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)

To determine the differences in behavioral effects between intrastriatal and intracerebroventricular glial cell-derived neurotrophic factor (GDNF) administration, spontaneous locomotor activity was measured after intrastriatal or intracerebroventricular injection of GDNF (10 microg) in normal adult rats with implanted guide cannulae. In addition, the distribution of GDNF after intracerebral injection was studied immunohistochemically. Intrastriatal administration of GDNF significantly increased rearing behavior 3-4 h after injection. Increases in all three aspects of locomotor activity (motility, locomotion, and rearing) were most pronounced 3 days after intrastriatal injection, and they lasted for several days. This hyperactivity was blocked by the selective dopamine D1 receptor antagonist SCH22390 and by the selective D2 receptor antagonist raclopride at doses of the dopamine receptor antagonists, which by themselves did not affect spontaneous locomotor activity. These results suggest that GDNF has both acute and long-lasting pharmacological effects on dopamine neurons in adult animals and stimulates locomotor activity by activating both dopamine D1 and D2 receptors. On the other hand, intracerebroventricular administration of the same dose of GDNF failed to increase locomotor activity at any time during the test period (12 days). The immunohistochemical study demonstrated widespread distribution of GDNF in the entire body of the striatum within 24 h after intrastriatal injection. It also revealed deep penetration of GDNF from the ventricular space into the brain parenchyma after intracerebroventricular injection. GDNF-immunoreactive neuronal cell bodies were seen in the ipsilateral substantia nigra pars compacta most frequently 6 h after intrastriatal injection. The number of such cell bodies after intracerebroventricular administration, on the other hand, was much lower than that seen after intrastriatal administration. Taken together, these data suggest that intrastriatal administration of GDNF is an effective approach for affecting DA transmission. Long-lasting behavior effects are mediated via dopamine D1 and D2 receptors. Higher doses of GDNF would probably be needed using the intracerebroventricular route as compared to intraparenchymal delivery to exert effects on the nigrostriatal system in Parkinson's disease patients.
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PMID:Dopamine D1 and D2 receptor-mediated acute and long-lasting behavioral effects of glial cell line-derived neurotrophic factor administered into the striatum. 987 69

Glial cell line-derived neurotrophic factor (GDNF) was identified as a consequence of the hypothesis that glia secrete factors that influence growth and differentiation of specific classes of neurons. Glia are a likely source of additional neurotrophic factors; however, this strategy has not been applied extensively. The discovery of GDNF in 1993 led to an abundance of studies that within only a few years qualified GDNF as a bona fide neurotrophic factor. Of particular interest are studies demonstrating the effectiveness of GDNF protein in ameliorating neurodegeneration in animal models of Parkinson's disease and amyotrophic lateral sclerosis (ALS). It remains to be determined whether GDNF will be an effective therapy in humans with these diseases. However, since these diseases are slowly progressive and the CNS relatively inaccessible, the delivery of GDNF as a therapeutic molecule to the CNS in a chronic manner is problematic. Studies addressing this problem are applying viral vector mediated transfer of the GDNF gene to the CNS in order to deliver biosynthesized GDNF to a specific location in a chronic manner. Recent studies suggest that these GDNF gene therapy approaches are effective in rat models of Parkinson's disease. These studies are reviewed in the context of what developments will be needed in order to apply GDNF gene therapy to the clinic.
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PMID:A commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule to gene therapy. 989 May 61

