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)

Among 406 patients with Parkinson's disease, the cancer rate (all sites combined) was bout one-third that for the general population. The risk of cancer increased during the treatment period but remained significantly low. Malignant and benign thyroid neoplasms were significantly more frequent than expected among patients with Parkinson's disease. We suggest that high levels of total body potassium in patients with Parkinson's disease is the protective factor against cancer.
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PMID:Low cancer rates among patients with Parkinson's disease. 400 73

Exposure of mouse thymocytes to dopamine caused apoptosis (programmed cell death). This was manifested by cellular condensation and membrane damage shown by flow cytometry measurements and scanning electron microscopic study. Dopamine also affected thymocytic nuclei and their genomic DNA integrity. Most of the DNA molecules accumulated in a subdiploid peak in flow cytometry analysis, indicating DNA fragmentation to small particles. DNA analysis showed the typical pattern of 'DNA ladder' caused by internucleosomal DNA cleavage. X-ray microanalysis of the cellular elements of dopamine-treated cells showed elevation of sodium (Na), chloride (Cl) and calcium (Ca) peaks, accompanied by reduction in phosphate (P) concentrations. Comparison of the potassium (K) and P concentrations showed significant differences between the two major death processes: necrosis (induced by exposure to sodium azide (NaN3)) and apoptosis (induced by dopamine). High concentrations of K indicated cell viability while reductions in P and elevations in Ca levels were found to be typical of apoptotic cell death. The antioxidant dithiothreitol (DTT) suppressed dopamine-induced apoptosis in thymocytes, suggesting that its toxicity may be mediated via generation of reactive oxygen radicals. Our study suggests that under certain circumstances, dopamine and/or its metabolites, may induce a process of apoptotic cell death of the dopamine-producing cells in the substantia nigra. Increased accessibility of dopamine to the nigral cell nucleus or inability to scavenge excess free radicals generated from dopamine oxidation triggering programmed cell death, may cause the progressive nigral degeneration in Parkinson's disease.
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PMID:Dopamine-induced programmed cell death in mouse thymocytes. 766 5

The search for trophic factors that can support injured dopaminergic neurons and can enhance dopaminergic graft survival and outgrowth for therapeutic uses in Parkinson's disease has lately focused on members of the transforming growth factor (TGF) beta super-family. In this paper we have studied the effects of a member of the TGB beta family, glial cell line-derived neurotrophic factor (GDNF), on immature and mature ventral mesencephalic tissue grafted to the anterior chamber of the eye. The results confirm that GDNF increases survival of TH-positive neurons and enhances TH-immunoreactive nerve fiber formation when the grafts are treated during their development. The distribution of nerve terminals is densest within the area of TH-immunoreactive neurons and at the surface of the grafts. However, there is no change in the number of calcium-binding protein (CaBP)-positive neurons, suggesting that the subpopulation of TH-positive neurons that is increased are the CaBP-negative neurons of the ventral tier of pars compacta. Terminals from those neurons form the striatal patches during normal development. When the grafts are treated with GDNF after maturation, no change in TH-positive cell survival is seen but an increase of nerve terminals is still found within the cell dense area of the graft. Potassium-evoked dopamine release, measured using in vivo chronoamperometry, revealed significantly increased extracellular overflow in transplants treated with GDNF during development. The dopamine uptake blocker nomifensine significantly increased the time for clearance of the released dopamine. These data suggest that GDNF treatment of immature grafts enhances survival of TH-positive neurons, which would have innervated the striatal patches, and also increases TH-immunoreactive nerve fiber formation and dopamine release. Furthermore, GDNF treatment of mature grafts also increases dopamine fiber formation within the TH-positive neuronal area, indicating that adult dopaminergic neurons are also responsive to this agent.
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PMID:Effects of glial cell line-derived neurotrophic factor on developing and mature ventral mesencephalic grafts in oculo. 767 36

