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)

Partial symptomatic relief from Parkinson's disease with levodopa has proven to be one of the rare success stories in the development of drugs to combat neurodegenerative diseases. However, no therapeutic agent has yet conclusively been shown to slow, halt, or reverse the underlying progression of neuronal loss in Parkinson's disease or any other human neurodegenerative disorder. This article reviews recent developments in the biology of neurotrophic growth factors, especially members of the nerve growth factor-related neurotrophin family, which may point to their potential as therapeutic agents for the treatment of Parkinson's disease. Parkinson's disease, characterized by the progressive loss of dopaminergic neurons of the substantia nigra, is one of the most well-characterized neurodegenerative disorders from both an anatomical and biochemical standpoint, but as yet the etiology of this disease remains poorly understood. Epidemiological, neurochemical, and pathological studies have provided a wealth of data that have spawned many theories of the underlying cause of Parkinson's disease, including environmental and genetic origins. Future elucidation of the disease process in Parkinson's disease may yield obvious therapeutic strategies, but even in the absence of such knowledge there are several general approaches that can be taken as strategies for the treatment of a "focal" neurodegenerative disease. These include: (a) mimetics, activation of the postsynaptic target(s) of the missing neurons through mimetics of the missing neurotransmitter, e.g., use of a dopamine precursor or dopamine receptor agonist in Parkinson's disease; (b) transplants, replenishment of the missing neurons via transplantation of neurons or nonneuronal cells secreting the appropriate neurotransmitter, e.g., fetal nigral grafts in Parkinson's disease; (c) neurotrophic factors or neuroprotectants, intervention with neurotrophic factors/neuroprotective agents which slow, halt, or reverse the progression of neuronal degeneration, e.g., a dopamine neurotrophic factor in Parkinson's disease. The scope of the present article is limited to a review of recent progress in the biology of neurotrophic factors that relates to their potential clinical use in treating the loss of dopamine neurons in Parkinson's disease.
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PMID:The therapeutic potential of neurotrophic factors in the treatment of Parkinson's disease. 828 68

Epidermal growth factor (EGF) is assumed to act as a neurotrophic factor on dopaminergic nigrostriatal neurons in cell cultures and animal brain. This led us to consider its possible role in the pathophysiology of Parkinson's disease. An autoradiographic study of the distribution of EGF-binding sites was performed in the mesencephalon of controls and patients with Parkinson's disease, a neurodegenerative disease associated with dramatic damage to the mesostriatal dopaminergic neurons. Scatchard analysis revealed a single type of binding sites with a high affinity constant, in the various mesencephalic dopaminergic areas examined. The characteristics and density of [125I]EGF-binding sites were similar in controls and parkinsonian patients. This suggests that EGF receptors in the mesencephalon are unaffected in Parkinson's disease and may therefore contribute to the increased activity and survival of the remaining dopaminergic neurons.
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PMID:Autoradiographic study of [125I]epidermal growth factor-binding sites in the mesencephalon of control and parkinsonian brains post-mortem. 831 72

A potent neurotrophic factor that enhances survival of midbrain dopaminergic neurons was purified and cloned. Glial cell line-derived neurotrophic factor (GDNF) is a glycosylated, disulfide-bonded homodimer that is a distantly related member of the transforming growth factor-beta superfamily. In embryonic midbrain cultures, recombinant human GDNF promoted the survival and morphological differentiation of dopaminergic neurons and increased their high-affinity dopamine uptake. These effects were relatively specific; GDNF did not increase total neuron or astrocyte numbers nor did it increase transmitter uptake by gamma-aminobutyric-containing and serotonergic neurons. GDNF may have utility in the treatment of Parkinson's disease, which is marked by progressive degeneration of midbrain dopaminergic neurons.
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PMID:GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. 849 47