Oxidative stress is thought to contribute to dopaminergic cell death in Parkinson's disease (PD). The neurotoxin 6-hydroxydopamine (6-OHDA), which is easily oxidized to reactive oxygen species (ROS), appears to induce neuronal death by a free radical-mediated mechanism, whereas the involvement of free radicals in N-methyl-4-phenylpyridinium (MPP+) toxicity is less clear. Using free radical-sensitive fluorophores and vital dyes with post hoc identification of tyrosine hydroxylase-positive neurons, we monitored markers of apoptosis and the production of ROS in dopaminergic neurons treated with either 6-OHDA or MPP+. Annexin-V staining suggested that 6-OHDA but not MPP+-mediated cell death was apoptotic. In accordance with this assignment, the general caspase inhibitor Boc-(Asp)-fluoromethylketone only blocked 6-OHDA neurotoxicity. Both toxins exhibited an early, sustained rise in ROS, although only 6-OHDA induced a collapse in mitochondrial membrane potential temporally related to the increase in ROS. Recently, derivatives of buckminsterfullerene (C60) molecules have been shown to act as potent antioxidants in several models of oxidative stress (Dugan et al., 1997). Significant, dose-dependent levels of protection were also seen in these in vitro models of PD using the C3 carboxyfullerene derivative. Specifically, C3 was fully protective in the 6-OHDA paradigm, whereas it only partially rescued dopaminergic neurons from MPP+-induced cell death. In either model, it was more effective than glial-derived neurotrophic factor. These data suggest that cell death in response to 6-OHDA and MPP+ may progress through different mechanisms, which can be partially or entirely saved by carboxyfullerenes.
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PMID:Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons. 995 6

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

Rat embryonic d 14 (E14) mesencephalic cells, 2.5% of which are glioblasts, were incubated in medium containing 10% of fetal bovine serum for 12 h and subsequently expanded in a serum-free medium using basic fibroblast growth factor (bFGF) as the mitogen. On a single occasion, after more than 15 d in culture, several islets of proliferating, glial-like cells were observed in one dish. The cells, when isolated and passaged, proliferated rapidly in either a serum-free or serum-containing growth medium. Subsequent immunocytochemical analysis showed that they stained positive for GFAP and vimentin, and negative for A2B5, O4, GalC, and MAP2. Serum-free conditioned medium (CM) prepared from these cells caused a fivefold increase in survival and promoted neuritic expansion of E14 mesencephalic dopaminergic neurons in culture. These actions are similar to those exerted by CM derived from primary, mesencephalic type-1 astrocytes. The pattern of expression of the region-selective genes; wnt-1, en-1, sis showed that 70% of the cells were heteroploid, and of these, 50% were tetraploid. No apparent decline in proliferative capacity has been observed after 25 passages. The properties of this cell line, named ventral mesencephalic cell line one (VMCL1), are consistent with those of an immortalized, type-1 astrocyte. The mesencephalic origin of the cell line, and the pattern and potency of the neurotrophic activity exerted by the CM, strongly suggest that the neurotrophic factor(s) identified are novel, and will likely be strong candidates with clinical utility for the treatment of Parkinson's disease.
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PMID:An immortalized, type-1 astrocyte of mesencephalic origin source of a dopaminergic neurotrophic factor. 1034 91

Neurodegenerative diseases are highly devastating disorders characterized by the damage and loss of discrete neuronal populations. Until recently, it was assumed that the ability of the central nervous system to recover from injury was extremely limited. However, many "in vitro" and "in vivo" studies have shown that neurotrophic factor are able to prevent or inhibit neuronal cell death induced by a variety of insults. Accordingly, trophic factors may represent a new tool for treating neuronal injury and death in a variety of neurodegenerative diseases. In his review, the therapeutic possibilities of neurotrophins in the treatment of Parkinson's disease, Alzheimer disease and amyotrophic lateral sclerosis are analysed.
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PMID:[Neurotrophins. II: therapeutic potential]. 1042 Sep 24

Neurodegeneration of dopamine neurons in the ventral mesencephalon projecting to the dorsal striatum (meso-striatal system) plays a major role in Parkinson's disease. The aim of this study was to establish a simple organotypic, in vitro co-culture model for investigating the survival of dopamine neurons stimulated by the novel growth factor, glial-cell-line-derived neurotrophic factor. This model should allow investigation of the effects of the dopaminergic neurotoxin, 6-hydroxydopamine, on the expression of the transcription factor c-fos and on TUNEL staining in vitro. The dopaminotrophic factor, glial-cell-line-derived neurotrophic factor, markedly enhanced dopamine tissue levels and dopamine neuron number. Nerve-fiber ingrowth of dopamine neurons into its striatal target was found to be enhanced with glial-cell-line-derived neurotrophic factor. Using an optimized protocol, it was shown that the neurotoxin 6-hydroxydopamine selectively destructed dopamine neurons. C-fos-like immunoreactivity was enhanced in the mesencephalic part of the co-slices 3 h after application of the neurotoxin. The TUNEL staining occurred 2-5 days after the application of the neurotoxin, but did not seem to be related to dopamine neurons. In conclusion, the organotypic co-culture model provides a simple model for studying survival of dopamine neurons and for observing expression of genes and proteins that could be related to Parkinson's disease. This simple model is useful for screening novel drugs and growth factors and may markedly reduce severe animal experiments.
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PMID:Dopamine neurons in a simple GDNF-treated meso-striatal organotypic co-culture model. 1045 14