In human brain, [3H]glibenclamide binds with high affinity (KD about 3.5 nM) to sulfonylurea binding sites which are associated with ATP-sensitive potassium (KATP) channels. Regarding to the important neuromodulatory action of KATP channels in some neuronal populations, sulfonylurea binding sites were measured in several cortical areas (frontal and temporal cortex, hippocampus) and striatum (caudate nucleus and putamen) in controls and patients with Parkinson's disease or progressive supranuclear palsy. There was no modification of [3H]glibenclamide specific binding in the cerebral regions studied in both pathologies. These results indicate that KATP channels do not seem to be involved in the pathophysiology of these degenerative processes. Brain samples from five patients with Huntington's disease were studied. A small decrease in sulfonylurea binding sites was measured in the frontal cortex, caudate nucleus and putamen which could be due to the loss of either neurons or nerve endings. This low decrease contrasts with the dramatic diminution of many other markers associated with the profound striatal degeneration occurring in Huntington's disease.
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PMID:Sulfonylurea binding sites in normal human brain and in Parkinson's disease, progressive supranuclear palsy and Huntington's disease. 803 96

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.
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PMID:6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine. 818 26

In the present study, we directly compare striatal dopamine metabolism in gonadectomized male and female CD-1 mice treated with 2 days of estrogen or oil vehicle. Basal and potassium-stimulated dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) release from in vitro superfused striatum as well as pre- and postsuperfusion tissue dopamine contents were measured. Both basal and potassium-stimulated dopamine release were significantly higher and DOPAC release was significantly lower in males than in females. However, striatal tissue dopamine content was lower in males than in females. Estrogen-treated female mice showed increased basal and potassium-stimulated dopamine release compared to oil-treated females without affecting tissue dopamine content. Estrogen did not affect striatal dopamine concentrations or release in males. These results demonstrate clear sex differences in striatal dopamine turnover and concentrations under conditions of equal hormonal status. The results also indicate that estrogen can exert substantial effects on striatal dopamine metabolism by acting specifically in females to increase neuronal dopamine synthesis and release without depleting dopamine content. These results have important implications for the observed sex differences in clinical movement disorders such as Parkinson's disease.
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PMID:Sex differences and effects of estrogen on dopamine and DOPAC release from the striatum of male and female CD-1 mice. 831 46

Encapsulation of neurosecretory cells within a semipermeable membrane may possibly isolate the enclosed cells from the host immune system and allow inward diffusion of nutrients and outward diffusion of neurotransmitters. Moreover, the encapsulation procedure may prevent the tumor formation of enclosed cells, when they are derived from tumor cells. In the present study, PC12 cells, a dopaminergic cell line derived from a rat pheochromocytoma, were enclosed within an agarose/poly (styrene sulfonic acid) (agarose/PSSa) mixture and transplanted into the brains of rats (allogeneic transplantation) or guinea pigs (xenogeneic transplantation). Tyrosine hydroxylase (TH) immunoreactive PC12 cells within the microcapsules were observed in all rats and guinea pigs at least up to five weeks after transplantation. PC12 cells were round in shape and of relatively uniform small size. Although PC12 cells occasionally formed cell clusters, the formation of a tumor was not observed. The host reaction to agarose/PSSa microcapsules was minimum. The degree of glial fibrillary acidic protein (GFAP) positive astrocyte density around the microcapsules was similar to that around injection tracks. There was no apparent immunological rejection around the capsules. High-performance liquid chromatography with electrochemical detection (HPLC-EC) showed basal and potassium-evoked release of dopamine from the PC12 cell-enclosed microcapsules in vitro. Although our data is preliminary, we believe that agarose/PSSa microcapsules are promising for producing semipermeable membranes that enable allo-and xenotransplantation of neurosecretory cells into the brain in the absence of systemic immunosuppression. This approach is expected to be applied in Parkinson's disease in the near future.
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PMID:[Encapsulated dopamine-secreting cells transplanted into the brain: a possible therapy for Parkinson's disease]. 855 62

