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)

Neural transplantation, a mode of cellular replacement, has been used as a therapeutic trial for Parkinson's disease. Studies indicate that tonic release of the metabolites from the graft that can be utilized by the host brain, is likely to be the major mechanism responsible for the therapeutic effect. The use of fetal tissue is complicated by ethical controversy and immunological incompatibility. Autografting adult tissue has not been successful mainly due to poor survival. Genetically engineered cells are promising alternative sources of donor cells. We have investigated the potential of primary skin fibroblasts as donor cells for intracerebral grafting. Primary skin fibroblasts survive in the brain and remain in situ. A number of genes (nerve growth factor, tyrosine hydroxylase, glutamic acid decarboxylase, and choline acetyltransferase) have been successfully introduced and expressed in the primary fibroblasts. The L-dopa-secreting primary fibroblasts exhibited a behavioral effect in a rat model of Parkinson's disease up to 8 weeks after being grafted into denervated striatum. Factors that can maximize gene transfer, transgene expression, and fibroblast survival in the brain make up the future direction of investigation.
 ...
PMID:Cellular replacement therapy for neurologic disorders: potential of genetically engineered cells. 206 74

The time course changes in levels of mRNA encoding glutamic acid decarboxylase (GAD) and proenkephalin (PPE) was analyzed in the rat striatum following unilateral lesion of substantia nigra with 6-hydroxydopamine. The levels of both GAD and PPE mRNAs increased after the dopaminergic deafferentation, reaching concomitantly a maximal twofold increase on day 25. Thereafter, the mRNA levels declined; at 4 months, the amount of PPE mRNA remained slightly elevated whereas GAD mRNA had returned to the control value, suggesting the action of a compensatory mechanism. We also observed a rise of glial fibrillary acidic protein mRNA level which reflects a reactive astrocytosis. In contrast, alpha-tubulin mRNA level remained unchanged, indicating that no significant synaptogenesis occurs in this experimental situation. No obvious modification in mRNA levels was detected in the striatum contralateral to the lesion. These results highlight the role of the modulation of gene expression in adaptive processes to dopamine deficiency in striatal efferent pathways. Its relevance to the pathophysiology of Parkinson's disease is discussed.
 ...
PMID:Similar time course changes in striatal levels of glutamic acid decarboxylase and proenkephalin mRNA following dopaminergic deafferentation in the rat. 245 7

The activity of glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) as presynaptic markers of gamma-aminobutyric acid (GABA)- and acetylcholine (ACh)-containing neurons, and the binding of [3H]muscimol and [3H]quinuclidinyl benzilate ([3H]QNB) as postsynaptic ones were measured in autopsied samples of the caudate nucleus, putamen, pallidum, substantia nigra and the cerebral cortex from L-dopa-treated patients with Stage V (terminally bedridden) patients with Parkinson's Disease (PD). In PD, GAD activities were significantly reduced in the caudate nucleus and substantia nigra relative to normal controls, but were normal when the values from protracted terminal illness (PTI) cases were used as the controls. ChAT activities were reduced in all regions studied. These reductions in GAD and ChAT activities were not accompanied by a concomitant increase in the density of GABAA or muscarinic receptors. GABAA receptor densities were significantly decreased in both the cortical and subcortical brain regions, while muscarinic receptor densities remained unchanged. We suggest that the decreased density of GABAA receptor in PD brains reflects degeneration of neurons on which the receptor is localized, i.e., degeneration of ascending monoaminergic neurons including nigral dopamine (DA) neurons.
 ...
PMID:GABAA receptor but not muscarinic receptor density was decreased in the brain of patients with Parkinson's disease. 285 79

The content of gamma-aminobutyric acid (GABA) and the activities of glutamic acid decarboxylase (GAD) and tyrosine hydroxylase (TH) were measured in whole putamen obtained at autopsy from 13 patients dying with idiopathic Parkinson's disease and 13 appropriate control subjects. Mean GABA content was significantly elevated (by 28%) in the putamen of the Parkinson's disease patients. TH activity was markedly reduced, while there was no significant reduction of GAD activity in the putamen of these patients. GABA content was also measured in both sides of the striatum in rats which had received unilateral injections of 6-hydroxydopamine (6-OHDA) in the vicinity of the axons of the nigrostriatal projection. Mean GABA content was found significantly elevated (by 33%) in the ipsilateral striatum. Loss of dopaminergic nigrostriatal neurons, in both human Parkinson's disease and in the rat 6-OHDA model, is accompanied by increased striatal GABA content. The assumption that GABAergic neurotransmission is reduced in the striatum in Parkinson's disease may not be correct.
 ...
PMID:Striatal GABAergic neuronal activity is not reduced in Parkinson's disease. 613 32

