Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iodine-123-labeled metaiodobenzylguanidine (MIBG) has a history of over 20 years as a marker of myocardial sympathetic activity in Japan and has been used for various cardiac diseases. Aside from conventional utilities in patients with cardiac diseases, including ischemic heart diseases, cardiomyopathy, heart failure and diabetes, neurological disorders have recently been drawing special attention. The [(123)I]MIBG study showed markedly decreased myocardial uptake in Parkinson's disease, dementia with Lewy bodies and pure autonomic failure, which is a common feature of Lewy-body diseases. The MIBG study can be used for differentiating patients with extrapyramidal signs and dementia. The unique application of MIBG in movement disorders and related neurological diseases is one of its most common uses in Japan, and further studies are expected worldwide.
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PMID:Iodine-123-MIBG sympathetic imaging in Lewy-body diseases and related movement disorders. 1908 92

Epidemiological studies suggest the involvement of pesticides in the etiology of Parkinson's disease. Exposure to rotenone results in degeneration of the nigrostriatal pathway through inhibition of complex I. Organotypic striatal slice cultures were prepared from brains of adult mice and treated with rotenone (0.01, 0.05, 0.1, and 1 mM) for 48 h. Lactate dehydrogenase activity was elevated by 167% at 1 mM of rotenone. Using fluorescent indicators, membrane damage was up to 130% as measured by propidium iodide fluorescence, and superoxide (DHE) and nitric oxide (DAF-FM) formation were increased by 195% and 774% at 1 mM of rotenone, respectively, compared to controls. The study concludes that formation of radicals mediated striatal degeneration by rotenone.
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PMID:Rotenone damages striatal organotypic slice culture. 1912 Jan 53

Neurotoxicity is involved in various neurodegenerative diseases including Parkinson's disease (PD), which affects mesencephalic dopaminergic neurons of the substantia nigra (SN). Positive alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators (PARMs, a.k.a. Ampakines, such as CX614) increase brain-derived neurotrophic factor (BDNF) protein levels in vivo and in cultured hippocampal slices. BDNF is a survival factor for various neuronal cell types including mesencephalic dopaminergic neurons. Using cultured mesencephalic and hippocampal slices, we investigated whether preincubation with CX614 could provide neuroprotection against MPP(+) toxicity and whether such neuroprotection was mediated by BDNF. Various treatment protocols were tested to demonstrate CX614-induced neuroprotection against MPP(+). Pretreatment with CX614 significantly reduced MPP(+)-induced toxicity and increased BDNF levels in both hippocampal and mesencephalic cultured slices; CX614 pretreatment for 6 h in hippocampal slices and 24 h in mesencephalic slices was sufficient to produce significant neuroprotection as assessed with lactate dehydrogenase release in slice medium and propidium iodide uptake in slices. Both a BDNF scavenger and an inhibitor of the BDNF receptor TrkB, abrogated CX614-mediated reduction of MPP(+)-induced toxicity. Inhibition of Ca(2+)-activated proteases, calpains, was also protective against MPP(+)-induced toxicity. However, co-application of calpain inhibitor with CX614 abolished CX614-mediated protection, suggesting a dual action of calpains in this model. We conclude that CX614 is neuroprotective against MPP(+)-induced toxicity, an effect mediated by increased BDNF expression and activation of BDNF-dependent signaling pathways. Our results provide support for using PARMs as a new therapy for neurodegenerative disorders, including PD.
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PMID:BDNF mediates the neuroprotective effects of positive AMPA receptor modulators against MPP+-induced toxicity in cultured hippocampal and mesencephalic slices. 1937 76

Aberrant mitochondrial function appears to play a central role in dopaminergic neuronal loss in Parkinson's disease (PD). 1-methyl-4-phenylpyridinium iodide (MPP(+)), the active metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. Recent findings suggest that Glycogen Synthase Kinase-3beta (GSK-3beta), a critical activator of neuronal apoptosis, is involved in the dopaminergic cell death. In this study, the role of GSK-3beta in modulating MPP(+)-induced mitochondrial dysfunction and neuronal death was examined in vivo, and in two neuronal cell models namely primary cultured and immortalized neurons. In both cell models, MPTP/MPP(+) treatment caused cell death associated with time- and concentration-dependent activation of GSK-3beta, evidenced by the increased level of the active form of the kinase, i.e. GSK-3beta phosphorylated at tyrosine 216 residue. Using immunocytochemistry and subcellular fractionation techniques, we showed that GSK-3beta partially localized within mitochondria in both neuronal cell models. Moreover, MPP(+) treatment induced a significant decrease of the specific phospho-Tyr216-GSK-3beta labeling in mitochondria concomitantly with an increase into the cytosol. Using two distinct fluorescent probes, we showed that MPP(+) induced cell death through the depolarization of mitochondrial membrane potential. Inhibition of GSK-3beta activity using well-characterized inhibitors, LiCl and kenpaullone, and RNA interference, prevented MPP(+)-induced cell death by blocking mitochondrial membrane potential changes and subsequent caspase-9 and -3 activation. These results indicate that GSK-3beta is a critical mediator of MPTP/MPP(+)-induced neurotoxicity through its ability to regulate mitochondrial functions. Inhibition of GSK-3beta activity might provide protection against mitochondrial stress-induced cell death.
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PMID:Involvment of cytosolic and mitochondrial GSK-3beta in mitochondrial dysfunction and neuronal cell death of MPTP/MPP-treated neurons. 1943 May 25

