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)

In sagittal brain sections of newborn male rats (1-day-old) there were no regional differences in the IC50 values of dopamine at [125I]iodosulpride binding sites. In contrast, in 20- and 60-day-old rats, there was a selective increase in the IC50 values of dopamine in the nucleus accumbens, caudate-putamen, and olfactory tubercule. The IC50 values of these regions decreased in 262-day-old rats. Some of the other brain areas appeared to behave in a similar, but much less pronounced, fashion. Thus, there were significant regional differences in the IC50 values of young, adult, and old rats. In addition, there was a rapid increase in [125I]iodosulpride binding between the newborn and the 20-day-old rats, which leveled off thereafter, and selectively decreased in the substantia nigra of the 262-day-old rats. In conclusion, these results indicate that a biphasic decrease-increase in the affinity of D2 agonist binding sites occurs selectively in the basal ganglia. These findings may be of relevance for developmental diseases in which dopaminergic mechanisms have been implicated, such as schizophrenia and Parkinson's disease.
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PMID:Regional and age-dependent differences in the affinity of dopamine D2 agonist binding in the rat brain. 763 33

Dystrophic neurites are present in olfactory epithelium (OE) of patients with Alzheimer's disease (AD), Parkinson's disease (PD), and Down syndrome (DS) and occasionally in normal individuals. Cultured olfactory neuroblasts from AD patients generate carboxy terminal amyloid precursor protein (APP) fragments that contain beta-amyloid (A beta), but it is not known if deposits of A beta and/or APP fragments occur in the OE of individuals with or without AD, PD, or DS. To determine if A beta accumulates in the OE in situ, we probed postmortem samples of olfactory mucosa from patients with AD, PD, and AD (PD/AD), and DS and AD (DS/AD), as well as from controls, using polyclonal and monoclonal antibodies to A beta and flanking sequences in APPs. Samples of OE also were examined by thioflavin-S and electron microscopy. Labeling of A beta was observed in 10 of 12 AD cases, 2 of 3 PD/AD cases, 3 of 4 DS/AD cases, 3 of 10 adult controls, and 4 of 6 fetal cases. The A beta staining was seen in the basal third of the OE, in axons projecting through the lamina propria, and in metaplastic respiratory epithelium within the OE. Antibodies to other APP domains stained the OE of patients and controls. Thioflavin-S staining was present in the basal third of the OE of 8 of 9 AD patients and several PD/AD and DS/AD patients, but only in rare cells of 3 controls. Electron microscopy did not reveal amyloid fibrils in the OE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Beta-Amyloid peptide and amyloid precursor proteins in olfactory mucosa of patients with Alzheimer's disease, Parkinson's disease, and Down syndrome. 763 77

Impaired olfaction occurs in patients with idiopathic Parkinson's disease (PD), and Lewy bodies have been found in the olfactory bulb and tract. We now confirm the latter finding and show that this presence of Lewy bodies is associated with significant neuronal loss. A quantitative study of the anterior olfactory nucleus (AON) was performed in tissue obtained postmortem from seven patients with PD and seven age-matched controls. Neuronal loss was seen in the PD bulb and tracts (p < 0.01), and a strong correlation of neuronal loss with disease duration was detected (R = -0.87). The presence of Lewy bodies was confirmed with immunocytochemical staining for ubiquitin in all the PD cases.
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PMID:The anterior olfactory nucleus in Parkinson's disease. 765 44

Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be useful for developing neuroprotective and neurotrophic therapies for Parkinson's disease. To develop such a model, different doses of 6-hydroxydopamine (0.0, 0.625, 1.25, 2.5 and 5.0 micrograms/microliters in 3.5 microliters of saline) were unilaterally injected into the striatum of rats. Animals that received 1.25 to 5.0 micrograms/microliters 6-hydroxydopamine displayed dose-dependent amphetamine and apomorphine-induced circling. 6-Hydroxydopamine also caused dose-dependent reductions in [3H]mazindol-labeled dopamine uptake sites in the lesioned striatum and ipsilateral substantia nigra pars compacta (up to 93% versus contralateral binding), with smaller losses in the nucleus accumbens, olfactory tubercle and ventral tegmental area. In the substantia nigra pars compacta and the ventral tegmental area, the number of Nissl-stained neurons decreases in parallel with the reduction in [3H]mazindol binding. The reduction in [3H]mazindol binding in the striatum and the nucleus accumbens, and the reduction in [3H]mazindol binding and in the number of Nissl-stained neurons in the substantia nigra pars compacta and the ventral tegmental area is stable for up to 12 weeks after the lesion. Macroscopically, forebrain coronal sections showed normal morphology, except for rats receiving 5.0 micrograms/microliters 6-hydroxydopamine in which striatal cross-sectional area was reduced, suggesting that this high dose non-specifically damages intrinsic striatal neurons. Nissl-stained sections revealed an area of neuronal loss and intense gliosis centered around the needle track, which increased in size with the dose of neurotoxin. Striatal [3H]sulpiride binding was increased by 2.5 micrograms/microliters and 5.0 micrograms/microliters 6-hydroxydopamine, suggesting up-regulation of dopamine D2 receptors. Striatal binding of [3H]CGS 21680-labeled adenosine A2a receptors, but not of [3H]SCH 23390-labeled dopamine D1 receptors, was reduced at the highest dose, suggesting preservation of the striatal intrinsic neurons with the lower doses. This study indicates that intrastriatal injection of different doses of 6-hydroxydopamine can be used to cause increasing amounts of dopamine denervation, which could model Parkinson's disease of varying degrees of severity. Injecting 3.5 microliters of 2.5 micrograms/microliters 6-hydroxydopamine appears to be particularly useful as a general model of early Parkinson's disease, since it induces a lesion characterized by robust drug-induced rotation, changes in binding consistent with approximately 70% dopamine denervation, approximately 19% dopamine D22 receptor up-regulation, negligible intrinsic striatal damage and stability for at least 12 weeks. This study outlines a technique for inducing partial lesions of the nigrostriatal dopamine pathway in rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. 767 92