Interpretation of biochemical measurements in the human brain after death is complicated by a variety of premortem, perimortem, and postmortem factors. The activity of glutamic acid decarboxylase (GAD) in particular has been found to vary considerably among human brains. In contrast to neurotransmitter-associated enzymes, metabolic enzymes are present in all brain cells and should not be specifically lost by patterned neuronal cell loss such as that which occurs in Parkinson disease. We compared the activity of GAD to that of the metabolic enzymes creatine kinase (CK), adenylate kinase, hexokinase, beta-glucuronidase, and malate, lactate, glucose-6-phosphate, and isocitrate dehydrogenases in 24 regions of six human brains. Of the metabolic enzymes, only CK showed a 5-fold variation approaching that of GAD. Like GAD, CK activity was stable postmortem, but its activity was apparently inversely related to the severity and duration of the preterminal illness. CK may be a useful marker of agonal deterioration.
 ...
PMID:Regional activities of metabolic enzymes and glutamate decarboxylase in human brain. 731 90

The effects of nigrostriatal denervation and L-dopa therapy on GABAergic neurons were analysed in patients with Parkinson's disease and in monkeys rendered parkinsonian by MPTP intoxication. The expression of the messenger RNA coding for the 67 kDa isoform of glutamic acid decarboxylase (GAD67 mRNA), studied by quantitative in situ hybridization, was used as an index of the GABAergic activity of the striatal neurons. A significant increase in GAD67 mRNA expression, generalized to all GABAergic neurons, was observed in MPTP-treated monkeys compared to control monkeys in the putamen and caudate nucleus (+44 and +67% respectively), but not in the ventral striatum. L-Dopa therapy significantly reduced GAD67 mRNA expression in the putamen and caudate nucleus to levels similar to those found in control monkeys. However, the return to normal of GAD67 mRNA expression was not homogeneous across all neurons since it was followed by an increase of labelling in one subpopulation of GABAergic neurons and a decrease in another. These data suggest that in MPTP-treated monkeys the degeneration of nigrostriatal dopaminergic neurons results in a generalized increase in GABAergic activity in all the GABAergic neurons of the striatum, which is partially reversed by L-dopa therapy. As the expression of GAD67 mRNA is less intense in the ventral than in the dorsal striatum, this increase in striatal GABAergic activity may be related to the severity of nigrostriatal denervation. In parkinsonian patients who had been chronically treated with L-dopa, GAD67 mRNA expression was significantly decreased in all GABAergic neurons, in the caudate nucleus (by 44%), putamen (by 43.5%) and ventral striatum (by 26%). The opposite variation of GAD67 mRNA in patients with Parkinson's disease, compared with MPTP-treated monkeys, might be explained by the combination of chronic nigrostriatal denervation and long-term L-dopa therapy.
 ...
PMID:Effects of nigrostriatal denervation and L-dopa therapy on the GABAergic neurons in the striatum in MPTP-treated monkeys and Parkinson's disease: an in situ hybridization study of GAD67 mRNA. 758 93