In Parkinson's disease substantia nigra neurons degenerate likely due to oxidative damage interacting with genetic risk factors. Here, SH-SY5Y cells expressing wild-type or A53T alpha-synuclein had increased sensitivity to methyl-4-phenylpyridinium iodide (MPP(+)), which induces mitochondrial dysfunction, and 6-hydroxydopamine (6-OHDA), which causes oxidative stress. Edaravone protected only against MPP(+), and EGCG ((-)-epigallocatechin-3-O-gallate) protected only against 6-OHDA. Thus genomic responses to MPP(+) and 6-OHDA in the presence of these antioxidants were analyzed using microarrays. Pathway analysis indicated that MPP(+) activated p53 (P < 0.001) while 6-OHDA induced the Nrf2 antioxidative stress response (P < 0.0001). EGCG was more effective at blocking 6-OHDA-mediated genomic responses, while edaravone was more effective against MPP(+). We identified 32 genes that responded to both toxins except in the presence of an effective anti-oxidant; eight are transcription factors and potentially constitute a stress-response transcriptional network. These data provide insights into the mechanisms of neurotoxicity and identifies genes that might mediate antioxidant efficacy.
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PMID:Genome-wide microarray analysis of the differential neuroprotective effects of antioxidants in neuroblastoma cells overexpressing the familial Parkinson's disease alpha-synuclein A53T mutation. 1964 7

Green tea polyphenol epigallocatechin-3-gallate (EGCG) is reported to have antioxidant abilities and to counteract beneficially mitochondrial impairment and oxidative stress. The present study was designed to investigate neuroprotective effects of EGCG on rotenone-treated dissociated mesencephalic cultures and organotypic striatal cultures. Rotenone is a potent inhibitor of complex I of the respiratory chain, which in vitro causes pathological and neurochemical characteristics of diseases in which mitochondrial impairment is involved, e.g., Parkinson's disease. Treatment with EGCG (0.1, 1, 10 muM) alone had no significant effects on mesencephalic cultures. In striatal slice cultures, EGCG led to a significant increase of propidium iodide (PI) uptake and 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM), but not dihydroethidium (DHE) fluorescence intensity. Rotenone (20 nM on the eighth DIV for 48 h) significantly decreased the numbers and the neurite lengths of TH ir neurons by 23 and 34% in dissociated mesencephalic cell cultures compared to untreated controls. Exposure of striatal slices to rotenone (0.5 mM for 48 h) significantly increased PI uptake, and DAF-FM and DHE fluorescence intensities by 41 and 136 and 19%, respectively, compared to controls. Against rotenone, in dissociated mesencephalic cultures, EGCG produced no significant effect on either the number or neurite lengths of THir neurons compared to rotenone-treated cultures, but EGCG significantly decreased PI uptake by 19% and DAF-FM fluorescence intensity by 19 and 58%, respectively, compared to increase in rotenone-exposed striatal slices. On the other hand, EGCG did not affect superoxide (O(2) (-)) formation as detected with DHE. These data indicate that EGCG slightly protects striatal slices by counteracting nitric oxide (NO(.)) production by rotenone. In conclusion, EGCG partially protects striatal slices but not dissociated cells against rotenone toxicity.
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PMID:Effects of epigallocatechin gallate on rotenone-injured murine brain cultures. 1970 49