Parkinson's disease results from the progressive degeneration of dopamine neurons that innervate the striatum. In rodents, glial-cell-line-derived neurotrophic factor (GDNF) stimulates an increase in midbrain dopamine levels, protects dopamine neurons from some neurotoxins, and maintains injured dopamine neurons. Here we extend the rodent studies to an animal closer to the human in brain organization and function, by evaluating the effects of GDNF injected intracerebrally in rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The recipients of GDNF displayed significant improvements in three of the cardinal symptoms of parkinsonism: bradykinesia, rigidity and postural instability. GDNF administered every four weeks maintained functional recovery. On the lesioned side of GDNF-treated animals, dopamine levels in the midbrain and globus pallidus were twice as high, and nigral dopamine neurons were, on average, 20% larger, with an increased fibre density. The results indicate that GDNF may be of benefit in the treatment of Parkinson's disease.
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PMID:Functional recovery in parkinsonian monkeys treated with GDNF. 863 74

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons and motor neurons in culture. It also protects these neurons from degeneration in vitro, and improves symptoms like Parkinson's disease induced pharmacologically in rodents and monkeys. Thus GDNF might have beneficial effects in the treatment of Parkinson's disease and amyotrophic lateral sclerosis. To examine the physiological role of GDNF in the development of the mammalian nervous system, we have generated mice defective in GDNF expression by using homologous recombination in embryonic stem cells to delete each of its two coding exons. GDNF-null mice, regardless of their targeted mutation, display complete renal agencies owing to lack of induction of the ureteric bud, an early step in kidney development. These mice also have no enteric neurons, which probably explains the observed pyloric stenosis and dilation of their duodenum. However, ablation of the GDNF gene does not affect the differentiation and survival of dopaminergic neurons, at least during embryonic development.
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PMID:Renal agenesis and the absence of enteric neurons in mice lacking GDNF. 865 6

Glial cell-line derived neurotrophic factor (GDNF) is a potent survival factor for embryonic midbrain dopaminergic, spinal motor, cranial sensory, sympathetic, and hindbrain noradrenergic neurons, and is available to these cells in vivo. It is therefore considered a physiological trophic factor and a potential therapeutic agent for Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here we show that at postnatal day 0 (P0), GDNF-deficient mice have deficits in dorsal root ganglion, sympathetic and nodose neurons, but not in hindbrain noradrenergic or midbrain dopaminergic neurons. These mice completely lack the enteric nervous system (ENS), ureters and kidneys. Thus GDNF is important for the development and/or survival of enteric, sympathetic and sensory neurons and the renal system, but is not essential for catecholaminergic neurons in the central nervous system (CNS).
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PMID:Renal and neuronal abnormalities in mice lacking GDNF. 865 8

Brain-derived neurotrophic factor (BDNF) promotes the survival of fetal mesencephalic dopaminergic cells and protects dopaminergic neurons against the toxicity of MPP+ in vitro. Supranigral implantation of fibroblasts genetically engineered to secrete BDNF attenuates the loss of substantia nigra pars compacta (SNc) dopaminergic neurons associated with striatal infusion of MPP+ in the adult rat. Using this MPP+ rat model of nigral degeneration, we evaluated the neurochemical effects of supranigral, cell-mediated delivery of BDNF on substantia nigra (SN) dopamine (DA) content and turnover. Genetically engineered BDNF-secreting fibroblasts (approximately 12 ng BDNF/24 h) were implanted dorsal to the SN 7 days prior to striatal MPP+ administration. The present results demonstrate that BDNF-secreting fibroblasts, as compared to control fibroblasts, enhance SN DA levels ipsilateral as well as contralateral to the graft without altering DA turnover. This augmentation of DA levels suggests that local neurotrophic factor delivery by genetically engineered cells may provide a therapeutic strategy for preventing neuronal death or enhancing neuronal function in neurodegenerative diseases characterized by dopaminergic neuronal dysfunction, such as Parkinson's disease.
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PMID:Cell-mediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration. 868 33

