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)

Employing primary cultures of astrocytes which seem to constitute a valid model of their in vivo counterparts, it has been demonstrated that this cell type is likely to be of importance in terminating the transmitter activity of GABA. It has been shown that the transport carrier in astrocytes is stereospecific for the C-4 hydrogens of the GABA molecule and that its structural requirements are distinct from those exhibited by the neuronal GABA carrier. beta-Proline was a selective inhibitor of GABA transport in astrocytes, whereas R-trans-4-methyl-4-aminocrotonic acid and S-nipecotic acid seemed to be selective inhibitors of neuronal GABA transport, as studied using very thin slices ("prisms") of brain cortex. These findings may be important for studies on the relative significance of the two transport systems in GABA-mediated neurotransmission, and thus for future pharmacological manipulations of the GABA system. This may eventually be beneficial for the treatment of neurological disorders such as epilepsy, Huntington's chorea and Parkinson's disease in which the GABA system seems to be disturbed (34,60,62).
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PMID:Effects of GABA-analogues on the high-affinity uptake of GABA in astrocytes in primary cultures. 4 81

Cerebrospinal fluid gamma-aminobutyric acid (CSF GABA) was analyzed in 151 patients who underwent evaluation for central nervous system disease. CSF GABA was not detected in 19 of these patients, who had no evidence of neurologic disease and who served as controls. GABA was most frequently detected in patients with cerebrovascular disease, and was detected only in Parkinson's syndrome of atherosclerotic origin and dementia of multi-infarct type. CSF GABA was not detected in Alzheimer's disease or Huntington's disease. Patients with grand mal seizures exhibited CSF GABA elevation within 24 hours of the ictus. In patients with multiple sclerosis GABA detection was related to the presence or exacerbation of spinal cord lesions. Further study is necessary to evaluate the significance of elevated CSF GABA in central nervous system disease.
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PMID:Cerebrospinal fluid gamma-aminobutyric acid in neurologic disease. 13 99

Huntington's chorea is a dominantly inherited disorder that usually leads to involuntary movements in the third or fourth decade. On gross pathological examination of the post-mortem brain there is a marked atrophy of the caudate nucleus and putamen. Histological examination reveals cell loss in most regions of the brain, although the hippocampus is usually remarkably free of any abnormalities. Studies to detect a biochemical defect in patients with chorea have been largely unrewarding. Since chorea appears to be the clinical counterpart of Parkinson's disease a number of investigations on dopamine metabolism have been carried out by measuring dopamine in the post-mortem choreic brain, and HVA, a metabolite of dopamine, in the CSF of patients. Most studies have found the dopamine concentrations to be normal or sometimes decreased and the activity of the biosynthetic enzyme for dopamine, tyrosine hydroxylase, is normal. The discovery that the inhibitory neurotransmitter, GABA, and the biosynthetic enzyme GAD are greatly decreased in the post-mortem choreic brain provides some rational explanation for the uncontrolled movements in this disorder. The other significant abnormality found in many, but not all, choreic post-mortem brains has been a decrease in the biosynthetic enzyme for acetylcholine, choline acetyl transferase. The evidence that GABA receptors are intact in choreic brain provides an added stimulus for the development of useful GABA-mimetic drugs. For the ultimate eradication of this distressing disorder, however, a search must continue for the primary defect in order that this can be detected before the onset of symptoms, or hopefully in amniotic fluid.
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PMID:Neurochemical findings in Huntington's chorea. 15 97

With respect to [3H]GABA-binding in material prepared from human post-mortem brain, the following observations have been made: (1) The [3H]GABA binding site in the cerebellum has the pharmacological characteristics of the physiological GABA-receptor observed in other species. Together with the post-mortem stability exhibited for [3H]GABA-binding, this provides an approach for determining the functional state of the GABA-receptor in various disease states; (2) In Parkinson's disease [3H]GABA-binding in the substantia nigra is significantly decreased whereas that in the putamen and caudate nucleus is unaltered. The former finding likely indicates that GABA binding sites (receptors) occur on nigral dopaminergic cell bodies and/or dendrites. The latter finding may signify that relatively few of the striatal [3H]GABA binding sites occur on dopaminergic nerve terminals in the human caudate or putamen; (3) In Huntington's disease [3H]GABA binding was decreased in the caudate nucleus and putamen, in parallel wih the massive cell loss and gliosis observed in this condition. Membranes prepared from cerebellar tissue of these patients possessed an increased affinity for [3H]GABA-binding; (4) Pre-treatment of cerebellar membranes from control brains with Triton-X-100 (0.02%) or phospholipase-C (0.001 units) results in kinetic changes very similar to those observed in Huntington's brains. In contrast, such treatment was virtually without effect on the IC50 or KD for [3H]GABA on cerebellar membranes prepared from Huntington's brains; (5) These results imply that a phospholipid, possibly related to phosphoglycerolethanolamine, is altered in the membrranes of Huntington's patients and that this phospholipid normally has a role in controlling accessibility to the GABA-receptor.
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PMID:Sodium-independent, high-affinity binding of [3H]gamma-aminobutyric acid in human neurological disorders. 16 Jan 92

