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)

Ro 19-6327 (lazabemide, L), MDL 72974, selegiline, AGN 1135 and MDL 72145 were investigated for their MAO inhibitory effect in rat tissues in vitro. The selectivity of MAO-B inhibition of L, selegiline and MDL 72974 was also measured in vitro in human brain tissue as well as ex vivo in rat brain and liver after acute and subchronic administration. Of all compounds investigated L was the most selective for MAO-B inhibition under in vitro and ex vivo conditions. In volunteers, L completely but reversibly inhibited platelet MAO-B with a dose-dependent duration. Clinical trials with L are under way in both Alzheimer's and Parkinson's disease (PD).
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PMID:Lazabemide (Ro 19-6327), a reversible and highly sensitive MAO-B inhibitor: preclinical and clinical findings. 793 Dec 45

The diagnosis of Alzheimer's disease (AD) neurodegeneration is based on histopathological detection of paired helical filament-associated lesions. Silver stains are routinely used but the results are fraught with intra- and interinstitutional variability. This study employed monoclonal antibodies to middle and high molecular weight neurofilament subunits in an immunohistochemical assay to assess the extent of paired helical filament-associated lesions in brains with AD, Down's syndrome plus AD lesions (AD+DN), Parkinson's disease dementia (PD), AD+PD, and normal aging changes. The densities of neurofilament-immunoreactive (NFI) cortical neurofibrillary tangles and plaques were significantly higher in AD and AD+DN than in PD and aged control brains (p < 0.001), and NFI neurofibrillary tangles and plaques were more abundant in AD and AD+DN compared with AD+PD and PD, yet all patients with AD, AD+PD, or PD died with end-stage dementia. In contrast, the densities of NFI dystrophic neurites (primarily dendrites) in cortical Layer 2 were similar among the AD, AD+DN, AD+PD, and PD groups, and all were significantly higher than control (p < 0.005). Stepwise multivariate regression analysis demonstrated significant correlations between AD diagnosis and high densities of NFI neurofibrillary tangles and plaques (p < 0.001) and between end-stage AD-type dementia and high densities of NFI dystrophic neurites (p < 0.001). This study demonstrates that the histopathological lesions correlated with AD dementia can be readily detected and quantified by immunostaining with monoclonal antibodies to phosphorylated and non-phosphorylated neurofilaments. Moreover, the findings suggest that NFI neurite pathology may be an important feature contributing to the clinically manifested AD-type dementia in individuals with Parkinson's disease.
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PMID:Diagnostic utility of quantitating neurofilament-immunoreactive Alzheimer's disease lesions. 798 63

In a series of 37 Parkinson's disease (PD) brains, cortical changes were reexamined by means of Bielschowsky silver impregnation and anti-ubiquitin immunocytochemistry. Compared to routine HE staining, anti-ubiquitin immunostaining revealed neocortical Lewy bodies (LBs) in a significantly higher percentage (76% vs. 32%). Neocortical senile plaques (SPs) occurred more frequently in brains with neocortical LBs than in cases without LBs (50% vs. 11%; p < 0.05). Semiquantitative assessment of neocortical LB density correlated with the frequency of occurrence and density of neocortical SPs. Dementia was confined to patients with abundant neocortical LBs, thus fulfilling histological criteria of diffuse Lewy body disease. We conclude that neocortical LBs are a very frequent feature of PD, although abundance of cortical LBs is confined only to a small subgroup with prominent dementia: diffuse Lewy body disease.
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PMID:Neocortical changes in Parkinson's disease, revisited. 820 26

The copper-zinc-dependent superoxide dismutase messenger RNA expression was studied at cellular level by in situ hybridization, using a 35S-labelled complementary DNA probe homologous to human copper-zinc-dependent superoxide dismutase messenger RNA, in the dopaminergic neuron-containing areas of the human mesencephalon (the substantia nigra pars compacta, ventral tegmental area, central gray substance and peri- and retrorubral region corresponding to catecholaminergic cell group A8). The autoradiographic labelling signal was localized in neurons. No detectable hybridization signal could be found in the glial cells. Copper-zinc-dependent superoxide dismutase messenger RNA was detected in melanin-containing neurons as well as in non-melanized neurons. Quantification at cellular level, taking the autoradiographic silver grain density as an index of the abundance of copper-zinc-dependent superoxide dismutase messenger RNA, indicated that hybridization level was higher in the melanized than in the non-melanized neurons within a region. Among melanized neurons, cellular copper-zinc-dependent superoxide dismutase messenger RNA content was lowest in the neurons of the substantia nigra. No significant difference in levels of transcripts was evidenced between the groups of non-melanized neurons. The data suggest that the abundance of copper-zinc-dependent superoxide dismutase messenger RNA is higher in the mesencephalic neurons containing neuromelanin compared to other neurons. Thus, the melanized neurons have a particular defence system against oxygen toxicity, which may represent a basis for their preferential vulnerability to Parkinson's disease.
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PMID:Preferential expression of superoxide dismutase messenger RNA in melanized neurons in human mesencephalon. 835 Sep 85

