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)

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophin which supports midbrain dopaminergic neurons and spinal cord motorneurons. GDNF has been proposed as a possible therapeutic agent for Parkinson's disease, spinal cord injury or motorneuron degenerative disorders. Administration of GDNF is complicated by its poor penetration across the blood-brain barrier (BBB). Central nervous system capillaries are uniquely enriched in transferrin receptors and antibodies to these receptors (OX-26) have been proposed as potential carriers to transport large molecules across the BBB. Intravenous administration of an OX-26-GDNF conjugate enhanced survival of spinal cord motorneurons in intraocular transplants, which possess an organotypic BBB. This suggests that the OX-26-GDNF conjugate could be utilized for non-invasive treatment of neurodegenerative diseases of the spinal cord or midbrain dopaminergic neurons.
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PMID:A non-invasive transport system for GDNF across the blood-brain barrier. 924 28

trkB is a high-affinity receptor for brain-derived neurotrophic factor, a neurotrophin acting on numerous cells, including dopaminergic neurons. Yet, little is known of its expression in the human brain. We report an in situ hybridization analysis of trkB messenger RNA, encoding the catalytic form of the receptor, in the human brain post mortem. Its expression was found to be widespread but heterogeneous among all the cerebral structures studied, the highest level being found in the cerebral cortex and the cerebellum. A strong but less intense staining was observed in the striatum, nucleus basalis of Meynert, hippocampus, tegmental pedonculopontinus nucleus and substantia nigra pars compacta. Combined immunohistochemistry for tyrosine hydroxylase and in situ hybridization for trkB messenger RNA showed that within the substantia nigra pars compacta a major proportion of dopaminergic neurons expressed trkB messenger RNA. Furthermore, we compared trkB messenger RNA expression in the mesencephalon of six control subjects and five patients with Parkinson's disease, a neurodegenerative disorder characterized by a severe loss of dopaminergic neurons. Despite the fact that the number of trkB messenger RNA-containing neurons was dramatically reduced in the substantia nigra pars compacta and ventral tegmental area of patients with Parkinson's disease, the level of trkB messenger RNA was unchanged in the remaining neurons in diseased brains. These results suggests that trkB is not involved in the process of neuronal death in Parkinson's disease. Furthermore, expression of brain-derived neurotrophic factor high-affinity receptor in patients could allow this neurotrophin to be used to prevent degeneration of surviving neurons at early stages of the disease.
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PMID:trkB messenger RNA expression in normal human brain and in the substantia nigra of parkinsonian patients: an in situ hybridization study. 969 19

To assess the action of neurotrophin in human dopaminergic neurons, we studied the immunolocalization of neurotrophins or trks in human substantia nigra pars compacta (SNc). The neuromelanin-containing neurons in the SNc showed immunoreactivities for neurotrophins or trks, suggesting an autocrine/paracrine regulation. Quantitative analysis revealed that the percentage of those expressing NGF-like immunoreactivity (NGF-LI), BDNF-LI, NT3-LI, trkA-LI, trkB-LI, or trkC-LI was 66%, 74%, 85%, 66%, 71% or 86%, respectively. The percentage of cells expressing neurotrophins or trks was higher in the medial part than in the lateral part of the SNc. The preferential expression of neurotrophin-trk systems in the medial neurons may, at least partially, explain the differential susceptibility in Parkinson's disease.
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PMID:Medial nigral dopamine neurons have rich neurotrophin support in humans. 976 Jan 32