Because there is biochemical evidence of decreased GABAergic function in Parkinson's disease, sodium valproate, an inhibitor of GABA catabolism, was administered to eight Parkinsonian patients. Valproate treatment did not significantly alter any Parkinsonian feature, but tended to increase the dyskinesia in the "on-off" patients. The increased dyskinesias were not a result of altered peripheral metabolism of L-dopa. Despite obtaining high plasma levels of valproate, no consistent alteration of CSF GABA levels could be demonstrated. Thus, in these patients, an effect of valproate on GABA metabolism is unproven, and in turn, the role of GABA in Parkinsonism and dyskinesia uncertain.
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PMID:Treatment of Parkinson's disease with sodium valproate: clinical, pharmacological, and biochemical observations. 38 31

The Authors, after giving some theoretical and pharmacodynamic opinions on GABA, report their clinical experience for 18 consecutive years with the use of gamma-aminobutyric acid in cases of central comas, psycho-organic post-operative syndromes, Parkinson's Disease. The drug, in the various above listed pathologies, shows respectively a wakening effect, with actual rising of the level of consciousness, a re-equilibrating action towards psycho-organic involutions, especially acute ones, and a considerable antiakinetic activity. After analyzing the original results obtained, considered especially in the light of the most modern researches on the importance of GABA-ergic mediation on the basal ganglia, some interesting neurofunctional hypotheses are put forward, which are connected with the problem of nervous conduction in human pathology. According to said hypotheses the aminoacid works clinically, owing to its role of inhibiting mediator (rather than of oxidable substrata), and is involved in extrapyramidal nigro-striatal lesions.
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PMID:Usefulness of gamma-aminobutyric acid (GABA) therapy in pathologies of neurosurgical competence. 52 1

The author analyzes parkinsonism and hyperkinesia in psychiatric patients with tardive dyskinesia before and during treatment with alpha-methyl-p-tyrosine (AMPT, a dopamine antagonist), biperiden (an acetylcholine antagonist), and baclofen (a GABA agonist); and in patients with paralysis agitans and L-dopa-induced hyperkinesia. AMPT and baclofen had similar influences on oral dyskinesia, resulting in reduced frequency, unchanged or slightly reduced amplitude, and increased duration of each movement. The author concludes that: 1) reduced dopaminergic activity may be the primary pathogenetic background for tardive dyskinesia; 2) dopaminergic hypersensitivity and/or cholinergic hypofunction is necessary before hyperkinesia breaks through; and 3) the neurotoxic effects of neuroleptics may be associated with age-dependent changes in nigrostriatal regions representing oral innervation.
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PMID:The relationship between parkinsonism and tardive dyskinesia. 86 56

Postmortem studies in brains from parkinsonian patients consistently reveal a minimum loss of 75% of the nigrostriatal dopamine neurons. This indicates that over a prolonged period, before Parkinson's disease is clinically evident, there is a physiological compensation for the slow loss of dopamine neurons (i.e. compensated stage of Parkinson's disease). Only when the dopamine neuron loss is sufficiently severe (greater than 75% of nigrostriatal dopamine neurons) does the disease become clinically evident (decompensated state). Postmortem examination of Parkinson's disease brains and study of animal models indicate that the following mechanisms may contribute to this CNS compensation: 1) A decrease in striatal cholinergic activity, in an attempt to maintain a critical DA:ACh balance; and 2) A decrease in activity of GABA neurons in the striatum and substantia nigra, resulting in an increased firing rate of nigral dopamine cells. These mechanisms allow the brain to readjust to the initial dopamine cell loss in Parkinson's disease.
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PMID:CNS compensation to dopamine neuron loss in Parkinson's disease. 93 Jul 46

Dystonia refers to involuntary, prolonged muscle contractions leading to sustained, often twisting, postures. High dose anticholinergic therapy for childhood onset dystonia, botulinum toxin injections for focal dystonia, and levodopa for diurnal dystonia provide symptomatic relief for some patients. Despite this, treatment of both idiopathic and secondary dystonia remains inadequate for many patients. Baclofen, a pre-synaptic acting GABA agonist, has been reported to benefit dystonia in a number of retrospective studies. Dramatic improvement in symptoms, especially in gait, was found in almost 30% of 31 children and adolescents with idiopathic dystonia in one retrospective study using doses ranging from 40 to 180 mg daily. The response to baclofen of adults with focal dystonia is less dramatic. One series of 60 adults with cranial dystonia found sustained benefit in 18%. Smaller series have not consistently found significant benefit in adults. Baclofen has been used to treat several secondary dystonias: tardive dystonia has occasionally been reported to improve and there are isolated reports of improvement in dystonia occurring in Parkinson's disease and in glutaric aciduria.
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PMID:Baclofen in the treatment of dystonia. 151 73

Early case reports note marked improvements in the signs of Parkinson's disease (PD) in several patients with coexisting psychiatric disorders after treatment with electroconvulsive therapy (ECT). Studies since 1959 reveal improvement of parkinsonism in over half of PD patients receiving ECT, regardless of the presence or absence of psychiatric comorbidity. Drug-induced parkinsonism, tardive dystonia, and tardive dyskinesia have also been shown to improve with ECT administration; tic syndromes have achieved mixed results. In animals, ECT enhances dopamine-mediated effects and increases GABA concentrations in the CNS. Optimal parameters relevant to the antiparkinsonism effects of ECT require further study.
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PMID:Electroconvulsive therapy in Parkinson's disease and other movement disorders. 175 47


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