1. The majority of neurons in the striatum (caudate-putamen, dorsal striatum; nucleus accumbens, ventral striatum) and in striatal projection regions (the pallidum, the entopeduncular nucleus and substantia nigra reticulata) use gamma-aminobutyric acid (GABA) as transmitter and express glutamic acid decarboxylase (GAD; rate limiting enzyme) in the synthesis of GABA. GABA is the major inhibitory transmitter in the mammalian brain. 2. GAD in brain is present as two isoenzymes, GAD65 and GAD67. GAD65 is largely present as an inactive apoenzyme, which can be induced by nerve activity, while most GAD67 is present as a pyridoxal phosphate-bound permanently active holoenzyme. Thus GAD65 and GAD67 seem to provide a dual system for the control of neuronal GABA synthesis. 3. GAD mRNA expression can be visualised and quantified using in situ hybridisation, and GABA release can be quantified using in vivo microdialysis. 4. Different populations of GABA neurons can be distinguished in both dorsal and ventral striatum as well as in other parts of the basal ganglia. 5. Inhibition of dopaminergic transmission in the striatum by lesion of dopamine neurons or by neuroleptic treatment is followed by an increased release of GABA and increased expression of GAD67 mRNA in a subpopulation of striatal medium-sized neurons which project to the globus pallidus, and increased striatal GAD enzyme activity. 6. Increased dopaminergic transmission by repeated but not single doses of amphetamine is followed by decreased striatal GABA release and decreased GAD67 mRNA expression in a subpopulation of medium-sized neurons in the striatum. 7. Two populations of medium-sized GABA neurons in the striatum seem to be under tonic dopaminergic influence. The majority of these GABA neurons are under inhibitory influence, whereas a small number seem to be stimulated by dopamine. 8. Specific changes in activity in subpopulations of striatal GABA neurons probably mediate the dopamine-dependent hypokinetic syndrome seen in Parkinson's disease and following neuroleptic treatment.
 ...
PMID:Dopaminergic regulation of glutamic acid decarboxylase mRNA expression and GABA release in the striatum: a review. 827

To examine the effects of nigrostriatal denervation on the substantia nigra pars reticulata (SNpr), one of the main outputs of the basal ganglia, we used quantitative in situ hybridization to analyze the messenger RNA coding for Mr 67,000 glutamic acid decarboxylase (GAD67 mRNA) in the SNpr neurons from patients with Parkinson's disease (PD), monkeys rendered parkinsonian by 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), and their respective controls. In MPTP-intoxicated monkeys, the expression of GAD67 mRNA was increased in the SNpr neurons, and the increase was reversed by L-dopa treatment. There were no differences in the level of GAD67 mRNA between PD patients who had been treated with L-dopa and control subjects. Combined with the previously reported increased expression of GAD67 mRNA in the internal segment of the pallidum of MPTP-intoxicated monkeys, these data suggest that the gamma-aminobutyric acid (GABAergic) activity of the output system of the basal ganglia is globally increased by nigrostriatal denervation. We also analyzed the level of GAD67 mRNA expression in the superior colliculus, a structure that receives the inhibitory influence of the GABAergic neurons of the SNpr and that is involved in eye movement control. GAD67 mRNA expression was reduced in both MPTP-intoxicated monkeys, whether or not they received L-dopa therapy, and PD patients, compared to their respective controls. This decrease may result from the hyperactivity of the inhibitory nigrotectal pathway, but also from other influences since it was not corrected by L-dopa therapy. These changes may account for the slight ocular motor and visuospatial cognitive impairment occurring in PD, even after L-dopa therapy.
 ...
PMID:Consequences of nigrostriatal denervation on the gamma-aminobutyric acidic neurons of substantia nigra pars reticulata and superior colliculus in parkinsonian syndromes. 861 87

To examine the consequences of nigrostriatal denervation and L-dopa treatment on the basal ganglia output system, we analyzed, by quantitative in situ hybridization, the messenger RNA coding for glutamic acid decarboxylase (Mr 67,000) (GAD67 mRNA) in pallidal cells from patients with Parkinson's disease (PD), monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) receiving or not receiving L-dopa, and their respective control subjects. In MPTP-treated monkeys, the expression of GAD67 mRNA was increased in cells from the internal pallidum, and this effect was abolished by L-dopa treatment. There were no differences in the levels of GAD67 mRNA between patients with PD, who were all treated with L-dopa, and control subjects. These results indicate that the level of GAD67 mRNA is increased in the cells of the internal pallidum after nigrostriatal dopaminergic denervation and that this increase can be reversed by L-dopa therapy.
 ...
PMID:Consequence of nigrostriatal denervation and L-dopa therapy on the expression of glutamic acid decarboxylase messenger RNA in the pallidum. 871 82

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.
 ...
PMID:Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. 893 92


1 2 3 4 5 6 7 Next >>