As part of a safety and tolerability study, a 65-year-old man with Parkinson's disease (PD) received monthly intracerebroventricular injections of glial-derived neurotrophic factor (GDNF). His parkinsonism continued to worsen following intracerebroventricular GDNF treatment. Side effects included nausea, loss of appetite, tingling, L'hermitte's sign, intermittent hallucinations, depression, and inappropriate sexual conduct. There was no evidence of significant regeneration of nigrostriatal neurons or intraparenchymal diffusion of the intracerebroventricular GDNF to relevant brain regions. Alternative GDNF delivery systems should be explored.
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PMID:Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease. 1048 76

Glial cell-line-derived neurotrophic factor (GDNF) is a protein known to enhance the survival of dopaminergic and motor neurons. It has been shown to have therapeutic potential in the treatment of Parkinson's disease and other neurodegenerative diseases. GDNF gene was modified by deletion and insertion mutagenesis using PCR methods. The various mutants were all highly expressed in Escherichia coli. The recombinant proteins were purified and their survival-promoting activities were determined by motor neurons. The result showed that the C-terminus was critical for structure stability of GDNF, and the alpha-helix, finger1 and finger2 regions were involved in receptor binding, while the N-terminus was not essential for the biological functions of GDNF.
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PMID:Human glial cell-line-derived neurotrophic factor: a structure-function analysis. 1067 67

Vasoactive intestinal peptide (VIP) provides neuroprotection against beta-amyloid toxicity in models of Alzheimer's disease. A superactive analogue, stearyl-Nle17-VIP (SNV) is a 100-fold more potent than VIP. In primary neuronal cultures, VIP protective activity may be mediated by femtomolar-acting glial proteins such as activity-dependent neurotrophic factor (ADNF), activity-dependent neuroprotective protein (ADNP), peptide derivatives ADNF-9 (9aa) and NAP (8aa), respectively. It has been hypothesized that beta-amyloid induces oxidative stress leading to neuronal cell death. Similarly, dopamine and its oxidation products were suggested to trigger dopaminergic nigral cell death in Parkinson's disease. We now examined the possible protective effects of VIP against toxicity of dopamine, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion (MPP+) in neuronal cultures [rat pheochromocytoma (PC12), human neuroblastoma (SH-SY5Y) and rat cerebellar granular cells]. Remarkably low concentrations of VIP (10(-16)-10(-8) M), ADNF-9 and NAP (10(-18)-10(-10) M) protected against dopamine and 6-OHDA toxicity in PC12 and neuroblastoma cells. VIP (10(-11)-10(-9) M) and SNV (10(-13)-10(-11) M), protected cerebellar granule neurons against 6-OHDA. In contrast, VIP did not rescue neurons from death associated with MPP+. Since dopamine toxicity is linked to the red/ ox state of the cellular glutathione, we investigated neuroprotection in cells depleted of reduced glutathione (GSH). Buthionine sulfoximine (BSO), a selective inhibitor of glutathione synthesis, caused a marked reduction in GSH in neuroblastoma cells and their viability decreased by 70-90%. VIP, SNV or NAP (over a wide concentration range) provided significant neuroprotection against BSO toxicity. These results show that the mechanism of neuroprotection by VIP/SNV/NAP may be mediated through raising cellular resistance against oxidative stress. Our data suggest these compounds as potential lead compounds for protective therapies against Parkinson's disease.
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PMID:Vasoactive intestinal peptide (VIP) prevents neurotoxicity in neuronal cultures: relevance to neuroprotection in Parkinson's disease. 1078 33


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