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)

In order to evaluate whether the stimulating effect of GABA on growth hormone (GH) secretion changes in patients affected by Parkinson's disease, ten male parkinsonian patients and ten age matched normal controls were tested with the GABA derivative and GABAergic agent Baclofen (10 mg in a single oral administration at 09.00 h) (experimental test). In a different occasion, normal men and parkinsonian patients were tested with a placebo (control test). Basal GH levels were similar in normal controls and parkinsonian patients and remained unmodified during the control test. Plasma GH levels rose three times within 120 min after the administration of baclofen in the normal subjects. In contrast, plasma GH concentrations remained unmodified after baclofen treatment in the parkinsonian patients. In agreement with previous reports in the literature showing alterations of GABAergic neurotransmission in the parkinsonian brain, these data show a reduced GABAergic control of GH secretion in patients with Parkinson's disease.
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PMID:Failure of the gamma-aminobutyric acid (GABA) derivative, baclofen, to stimulate growth hormone secretion in Parkinson's disease. 177 78

The size of neurons in the pars reticulata of the substantia nigra in patients dying with Parkinson's disease has been compared with that in non-parkinsonian control cases. Parkinson's disease is accompanied by a significant (+53%) hypertrophy of reticulata neurons. This is similar to changes seen in experimental rats with ipsilateral damage of the striatum. It is suggested that the enlargement seen in Parkinson's disease, similar to that in the rat, is indicative of plasticity in the GABA-ergic reticulata neurons, and may be associated with increased inhibitory flux in pathways arising from the pars reticulata to the superior colliculus and thalamus.
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PMID:Neuronal hypertrophy in the pars reticulata of the substantia nigra in Parkinson's disease. 189 Oct 64

Toxicity of 6-hydroxydopamine (6-OHDA) and dopamine were studied in cultures of dissociated fetal rat mesencephalic cells. To assess survival and function of dopaminergic cells we quantified the number of tyrosine hydroxylase-positive cells and measured dopamine uptake. Non-dopaminergic cells were monitored by counting the number of cells visible with phase-contrast microscopy and measuring GABA uptake. 6-OHDA, in contrast to MPP+, which selectively destroyed dopaminergic neurons, was found to be a non-selective neurotoxin in this culture system. Between 10 and 100 microM, dopaminergic and non-dopaminergic cells were destroyed. At concentrations higher than 100 microM, i.e., concentrations frequently used to lesion catecholaminergic neurons in vivo, 6-OHDA resulted in structural fixation and loss of viability of dopaminergic and non-dopaminergic cells. Dopamine produced the same actions at slightly higher concentrations. One hundred to 300 microM was toxic for all cell types, and concentrations above 300 microM resulted in fixation. The findings suggest that 6-OHDA cannot be considered a selective toxin for catecholaminergic neurons in vitro. The demonstrated toxicity of dopamine tends to support speculations that processes related to dopamine metabolism may play a role in the pathogenesis of Parkinson's disease.
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PMID:Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture. 197 25

Drug-induced Parkinsonism is a common serious side-effect of neuroleptic therapy. In cases of irreversible drug-induced Parkinsonism, pharmacological management is notoriously difficult. A schizophrenic patient with severe neuroleptic-induced Parkinsonism and Tardive Dyskinesia is presented in whom administration of pyridoxine (vitamin B6) (100 mg/d) resulted in dramatic and persistent attenuation of the movement disorders as well as reduction of psychotic behavior. Since pyridoxine deficiency is associated with marked reduction of cerebral serotonin concentrations and pineal melatonin production in rats, the effects of pyridoxine on the movement disorder and psychosis may have been mediated largely by enhancing serotonin and melatonin functions. An additional effect of excess pyridoxine administration on GABA and dopamine activity cannot be excluded. Pyridoxine has been reported to attenuate the severity of levodopa-induced dyskinesias in patients with Parkinson's disease and it is suggested that pyridoxine supplementation should be considered in psychiatric patients with drug-induced movement disorders including persistent Parkinsonism. An underlying pyridoxine deficiency in these patients may exacerbate the psychotic behavior and additionally, potentially increase the risk of drug-induced movement disorders.
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PMID:Pyridoxine improves drug-induced parkinsonism and psychosis in a schizophrenic patient. 226 9