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTP-induced neurotoxicity. The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.
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PMID:Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. 864 44

Effectively, modern research has confirmed Hortega's view of the origin of the microgliacyte from circulating monocytes of the monocyte-macrophage series that invade the brain during embryonic and early postnatal life. Their phagocytic capacity is exercised during the brain remodelling that marks brain maturation. They then convert to the ramified resting microglial cell visualized in the silver carbonate staining technique of Hortega and by modern lectin-binding methods. In response to injury, reactive microglia exhibit hypertrophy and hyperplasia, and may or may not go on to form typical lipid-laden phagocytes. Activated microglia show upregulation of the many marker antigens they share with circulating monocytes, including the major histocompatibility class (MHC) class II antigens that bespeak their immunocompetent nature. However, MHC class I and II expression and development of immunohistochemical positivity for cytoplasmic and plasma membrane antigens that characterize the monocyte-macrophage do not necessarily indicate an immunological response though there is ample evidence that microglia can serve as antigen-presenting cells. Rather, microglia are extraordinarily sensitive to changes in the brain microenvironment, whatever the nature of the exciting mechanism or substance. They may be considered to serve an ever alert, protective and supportive function that can be assembled rapidly to deal with infections, physical injuries, physiologic changes and systemic influences. In addition to elaboration and secretion of cytokines with varied actions, e.g., suppression of astrogliosis, they secrete factors, including nerve growth factor, which are supportive of neurons. They have an important role in iron metabolism and the storage of iron and ferritin. They may promote central nervous system regeneration. They are prominently involved in such pathologic processes as the acquired immunodeficiency syndrome, multiple sclerosis, prion diseases and the degenerative disorders, e.g., Alzheimer's disease and Parkinson's disease. With aging, they grow more numerous, become richer in iron and ferritin and exhibit phenotypic alteration, e.g., the expression of MHC class II antigens that are not ordinarily demonstrable immunohistochemically in the resting state. The rate of growth of our knowledge of microglia during the last decade has been exponential and continues.
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PMID:The microglial cell. A historical review. 884 46

Expression of glutamate decarboxylase-67 messenger RNA was examined in the basal ganglia of normal controls and of cases of Parkinson's disease using in situ hybridization histochemistry in human post mortem material. In controls glutamate decarboxylase-67 messenger RNA expression was detected in all large neurons in both segments of the globus pallidus and in three neuronal subpopulations in the striatum as well as in substantia nigra reticulata neurons and in a small sub-population of subthalamic neurons. In Parkinson's disease, there was a statistically significant decrease of 50.7% in glutamate decarboxylase-67 messenger RNA expression per neuron in the lateral segment of the globus pallidus (controls: mean 72.8 microns2 +/- S.E.M. 8.7 of silver grain/neuron, n = 12; Parkinson's disease: mean 35.9 microns2 +/- S.E.M. 9.7 of silver grain/neuron, n = 9, P = 0.01, Student's t-test). In the medial segment of the globus pallidus, there was a small, but non-significant decrease of glutamate decarboxylase-67 messenger RNA expression in Parkinson's disease (controls: mean 100.6 microns2 +/- S.E.M. 7.2 of silver grain/neuron, n = 11; Parkinson's disease: mean 84.8 microns2 +/- S.E.M. 13.0 of silver grain/neuron, n = 7, P = 0.1, Student's t-test). No significant differences in glutamate decarboxylase-67 messenger RNA were detected in striatal neuronal sub-populations between Parkinson's disease cases and controls. These results are the first direct evidence in humans that there is increased inhibitory drive to the lateral segment of the globus pallidus in Parkinson's disease, as suggested by data from animal models. We therefore provide theoretical support for current experimental neurosurgical approaches to Parkinson's disease.
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PMID:Glutamate decarboxylase-67 messenger RNA expression in normal human basal ganglia and in Parkinson's disease. 893 Oct 5

