricular and intraparenchymal infusion of radiolabeled bFGF, retrograde neuronal labeling was found in the telecephalon, diencephalon, mesencephalon and pons. In contrast retrograde labeling for aFGF was found only in the hypothalamus and midbrain. Since select neurotrophins traffic anterogradely and retrogradely within the nervous system, these proteins could be used to treat neurological diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.
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PMID:Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. 1008 Mar 85

The biomedical literature on the subject of neurotrophic growth factors has expanded prodigiously. This essay reviews neurotrophic factors (NTF) and their receptors in Alzheimer's disease (AD) and Parkinson's disease (PD) brain and recent updates on receptor signaling. The hypotheses for specific NTF involvement in neurodegenerative diseases in human and as potential therapy are based mainly on experimental animal and in vitro models. There are wide gaps in information on regional synthesis and cell contents of NTFs and their receptors in human brain. Observations on AD brain indicate increases in NGF and decreases in BDNF in surviving neurons of hippocampus and certain neocortical regions and decreases in TrkA in cortex and nucleus basalis. In PD brain, the few data available indicate decreases in neuronal content of GDNF and bFGF in surviving substantia nigra dopaminergic neurons. There are very few data regarding age-dependent effects on NTFs and on their receptors in human brain. Since NTFs in neurons are subject to retrograde and, in at least some cases, to anterograde transport from and to target neurons, their effects may be related to synthesis in local or remote sites or to changes in axoplasmic transport. Also, certain NTFs and their receptors are found to be expressed in activated glia. Thus, comparative in situ data for transcription levels and protein contents for NTFs and their receptors in both sites of neuronal origin and termination in human brain are needed to understand their potential roles in treating human diseases.
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PMID:Neurotrophic factors in Alzheimer's and Parkinson's disease brain. 1101 Oct 66

The use of in vitro expanded human CNS precursors has the potential to overcome some of the ethical, logistic and technical problems of fetal tissue transplantation in Parkinson disease. Cultured rat mesencephalic precursors proliferate in response to bFGF and upon mitogen withdrawal, differentiate into functional dopamine neurons that alleviate motor symptoms in Parkinsonian rats (Studer et al. [1998] Nat. Neurosci. 1:290-295). The successful clinical application of CNS precursor technology in Parkinson disease will depend on the efficient in vitro generation of human dopaminergic neurons. We demonstrate that human dopamine neurons can be generated from both midbrain and cortical precursors. Transplantation of midbrain precursor-derived dopamine neurons into Parkinsonian rats resulted in grafts rich in tyrosine hydroxylase positive neurons 6 weeks after transplantation. No surviving tyrosine hydroxylase positive neurons could be detected when dopamine neurons derived from cortical precursors were grafted. Our data demonstrate in vitro derivation of human dopamine neurons from expanded CNS precursors and encourage further studies that systematically address in vivo function and clinical potential.
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PMID:In vitro generation and transplantation of precursor-derived human dopamine neurons. 1149 63


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