An ATP-sensitive potassium channel (KATP) is known to modulate insulin release from pancreatic beta cells. It has been proposed that potassium channels related to KATP in the nervous system might similarly modulate neurotransmitter release. We have therefore investigated the effects of KATP opening agents on GABA release in the globus pallidus. Diazoxide and cromakalim decreased the K(+)-evoked release of [3H]GABA from pallidal slices. The maximum inhibition observed for diazoxide (59%) and cromakalim (66%) was achieved at a concentration of 100 microM. The effects of both cromakalim and diazoxide were significantly antagonized by the concurrent application of the sulfonylurea glibenclamide (100 microM). Intrapallidal injections of diazoxide in the reserpine-treated rat model of Parkinson's disease reduced akinesia in a dose-dependent manner. These data suggest that manipulation of neuronal potassium channels with pharmacological properties similar to KATP may prove useful in the treatment of Parkinson's disease.
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PMID:Modulation of GABA transmission by diazoxide and cromakalim in the globus pallidus: implications for the treatment of Parkinson's disease. 863 58

Brain iron research began in the late nineteenth century when Zaleski (1886) made a quantitative analysis of one human brain and correlated iron levels with observations on stained slices and some microscopic sections. Gradually, the realization grew that the central nervous system (CNS) contained iron which was different from hemoglobin-iron. This non-heme iron was found in highest concentrations in globus pallidus, substantia nigra, red nucleus, and dentate nucleus. The enhancement of the traditional histochemical stain, potassium ferrocyanide in hydrochloric acid, by incubating the reacted sections in a solution of diaminobenzidine and hydrogen peroxide, revealed iron in many cell types of the CNS, including neurons, microglia, oligodendroglia, and some astrocytes. A large proportion of the soluble brain iron was shown to be present in ferritin. Brain ferritin was found to be very similar to the protein from other organs in that it contained heavy and light subunits. Several investigators reported the presence of other iron-related proteins in the central nervous system, including transferrin, transferrin receptor, and the ferritin repressor protein. Brain was shown to respond to the extravasation of blood by converting the iron in heme to hemosiderin by a sequence of steps which was quite similar to the process in extracerebral organs. The methods of molecular biology have contributed greatly to our understanding of brain iron but many questions remain about its unique anatomical distribution and its role in degenerative diseases such as Parkinson's disease and Alzheimer's dementia.
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PMID:The history of iron in the brain. 884 38

To date, few studies have systematically evaluated the most appropriate location for grafting catecholaminergic cells as a potential treatment for Parkinson's disease (PD). The following study was conducted to determine 1) if placement of catecholamine-secreting encapsulated PC12 cells into the lateral ventricle of 6-OHDA-treated rats is as effective as intrastriatal implants on reducing apomorphine-induced rotational behavior, and 2) to determine if the survival of encapsulated PC12 cells is differentially affected by the implant site. Polymerencapsulated PC12 cells were implanted into either the striatum or lateral ventricle of unilateral 6-OHDA-lesioned rats. Animals were tested for apomorphine-induced rotations over a 6-wk period. Only those animals that received intrastriatal implants of encapsulated PC12 cells showed a reduction in rotation behavior. Moreover, removal of the devices from the striatum resulted in a return to preimplant rotation levels. Postexplant neurochemical analyses demonstrated that the potassium-evoked L-dopa device output increased in vivo while the potassium-evoked dopamine output from the devices decreased over time in vivo. The location of the implant significantly affected catecholamine output from the PC12 cell-loaded devices. The increase in potassium-evoked L-dopa output was greatest, as was the decrease in potassium-evoked dopamine output, from those devices implanted in the striatum. Basal output of dopamine and DOPAC was also significantly higher from devices explanted from the lateral ventricle. These results demonstrate that the continued presence of intrastriatal implants of encapsulated PC12 cells is required to maintain the behavioral effects in 6-OHDA-lesioned rats. In addition, the site of implantation appears to affect device output. These results provide additional support for intraparenchymal delivery of L-dopa and dopamine via polymer encapsulation as a possible treatment for PD.
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PMID:Continued presence of intrastriatal but not intraventricular polymer-encapsulated PC12 cells is required for alleviation of behavioral deficits in Parkinsonian rodents. 888 17


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