The serine protease inhibitor and neurite outgrowth promoter glia derived nexin (GDN) is expressed in the rat CNS during embryogenesis and persists in the olfactory system of the adult where receptor neurons are replaced throughout life. We investigated whether GDN-immunoreactivity also appears in the adult at sites of synaptic rearrangement following nerve cell death and anterograde terminal degeneration in experimental models for Parkinson's disease. Rat substantia nigra was unilaterally lesioned by stereotaxic application of different toxins: 6-hydroxydopamine, which selectively destroys dopaminergic neurons, the excitotoxic glutamate analog ibotenic acid, or the glutamate receptor agonists N-methyl-D-aspartate and quisqualate, which cause circumscript lesions of the whole substantia nigra. Nerve cell death and astroglial reactivity were monitored by parallel cresyl staining and immunocytochemistry for glial fibrillary acidic protein, at survival times ranging from 2 to 100 days. Sustained de novo synthesis of GDN occurred in the dopamine depleted caudate putamen following excitotoxin or 6-hydroxydopamine induced degeneration of the substantia nigra and of the nigrostriatal pathway provided that the lesions were nearly complete. This is consistent with compensatory changes occurring in deafferented caudate putamen and suggests a permissive role of GDN in neuronal plasticity. In the substantia nigra astroglia exhibited GDN-immunoreactivity following excitotoxin injection but not after application of 6-hydroxydopamine. Thus differences in action mechanisms of neurotoxins may have distinct consequences on the astrocyte mediated response of the same affected brain region.
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PMID:Re-expression of glia-derived nexin/protease nexin 1 depends on mode of lesion-induction or terminal degeneration: observations after excitotoxin or 6-hydroxydopamine lesions of rat substantia nigra. 790 98

Aside from motor and cognitive deficits, Parkinson patients also manifest a little-studied olfactory deficit. Since in Parkinson's disease there is a dopamine depletion of the amygdala due to mesocorticolimbic system degeneration, we decided to test olfactory and taste performance of 6-OHDA amygdala lesioned rats, as well as the possible restoration of either function with adrenal medullary transplants. Two 6-OHDA lesioned groups and one control group were tested in the potentiation of odor by taste aversion paradigm. On taste aversion none of the groups showed any impairment. In contrast, the 6-OHDA lesioned rats showed a marked impairment in olfactory aversion. At this point, one of the lesioned groups received a bilateral adrenal medullary graft within the lesioned area. After two months, all groups were submitted again to the behavioral paradigm. Taste remained unaffected, but the lesioned only group did not recover either olfactory aversion or normal catecholamine levels. The grafted group, on the other hand, restored olfactory aversion and catecholamine levels. It can be concluded from this study that catecholamine depletion of the amygdala is sufficient to produce a selective olfactory deficit, not accompanied by taste impairments, and that such a deficit can be reversed by adrenal medullary transplants, which in turn restore catecholamine levels.
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PMID:Adrenal medullary grafts restore olfactory deficits and catecholamine levels of 6-OHDA amygdala lesioned animals. 794 79