Parkinson's disease, known also as striatal dopamine deficiency syndrome, is a degenerative disorder of the central nervous system characterized by akinesia, muscular rigidity, tremor at rest, and postural abnormalities. In early stages of parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, the number of dopamine receptors decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H2O2, thus leading to generation of highly neurotoxic hydroxyl radicals (OH.). The generation of free radicals can also be produced by 6-hydroxydopamine or MPTP which destroys striatal dopaminergic neurons causing parkinsonism in experimental animals as well as human beings. Studies of the substantia nigra after death in Parkinson's disease have suggested the presence of oxidative stress and depletion of reduced glutathione; a high level of total iron with reduced level of ferritin; and deficiency of mitochondrial complex I. New approaches designed to attenuate the effects of oxidative stress and to provide neuroprotection of striatal dopaminergic neurons in Parkinson's disease include blocking dopamine transporter by mazindol, blocking NMDA receptors by dizocilpine maleate, enhancing the survival of neurons by giving brain-derived neurotrophic factors, providing antioxidants such as vitamin E, or inhibiting monoamine oxidase B (MAO-B) by selegiline. Among all of these experimental therapeutic refinements, the use of selegiline has been most successful in that it has been shown that selegiline may have a neurotrophic factor-like action rescuing striatal neurons and prolonging the survival of patients with Parkinson's disease.
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PMID:Oxidative stress and antioxidant therapy in Parkinson's disease. 883 Mar 46

Glial cell line-derived neurotrophic factor (GDNF) is a highly selective neurotrophic factor for midbrain dopaminergic neurons and might thus be of potential use in the therapy of Parkinson's disease. In this study, we present evidence that the survival-promoting action of GDNF on dopaminergic neurons requires the concurrent activation of cAMP-dependent signaling pathways. In serum-free low density cultures of the dissociated embryonic day 15 mesencephalon, dopaminergic neurons undergo constant cell death as evidenced by a 90% reduction in tyrosine hydroxylase-immunoreactive (TH-IR) cell numbers between days 1 and 9 of cultivation. This decline was not affected by GDNF (5 ng/ml) within the initial 3 days of cultivation, but was in part attenuated with prolonged treatment. In contrast, stimulation of 3-day-old mesencephalic cultures with GDNF induced c-fos expression in 73% of all TH-IR neurons, indicative for the early presence of efficient signal-transduction coupling in these neurons. Combined treatment of mesencephalic cultures with dibutyryl cyclic AMP (dbcAMP; 100 microM) and GDNF accelerated the onset of the survival effects of GDNF on dopaminergic neurons, resulting in a 1.5-fold increase in the number of surviving TH-IR neurons at 3 days in vitro. In addition, activation of cAMP-dependent signal pathways significantly potentiated the survival-promoting effects of GDNF on dopaminergic neurons in older cultures. dbcAMP alone had no effect on dopaminergic cell survival. Taken together, our findings suggest that the action of GDNF on midbrain dopaminergic neurons is modulated by other extracellular signals.
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PMID:Effects of glial cell line-derived neurotrophic factor (GDNF) on dopaminergic neurons require concurrent activation of cAMP-dependent signaling pathways. 885 92

The cause of dopamine cell death, thought to be the primary neurocytologic defect in idiopathic Parkinson's disease, remains unknown. Mitochondrial oxidative dysfunction causes premature cell death, and may be linked to accelerated apoptosis, excessive free and toxic radicals, deficient neurotrophic factors or combinations of these detrimental factors. Neurochemical imbalances result both in the substantia nigra and neostriatum, resulting in compensatory mechanisms that make this chronic neurodegenerative disease difficult to evaluate. Acute parkinsonism models have limitations when compared with chronic disease states, and caution should be present when comparing 'parkinsonism' data with human disease. Better understanding of classical neurotransmitters, neuroactive peptides and neurotrophic factors, will hopefully lead to more rational treatment approaches, cellular support strategies, and an understanding of the causes of this disease. Glial derived neurotrophic factor looks the most promising neurotrophic candidate so far tested in culture and in vivo. The result of clinical trials utilizing neurotrophic factors, both as mesencephalic implant support strategies and as definitive treatment of idiopathic Parkinson's disease, are awaited with cautious optimism.
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PMID:Parkinson's disease: biology and aetiology. 885 89


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