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)

Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no effective neuroprotective therapy. Patients are typically treated with a combination of drug therapies and/or receive deep brain stimulation to combat behavioral symptoms. The ideal candidate therapy would be the one which prevents neurodegeneration in the brain, thereby halting the progression of debilitating disease symptoms. Neurotrophic factors have been in the forefront of PD research, and clinical trials have been initiated using members of the GDNF family of ligands (GFLs). GFLs have been shown to be trophic to ventral mesencephalic cells, thereby making them good candidates for PD research. This paper examines the use of GDNF and neurturin, two members of the GFL, in both animal models of PD and clinical trials.
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PMID:Trophic factors therapy in Parkinson's disease. 1966 Jun 58

Neuroprotective therapy has been proposed for age-related neurodegenerative disorders, including Parkinson's disease. Inhibitors of type B monoamine oxidase (MAOB-Is), rasagiline and (-)deprenyl, are the most promising candidate neuroprotective drugs. Clinical trials of rasagiline in patients with Parkinson's disease suggest that rasagiline may have some disease-modifying effects. Results using animal and cellular models have proved that the MAOB-Is protect neurons by the intervention of 'intrinsic' mitochondrial apoptotic cascade and the induction of prosurvival antiapoptotic Bcl-2 and neurotrophic factors. Rasagiline-related MAOB-Is prevent mitochondrial permeability transition induced by various insults and activation of subsequent apoptotic cascades: cytochrome c release, casapase activation, and condensation and fragmentation of nuclear DNA. MAOB-Is increase transcription of prosurvival genes through activating the nuclear transcription factor-(NF) system. Rasagiline increases the protein and mRNA levels of GDNF in dopaminergic SH-SY5Y cells, whereas (-)deprenyl increases those of BDNF. Systemic administration of (-)deprenyl and rasagiline increases these neurotrophic factors in the cerebrospinal fluid from patients with Parkinson's disease and nonhuman primates. This review presents recent advances in our understanding of the neuroprotection offered by MAOB-Is and possible evaluation of neuroprotective efficacy in clinical samples is discussed.
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PMID:Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson's disease. 1967 10

Parkinson's disease (PD) results from the degeneration of dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine released in the striatum. Current oral dopamine replacement or surgical therapies do not address the underlying issue of neurodegeneration, they neither slow nor halt disease. Neurotrophic factors have shown preclinical promise, but the choice of an appropriate growth factor as well as the delivery has proven difficult. In this study, we used a rotenone rat midbrain culture model to identify genes that are changed after addition of the neurotoxin. (1) We challenged rat midbrain cultures with rotenone (20 nM), a pesticide that has been shown to be toxic for dopaminergic neurons and that has been a well-characterized model of PD. A gene chip array analysis demonstrated that several genes were up-regulated after the rotenone treatment. Interestingly transcriptional activation of vascular endothelial growth factor B (VEGF-B) was evident, while vascular endothelial growth factor A (VEGF-A) levels remained unaltered. The results from the gene chip array experiment were verified with real time PCR and semi-quantitative western analysis using beta-actin as the internal standard. (2) We have also found evidence that exogenously applied VEGF-B performed as a neuroprotective agent facilitating neuron survival in an even more severe rotenone culture model of PD (40 nM rotenone). VEGF-B has very recently been added to the list of trophic factors that reduce effects of neurodegeneration, as was shown in an in vivo model of motor neuron degeneration, while lacking potential adverse angiogenic activity. The data of an in vivo protective effect on motor neurons taken together with the presented results demonstrate that VEGF-B is a new candidate trophic factor distinct from the GDNF family of trophic factors. VEGF-B is activated by neurodegenerative challenges to the midbrain, and exogenous application of VEGF-B has a neuroprotective effect in a culture model of PD. Strengthening this natural protective response by either adding exogenous VEGF-B or up-regulating the endogenous VEGF-B levels may have the potential to be a disease modifying therapy for PD. We conclude that the growth factor VEGF-B can improve neuronal survival in a culture model of PD.
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PMID:Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease. 2000 14

The core loss of dopaminergic neurons in the substantia nigra in Parkinson's disease (PD) coupled to the therapeutic benefits of dopaminergic therapies in patients, simplifies the treatment strategy for this disease. In the context of neurotrophic factors, this distils down to the simple question as to whether a factor exists for these cells that can promote their survival in the face of the degenerative disease process. If such a factor exists, and GDNF seems a strong candidate, then one could anticipate that this treatment would be as effective as L-dopa therapy. However it would not be better than this, nor curative, given the extensive pathology in PD. To date a number of clinical trials have been undertaken in which GDNF has been directly delivered to the PD brain. In addition there have been studies in which neurturin (part of the GDNF family) has also been delivered to the CNS using a viral vector delivery system. These trials have produced mixed results. Importantly though, some patients have shown a sustained clinical response to this treatment which correlates with evidence of increased dopaminergic activity in the brain at the site of delivery using F-dopa PET as well as in a single post-mortem study. The challenge therefore is not whether this approach works, because it self-evidently does in some patients, but rather how we can do this more consistently.
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PMID:Parkinson's disease and growth factors - are they the answer? 2008 86