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

Glial cell line-derived neurotrophic factor (GDNF) was first discovered as a potent survival factor for midbrain dopaminergic neurons and was then shown to rescue these neurons in animal models of Parkinson's disease. GDNF is a more potent survival factor for dopaminergic neurons and the noradrenergic neurons of the locus coeruleus than other neurotrophic factors, and an almost 100 times more efficient survival factor for spinal motor neurons than the neurotrophins. The members of the GDNF family, GDNF, neurturin (NTN), persephin (PSP), and artemin (ART), have seven conserved cysteine residues with similar spacing, making them distant members of the transforming growth factor-beta (TGF-beta) superfamily. Like the members of the neurotrophin family, the GDNF-like growth factors belong structurally to the cysteine knot proteins. Like neurotrophins, GDNF family proteins are responsible for the development and maintenance of various sets of sensory and sympathetic neurons but, in addition, GDNF and NTN are also responsible for the development and survival of the enteric neurons, and NTN for parasympathetic neurons. All neurotrophins bind to the p75 low-affinity receptor, but their ligand specificity is determined by trk receptor tyrosine kinases. GDNF, NTN, PSP, and ART mediate their signals via a common receptor tyrosine kinase, Ret, but their ligand specificity is determined by a novel class of glycosylphosphatidylinositol (GPI)-anchored proteins called the GDNF family receptor alpha (GFR alpha). GDNF binds preferentially to GFR alpha1, NTN GFR alpha2, ART GRF alpha3, and PSP GFR alpha4 as a co-receptor to activate Ret. GFR alpha4 has until now been described only from chicken. Although the GDNF family members signal mainly via Ret receptor tyrosine kinase, there is recent evidence that they can also mediate their signals via GFR alpha receptors independently of Ret. The GDNF family of growth factors, unlike neurotrophins, has a well-defined function outside the nervous system. Recent transgenic and organ culture experiments have clearly demonstrated that GDNF is a mesenchyme-derived signaling molecule for the promotion of ureteric branching in kidney development. NTN, ART, and PSP are also expressed in the developing kidney, and NTN and PSP induce ureteric branching in vitro, but their true in vivo role in kidney morphogenesis is still unclear.
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PMID:Other neurotrophic factors: glial cell line-derived neurotrophic factor (GDNF). 1038 22

Degeneration of the dopamine (DA) neurons of the substantia nigra pars compacta and the resulting loss of nerve terminals accompanied by DA deficiency in the striatum are responsible for most of the movement disturbances called parkinsonism, observed in Parkinson's disease (PD). One hypothesis of the cause of degeneration of the nigrostriatal DA neurons is that PD is caused by programmed cell death (apoptosis) due to increased levels of cytokines and/or decreased ones of neurotrophins. We and other workers found markedly increased levels of cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2, IL-4, IL-6, transforming growth factor (TFG)-alpha, TGF-beta1, and TGF-beta2, and decreased ones of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in the nigrostriatal DA regions and ventricular and lumbar cerebrospinal fluid of PD patients. Furthermore, the levels of TNF-alpha receptor R1 (TNF-R1, p55), bcl-2, soluble Fas (sFas), and the activities of caspase-1 and caspase-3 were also elevated in the nigrostriatal DA regions in PD. In experimental animal models of PD, IL-1beta level was increased and NGF one decreased in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice, and TNF-alpha level was increased in the substantia nigra and striatum of the 6-hydroxydopamine (6OHDA)-injected side of hemiparkinsonian rats. L-DOPA alone or together with 6OHDA does not increase the level of TNF-alpha in the brain in vivo. Increased levels of proinflammatory cytokines, cytokine receptors and caspase activities, and reduced levels of neurotrophins in the nigrostriatal region in PD patients, and in MPTP- and 6OHDA-produced parkinsonian animals suggest increased immune reactivity and programmed cell death (apoptosis) of neuronal and/or glial cells. These data indicate the presence of such proapoptotic environment in the substantia nigra in PD that may induce increased vulnerability of neuronal or glial cells towards a variety of neurotoxic factors. The probable causative linkage among the increased levels of proinflammatory cytokines and the decreased levels of neurotrophins, candidate parkinsonism-producing neurotoxins such as isoquinoline neurotoxins (Review; Nagatsu, 1997), and the genetic susceptibility to toxic factors, remains for further investigation in the molecular mechanism of PD. The increased cytokine levels, decreased neurotrophin ones, and the possible immune response in the nigrostriatal region in PD indicate new neuroprotective therapy including nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, immunosuppressive or immunophilin-binding drugs such as FK-506, and drugs increasing neurotrophins.
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PMID:Changes in cytokines and neurotrophins in Parkinson's disease. 1120 47

Nuclear factor kappa B (NF-kappa B) is a transcription factor crucially involved in glial and neuronal function. NF-kappa B is ubiquitously distributed within the nervous system, and its inducible activity can be discerned from constitutive activity. Prototypic inducible NF-kappa B in the nervous system is composed of the DNA-binding subunits p50 and p65 complexed with an inhibitory I kappa B-alpha molecule. A number of signals from the cell surface can lead to rapid activation of NK-kappa B, thus releasing the inhibition by I kappa B. This activates translocation of NF-kappa B to the nucleus, where it binds to kappa B motifs of target genes and activates transcription. Previous findings have identified reactive oxygen intermediates (ROI) as a common denominator of NF-kappa B activating signals. More specifically, hydrogen peroxide (H2O2) might be used as second messenger in the NF-kappa B system, despite its cytotoxicity. Analysis of pathways leading to NF-kappa B activation in the nervous system has identified a number of ROI-dependent pathways such as cytokine- and neurotrophin-mediated activation, glutamatergic signal transduction, and various diseases with crucial ROI involvement (e.g., Alzheimer's disease, Parkinson's disease, experimental autoimmune encephalomyelitis, multiple sclerosis, amyotrophic lateral sclerosis, and injury). A number of NF-kappa B-specific target genes contribute to the production of ROI or are involved in detoxification of ROIs. In this review, possible mechanisms and regulatory pathways of ROI-mediated NF-kappa B activation are discussed.
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PMID:Activation of NF-kappa B by reactive oxygen intermediates in the nervous system. 1122 42