Nineteen Macaca fascicularis monkeys were divided into four different groups: Group A (n = 3), control; Group B (n = 3), monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Group C (n = 8), animals treated with MPTP in which the subthalamic nucleus (STN) was unilaterally lesioned by kainic acid injection; in Group D (n = 5), the STN was lesioned prior to MPTP administration. Subthalamotomy resulted in a bilateral improvement of tremor, spontaneous activity, bradykinesia (evaluated by a manual motor test) and freezing in Group C. All these monkeys developed hemichorea contralateral to the lesion. The improvement was maintained and the hemichorea continued until death. The monkeys in group D showed severe hemiballism which persisted throughout MPTP administration and developed parkinsonian signs mainly on the side ipsilateral to the lesion. Analysis of the in situ hybridization of the mRNA coding for glutamic acid decarboxylase (GAD) of MPTP monkeys showed a significant increase in the mean density of silver grains over every labelled neuron in the globus pallidum lateralis (56.8% over control) as well as the globus pallidus medialis (GPM) (45.7% over control) and the substantia nigra reticulata (SNR) (35.8% over control). No significant change was observed in the thalamic nucleus reticularis. Subthalamotomy (Groups C and D) produced a significant reduction in mRNA GAD expression on the side of the lesion in the GPM and the SNR (34% and 42.3%, respectively) with respect to the ipsilateral (non-lesioned) side and also when compared with parkinsonian monkeys. These results confirm and expand, at the cellular level, the paramount role of STN hyperactivity in the pathophysiology of parkinsonism. The therapeutic consequences of these findings for surgical treatment of Parkinson's disease are discussed.
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PMID:Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. 893 92

Prior to any evaluation of morphologic brain changes, a decision must be made whether a given alteration is associated with aging or with disease. Patients with disease-related lesions may be in a clinically silent phase of a disease or show overt symptoms. Neurofibrillary tangles and neuropil threads are the hallmarks of Alzheimer's disease. They should not be considered to be age-related changes, even when they are present only in small numbers. In general, the initial changes consist of neurofibrillary tangles and neuropil threads. Plaques (amyloid deposits and/or neuritic plaques) are consistently present in the end stage of the disease. Initial neurofibrillary tangles and neuropil threads develop at specific cortical predilection sites. The changes then spread in a predictable, nonrandom manner across other portions of the telencephalic cortex. The sequential changes in the distribution pattern of the lesions provide the basis for a staging procedure that takes the slow and gradual progression of the destructive process into consideration. The staging procedure provides accurate diagnoses in the initial stages and even reveals brain changes developing prior to the appearance of clinical symptoms. It is thus advantageous in characterizing nondemented controls. The staging procedure can be carried out easily and does not require knowledge of clinical data, quantitative assessments, or adjustments for the age of the patients. Application of advanced silver techniques (Gallyas, Campbell-Switzer) to demonstrate Alzheimer's disease-related lesions also allows recognition of the hallmarks of other disorders, such as Lewy body disease (Parkinson's disease) and dementia with argyrophilic grains, which frequently co-occur with Alzheimer's disease.
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PMID:Diagnostic criteria for neuropathologic assessment of Alzheimer's disease. 933 Sep 92

Levels of the neurotransmitter somatostatin (SS) have previously been shown to be reduced in the cortex and hippocampus of demented parkinsonian patients and patients with Alzheimer's disease. In situ hybridisation histochemistry (ISHH) was performed with an 35S tail-labelled oligonucleotide DNA probe to human SS mRNA, to examine its expression within the striatum, medial medullary lamina (MML) and reticular thalamic nucleus in Parkinson's disease (PD) and in matched controls. A chronic unilaterally MPTP-lesioned L-DOPA-naive primate model was also examined for comparison of SS mRNA expression with that in human L-DOPA treated PD subjects. Quantitation of SS mRNA expression on emulsion dipped sections revealed a significant increase (82%) in the MML of the globus pallidus in PD (56.5 microm2 of silver grain/cell, n = 9 cases) compared to controls (26.3 microm2/cell, n = 13 cases, p < 0.01, Student's t-test), paralleling the increase previously observed by this group for NOS mRNA. SS mRNA expression was higher in the dorsolateral than ventromedial putamen in controls (p < 0.001; DL: 24.89 +/- SEM 1.35; VM: 17.96 +/- SEM 2.63; n = 14) but this gradient was lost in PD cases (p > 0.05; DL: 22.68 +/- 1.94; VM: 22.17 +/- 2.94; n = 10). These findings suggest specific modification of basal ganglia SS-ergic pathways in PD.
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PMID:Selective increase in somatostatin mRNA expression in human basal ganglia in Parkinson's disease. 940 18


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