Presymptomatic detection of Parkinson's disease is necessary if neuroprotective therapies are to be utilized in its treatment. Various methods (PET, electrophysiology, enzyme assays, olfactory function) may be applicable but none has been rigorously evaluated. Other possible approaches are now considered. Plasma HVA levels (pHVA) in the presence of debrisoquine may reflect cerebral dopamine function. However, there are no detectable differences in pHVA between newly diagnosed and untreated parkinsonian patients and control subjects. Compensatory increases in dopamine turnover may mask a decrease in pHVA in the early stages of the disease. So, at present this technique could not be used as a diagnostic tool. Post-mortem studies of brain in Parkinson's disease may provide clues to biochemical markers indicative of nigral pathology. Mitochondrial complex I activity is reduced in substantia nigra in Parkinson's disease and it was reported also to be markedly reduced in blood platelets. However, subsequent studies suggest that the difference in platelet complex I activity is too small to be diagnostic of Parkinson's disease. There are also selective reductions in brain glutathione levels in Parkinson's disease restricted to substantia nigra, which do not occur in other neurodegenerative disorders and are not due to drug treatment. Importantly, in incidental Lewy body disease (preclinical Parkinson's disease) nigral glutathione levels are reduced to the same degree as in advanced Parkinson's disease. So, some peripheral index of altered glutathione function may be valuable in the early detection of the disease process.
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PMID:Presymptomatic detection of Parkinson's disease. 829 98

Neurological disorders, bearing many similarities to Parkinson's disease, have been associated with environmental and occupational exposure to manganese (Mn). To document early nervous system dysfunction associated with long-term exposure to Mn, a battery of neurofunctional tests was administered to workers employed in Mn alloy production. Study participation was 95% (n = 115). A matched pair design was used; actively working men, with no history of workplace exposure to neurotoxins, were recruited from the region as referents. Matching was done on the variables: age (+/- 3 years), educational level (+/- 2 years), smoking status, and number of children. Stationary environmental sampling indicated that Mn levels varied widely (geometric means: Mn dust, 0.89 mg/m3; respirable Mn, 0.04 mg/m3). The alloy workers had significantly higher levels of whole blood Mn (geometric mean: 1.03 microgram/100 ml vs 0.68 microgram/100 ml); no differences were observed for urinary Mn. Univariate analysis (paired t test, Signed Rank and McNemar) and multivariate analysis of variance (Hotelling-Lawley statistic) revealed that the pairs differed on symptom reporting, emotional state, motor functions, cognitive flexibility, and olfactory perception threshold; verbal fluency, basic mathematics, reading capability, and attentional capacity were similar. These findings are consistent with current knowledge on brain Mn activity and suggest that manifestations of early manganism can be observed in well designed population studies, using sensitive testing methods.
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PMID:Nervous system dysfunction among workers with long-term exposure to manganese. 830 49

Decreased olfactory function commonly occurs in idiopathic Parkinson's disease (PD), regardless of stage, treatment, or duration of disease. In the present study, we sought to determine whether different subtypes of PD, categorized according to well-defined clinical criteria, evidence different degrees of olfactory dysfunction. Significantly different scores on the University of Pennsylvania Smell Identification Test (UPSIT) were present between patients with benign PD and malignant PD (respective means [SD] = 22.51 [8.50] and 17.38 [6.29]) and between tremor-predominant PD and postural instability-gait disorder (PIGD)-predominant PD (23.43 [8.18] versus 17.35 [6.00]). No statistically significant differences in UPSIT scores were observed between young-onset and older-onset PD patients. Women outperformed men in most subtypes examined.
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PMID:Olfactory function in Parkinson's disease subtypes. 830 71

When lesions are placed unilaterally in the nigrostriatal system of experimental animals, rotational behavior occurs in response to peripheral administration of dopamine (DA) agonists. In spite of considerable evidence to the contrary, it is assumed that in order for this rotation to occur, an almost complete depletion of striatal DA must be achieved. To test this hypothesis further, 20 male Sprague-Dawley rats were injected unilaterally with 2 microL of 8 micrograms/microL of 6-hydroxydopamine (6-OHDA) via acute injection needles or chronically indwelling cannulae. Acute injection of 6-OHDA resulted in a rotation rate of 7.2 to 18.9 revolutions per minute in response to peripheral amphetamine injection (5 mg/Kg) while injection of 6-OHDA through chronically indwelling cannulae produced rotation ranging from 1.4 to 9.9 rotations per minute. Under the conditions of either method of injection, the animals displaying the most severe rotation still showed partial denervation of striatal DA as revealed by catecholamine fluorescence histochemistry. Conversely, numerous animals demonstrating very low rates of amphetamine-induced rotation often displayed a complete loss of striatal, accumbens, and olfactory tubercle catecholamine fluorescence. Moreover, large quantities of lateral hypothalamic amine accumulation were observed in rotating rats indicating that this neurochemical change may be of functional significance for rotational responses. The present results, when taken into consideration with previous work, indicate that the routine selection of rotating animals for pharmacological testing for potential antiParkinsonian medication or intracerebral grafting purely on the basis of their rotational behavior does not necessarily imply that complete striatal denervation has occurred. Moreover, these findings demonstrate that amine accumulation in the lateral hypothalamus of rotating animals with DA depleting lesions is an important phenomenon implicated in the expression of rotational behavior in animals and possibly in the pathophysiology of Parkinson's disease.
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PMID:Amphetamine-induced rotational behavior in rats: relationship to hypothalamic and striatal degeneration. 840 40


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