We are testing the hypothesis that exercise is neuroprotective in animal models of the dopamine (DA) deficiency in Parkinson's disease. Our studies include mice or rats provided access to a running wheel and subsequently treated with MPTP (mice) or 6-hydroxydopamine (rats) and monkeys provided access to a treadmill and subsequently treated with MPTP. Typically, the exercise occurs for 3 months prior to the toxin treatment and often for 1-2 months thereafter. Our findings indicate that exercise reduces the behavioral impairments elicited by the dopaminergic neurotoxins as well as the loss of DA neurons as assessed by PET imaging and biochemical or histochemical assessment of tissue samples. Our studies are focused on one of several possible explanations for the beneficial effects of exercise: an exercise-induced increase in the expression of neurotrophic factors, particularly GDNF. Our observations indicate that GDNF can reduce the vulnerability of DA neurons, in part due to the activation of key intracellular cascades. We also find that mild cellular stress itself can provide protection against more intensive stress, a form of preconditioning. We conclude that dopamine neurons have the capacity to respond to intracellular and extracellular signals by triggering endogenous neuroprotective mechanisms. This raises the possibility that some individuals with Parkinson's disease suffer from a reduction of these neuroprotective mechanisms, and that treatments that boost these mechanisms - including exercise - may provide therapeutic benefit.
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PMID:Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. 2008 5

In Parkinson's disease, cell death is selectively induced in mesencephalic nigral dopaminergic neurons. At present, no disease modifying therapy or radical treatment has been found for this disease. Some dopamine agonists may have a neuroprotective action in cultured cells and animal models. In the present study, we examined stimulating effects of a non-ergoline D(2) dopamine agonist, ropinirole, on synthesis/secretion of neurotrophic factors, including NGF, BDNF, and GDNF, in cultured mouse astrocytes. These effects were compared with those of ergoline dopamine agonists, SKF-38393, a D(1) agonist, bromocriptine, D(2) agonist, and apomorphine, D(1)/D(2) agonist. Ropinirole elevated GDNF levels to 4-fold, and NGF levels to 6.3-fold, compared with the control group. Of the dopamine agonists examined, ropinirole produced and secreted more GDNF than a 1.8-fold greater amount of apomorphine, a lesser amount of bromocriptine, or a 2.8-fold greater amount of SKF-38393, which served as the control group.
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PMID:The effect of dopamine agonists: the expression of GDNF, NGF, and BDNF in cultured mouse astrocytes. 2012 27

The mechanisms underlying the selective death of substantia nigra (SN) neurons in Parkinson disease (PD) remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA) neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 and Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD.
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PMID:Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons. 2038 24

Aberrant microglia activation causes dopaminergic neuronal loss and nitric oxide produced by microglia plays a critical role in dopaminergic neuronal degeneration. However, no study has determined if GDNF protects dopaminergic neurons via inhibiting nitric oxide generation in Parkinson's disease animal model. We report that GDNF not only reduces lipopolysaccharide-induced degeneration of dopaminergic neurons, suppresses microglia activation and nitric oxide generation, but also reverses the inhibition of phosphoinositide 3-kinase (PI3K) in dopaminergic neurons and microglia. It suggests that the neuroprotective effect of GDNF on dopaminergic neurons may be related to its suppression of microglia activation-mediated nitric oxide via releasing the inhibition of PI3K in both neurons and microglia.
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PMID:Glial cell line-derived neurotrophic factor protects midbrain dopaminergic neurons against lipopolysaccharide neurotoxicity. 2047 98

Parkinson's disease (PD), a progressive neurodegenerative movement disorder, is known to be caused by diverse pathological conditions resulting from dysfunction of the ubiquitin-proteasome system (UPS), mitochondria, and oxidative stress leading to preferential nigral dopamine (DA) neuron degeneration in the substantia nigra. In the present study, we evaluated the novel D3 receptor-preferring agonist D-264 in a mouse model of PD to evaluate its neuroprotective properties against both the nigrostriatal dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and the proteasome inhibitor lactacystin-induced dopaminergic degeneration. C57BL/6 male mice either were given MPTP by intraperitoneal injection twice per day for 2 successive days at a dose 20 mg/kg or were microinjected with lactacystin bilaterally (1.25 microg/side) into the medial forebrain bundle (MFB). Pretreatment with D-264 (1 mg/kg and 5 mg/kg, intraperitoneally, once per day), started 7 days before administration of MPTP or lactacystin. We found that D-264 significantly improved behavioral performance, attenuated both MPTP- and lactacystin-induced DA neuron loss, and blocked proteasomal inhibition and microglial activation in the substantia nigra (SN). Furthermore, D-264 treatment was shown to increase the levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived factor (GDNF) in MPTP- and lactacystin-treated mice, possibly indicating, at least in part, the mechanism of neuroprotection by D-264. Furthermore, pretreatment with the D3 receptor antagonist U99194 significantly altered the effect of neuroprotection conferred by D-264. Collectively, our study demonstrates that D-264 can prevent neurodegeneration induced by the selective neurotoxin MPTP and the UPS inhibitor lactacystin. The results indicate that D-264 could potentially serve as a symptomatic and neuroprotective treatment agent for PD.
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PMID:Novel D3 dopamine receptor-preferring agonist D-264: Evidence of neuroprotective property in Parkinson's disease animal models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and lactacystin. 2062 19

Parkinson's disease (PD) is a chronic, progressive neurodegenerative movement disorder for which there is currently no effective therapy. Over the past several decades, there has been a considerable interest in neuroprotective therapies using trophic factors to alleviate the symptoms of PD. Neurotrophic factors (NTFs) are a class of molecules that influence a number of neuronal functions, including cell survival and axonal growth. Experimental studies in animal models suggest that members of neurotrophin family and GDNF family of ligands (GFLs) have the potent ability to protect degenerating dopamine neurons as well as promote regeneration of the nigrostriatal dopamine system. In clinical trials, although no serious adverse events related to the NTF therapy has been reported in patients, they remain inconclusive. In this chapter, we attempt to give a brief overview on several different growth factors that have been explored for use in animal models of PD and those already used in PD patients.
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PMID:Neurotrophic factor therapy for Parkinson's disease. 2088 79


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