Genetic, neurochemical, and environmental factors have been implicated in neurodegenerative disease, and a combination of these factors is likely responsible for disease onset and progression. Environmental toxicants implicated in Parkinson's disease include organic compounds, reactive oxygen species, metal ions and others. Exposure to a combination of environmental toxicants may produce a synergistic insult leading to neuronal death, even though levels of individual toxicants may be below detection by conventional methods. Rodent models of toxicant-induced neurodegeneration are hampered by the high resistance of these animals to many environmental toxicants. Extensive literature on aquatic toxicology and the high homology between many human and fish neurotrophic factors makefish a useful model for investigating environmental toxicants and neurodegeneration. Skin color in salmonids is under catecholaminergic control; pigment-containing melanophores aggregate when stimulated, resulting in paling. We demonstrate that lesions to nerves innervating melanophores prevent aggregation and produce dark skin color. The time course for return of skin color corresponds to neuronal regeneration, a neurotrophin-dependent event. Observations from this model system may be useful for predicting risks associated with environmental toxicants and nervous system integrity, and may have important implications for the identification of risk factors.
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PMID:Catecholaminergic neuronal degeneration in rainbow trout assessed by skin color change: a model system for identification of environmental risk factors. 1242 27

Nerve growth factor was the first identified protein with anti-apoptotic activity on neurons. This prototypic neurotrophic factor, together with the three structurally and functionally related growth factors brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5), forms the neurotrophin protein family. Target T cells for neurotrophins include many neurons affected by neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and peripheral polyneuropathies. In addition, the neurotrophins act on neurons affected by other neurological and psychiatric pathologies including ischemia, epilepsy, depression and eating disorders. Work with cell cultures and animal models provided solid support for the hypothesis that neurotrophins prevent neuronal death. While no evidence exists that a lack of neurotrophins underlies the etiology of any neurodegenerative disease, these studies have spurred on hopes that neurotrophins might be useful symptomatic-therapeutic agents. However first clinical trials led to variable results and severe side effects were observed. For future therapeutic use of the neurotrophins it is therefore crucial to expand our knowledge about their physiological functions as well as their pharmacokinetic properties. A major challenge is to develop methods for their application in effective doses and in a precisely timed and localized fashion.
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PMID:Neurotrophins. 1257 26

The survival signal elicited by the phosphatidylinositol 3-kinase (PI3K)/Akt1 pathway has been correlated with inactivation of pro-apoptotic proteins and attenuation of the general stress-induced increase in reactive oxygen species (ROS). However, the mechanisms by which this pathway regulates intracellular ROS levels remain largely unexplored. In this study, we demonstrate that nerve growth factor (NGF) prevents the accumulation of ROS in dopaminergic PC12 cells challenged with the Parkinson's disease-related neurotoxin 6-hydroxydopamine (6-OHDA) by a mechanism that involves PI3K/Akt-dependent induction of the stress response protein heme oxygenase-1 (HO-1). The effect of NGF was mimicked by induction of HO-1 expression with CoCl(2); by treatment with bilirubin, an end product of heme catabolism; and by infection with a retroviral expression vector for human HO-1. The relevance of HO-1 in NGF-induced ROS reduction was further demonstrated by the evidence that cells treated with the HO-1 inhibitor tin-protoporphyrin or infected with a retroviral expression vector for antisense HO-1 exhibited enhanced ROS release in response to 6-OHDA, despite the presence of the neurotrophin. Inhibition of PI3K prevented NGF induction of HO-1 mRNA and protein and partially reversed its protective effect against 6-OHDA-induced ROS release. By contrast, cells transfected with a membrane-targeted active version of Akt1 exhibited increased HO-1 expression, even in the absence of NGF, and displayed a greatly attenuated production of ROS and apoptosis in response to 6-OHDA. These observations indicate that the PI3K/Akt pathway controls the intracellular levels of ROS by regulating the expression of the antioxidant enzyme HO-1.
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PMID:Nerve growth factor protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a phosphatidylinositol 3-kinase-dependent manner. 1257 34


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