To study the potential impact of iodine-124-beta-carbomethoxy-3beta(4-iodophenyl)tropane (I-124 betaCIT) in Parkinson disease, a I-124 betaCIT-PET scan was performed in 30-year-old man with suspected early Parkinson disease. The scan showed normal striatum uptake together with a focal spot in the left parietal cortex. The subsequent magnetic resonance imaging of the brain revealed a corresponding nodular lesion, presumably representing a metastasis. After clinical and diagnostic evaluation, a malignant metastatic melanoma was discovered. betaCIT is a cocaine derivative with a high affinity for dopamine and serotonin transporters mainly used to image the density of the dopamine reuptake transporter. In fact the role of I-123 betaCIT is typically represented by Parkinsonian syndromes of uncertain classification. The iodine-124 betaCIT uptake is a marker of dopamine transporters density, and the presence of focal uptake corresponding to a lesion on magnetic resonance images suggests a specific binding in this case of melanoma brain metastasis.
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PMID:Unexpected detection of melanoma brain metastasis by PET with iodine-124 betaCIT. 1989 6

Changes in regional cerebral blood flow (rCBF) induced by unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) were investigated in 7 consecutive patients with Parkinson's disease, 4 men and 3 women (mean age 62.3 +/- 8.1 years), who underwent rCBF measurement by N-isopropyl-p-(iodine-123)-iodoamphetamine single photon emission computed tomography at rest before and after unilateral STN DBS preoperatively in the on-drug condition, and postoperatively in the on-drug and on-stimulation condition. Statistical parametric mapping was used to identify significant changes in rCBF from the preoperative to the postoperative conditions. rCBF was increased in the bilateral cingulate cortices and bilateral cerebellar hemispheres. rCBF was decreased in the bilateral medial frontal cortices and left superior temporal cortex. Unilateral STN DBS produced rCBF changes in the bilateral cingulate cortices, cerebellar hemispheres, and medial frontal cortices. These findings indicate that unilateral STN DBS affects rCBF in both hemispheres.
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PMID:Changes in regional blood flow induced by unilateral subthalamic nucleus stimulation in patients with Parkinson's disease. 1994 Mar 98

The morphological and chemical changes associated with the exposure of melanosomes to methyl iodide are assessed by a variety of analytical, imaging and spectroscopic methods. Scanning electron microscopy, light scattering and N(2) adsorption measurements all indicate significant changes in the morphology of the pigment following methylation. Solid-state nuclear magnetic resonance (SS-NMR) spectroscopy and chemical degradation analysis reveals the methylation results in the introduction of ester groups into the pigment structures. Amino acid analysis further reveals that Arg, Cys, His, Ser and Tyr undergo methylation; the SS-NMR data provide additional evidence for the methylation of the sulfur of Cys. Methylation results in increased solubility of the melanosome; the absorption properties of the dissolved material are characterized by an absorption maximum at 225 nm, with a long tail throughout the UV-A and UV-B, indicating that the solubilized material is a combination of protein and pigment. The methylation-induced decomposition of the melanosomes provides new insights into both the observed increase in O-methyl derivatives of the indolic precursor to eumelanin in the urine of melanoma patients and how increased levels of biologic methylating agents in the brain induce symptoms that resemble Parkinson's disease.
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PMID:Imaging, chemical and spectroscopic studies of the methylation-induced decomposition of melanosomes. 2033 25

There is great interest in testing neuroprotectants which inhibit the neurodegeneration that results from excessive activation of N-methyl-D-aspartate (NMDA) receptors. As an alternative to in vivo testing in animal models, we demonstrate here the use of a complex in vitro model to compare the efficacy and toxicity of NMDA receptor inhibitors. Organotypic hippocampal slice cultures were used to compare the effectiveness of the Alzheimer's disease drug, memantine, the Parkinson's disease drug, procyclidine, and the novel neuroprotectant, gacyclidine (GK11), against NMDA-induced toxicity. All three drugs are non-competitive NMDA receptor open-channel blockers that inhibit excitotoxic injury, and their neuroprotective capacities have been extensively investigated in vivo in animal models. They have also been evaluated as potential countermeasure agents against organophosphate poisoning. Quantitative densitometric image analysis of propidium iodide uptake in hippocampal regions CA1, CA3 and DG, showed that, after exposure to 10microM NMDA for 24 hours, GK11 was the most potent of the three drugs, with an IC50 of about 50nM and complete protection at 250nM. When applied at high doses, GK11 was still the more potent neuroprotectant, and also the least cytotoxic. These findings are consistent with those from in vivo tests in rodents. We conclude that the slice culture model provides valuable pre-clinical data, and that applying the model to the screening of neuroprotectants might significantly limit the use of in vivo tests in animals.
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PMID:The use of organotypic hippocampal slice cultures to evaluate protection by non-competitive NMDA receptor antagonists against excitotoxicity. 2037 5


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