The GABA/benzodiazepine receptor complex in the basal ganglia of primates treated with the neurotoxin n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied by semi-quantitative autoradiography with [3H]flunitrazepam ([3H]FNZ). Systemic treatment with MPTP produced a stable and lasting parkinsonian condition, with pronounced bradykinesia, akinesia and tremor. In the lateral segment of the globus pallidus (GPL) there was a significant reduction of [3H]FNZ binding compared with non-treated animals. There were no significant changes in the [3H]FNZ binding in the caudate nucleus, putamen and medial globus pallidus (GPM). This suggests that MPTP-treatment increases GABA release within the GPL exclusively. In view of the available evidence suggesting increased striatal output, and reduced unit activity within the GPL of the MPTP-treated primate, it seems likely that the striatal GABAergic output to the GPL is overactive in this model of Parkinson's disease. Furthermore, as there is no evidence for a change in GABA function within the GPM using this measure, the striatal neurones which innervate the GPM may be differentially affected by loss of dopamine innervation. In line with structural evidence and extrastriatal dopamine receptor distribution this suggests that the two striatopallidal systems are functionally heterogeneous. A hemi-parkinsonian primate model has also been used in this study. This model was produced by injection of MPTP directly into one carotid artery. The substantia nigra pars compacta (SNc) was destroyed on the injected side alone, and consequently the appearance of parkinsonian symptoms was confined to the contralateral side. [3H]FNZ binding in the GPL appears to be bilaterally reduced in this model, suggesting an interaction between the treated and non-treated side of the brain. In addition there is increased binding in the putamen and GPM with respect to the non-treated side of the brain. The increased [3H]FNZ binding in the GPM of the unilateral model may be due to the greater disruption of the nigropallidal and/or nigrostiatal dopamine neurones relative to the systemic model. The former would have the effect of uncoupling D1 dopamine receptors located on the terminals of striatal efferents from nigropallidal dopamine input, and as D1 dopamine receptors are implicated in the presynaptic control of GABA release from the terminals of striatal efferents, this would consequently reduce the level of GABA release in the GPM. The latter possibility would suggest that striatopallidal neurones projecting to GPM are more resistant to the effects of dopaminergic denervation than those projecting to GPL.
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PMID:The role of striatopallidal neurones utilizing gamma-aminobutyric acid in the pathophysiology of MPTP-induced parkinsonism in the primate: evidence from [3H]flunitrazepam autoradiography. 228 39

Microdialysis in the human brain has been performed for the first time during thalamotomy intended to relieve tremor in patients with Parkinson's disease. The aim was to test the reliability of the microdialysis technique for biochemical characterization of a target area in the human brain during a routine operation. Microdialysis probes were introduced through the same trajectory as the lesioning electrode thus causing no additional damage to the brain. Dopamine, DOPAC, HVA, 5-HIAA, hypoxanthine, inosine, guanosine, adenosine, GABA, taurine, aspartate and glutamate were measured in the perfusate from the target region - the Vim nucleus. The results show initial high levels that reach baseline levels after 10-20 minutes. Surprisingly, consistent and reproducible levels were found, the only exception being one patient on 1-DOPA therapy who had elevated DA and metabolite levels.
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PMID:Microdialysis in the human brain: extracellular measurements in the thalamus of parkinsonian patients. 230 73

The findings in this feline study indicate that the enkephalin-positive subcommissural part of the globus pallidus, which is known to contain GABA and cholinergic cells projecting to the cortex, is innervated by the anterodorsal region of the caudate nucleus, but not by the core. Like stimulation of a particular subclass of dopamine receptors in the anterodorsal region of the caudate nucleus, inhibition of the GABA receptors in the noted part of the globus pallidus resulted in orofacial dyskinesia, viz. tic-like contractions of the facial, eye and ear muscles, and tongue protrusions. This phenomenon was elicited by intrapallidal injections of the GABA antagonist picrotoxin in a dose-dependent manner and could be attenuated by the GABA agonist muscimol. Previous studies have already shown that neither stimulation of the dopamine receptors in the core of the caudate nucleus nor any manipulation with the first- and second-order output-stations of the latter brain region, viz. (a) those regions of the substantia nigra, pars reticulata which receive afferents from the caudate nucleus, and (b) those regions of the intermediate layers of the superior colliculus which receive afferents from the latter nigral region, ever resulted in orofacial dyskinesia. These findings support the hypothesis that the anatomically distinct input-output channels of the caudate nucleus are differentially involved in orofacial dyskinesia. The clinical impact of these findings is discussed in view of the L-3,4-dihydroxyphenylalanine-induced tardive dyskinesia in man. In addition, the relevance of the anatomical data is discussed in view of the co-occurrence of Parkinson's Disease and Dementia of Alzheimer-type in certain patients.
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PMID:Anatomically distinct output channels of the caudate nucleus and orofacial dyskinesia: critical role of the subcommissural part of the globus pallidus in oral dyskinesia. 256 20

1. NPY is a 36 amino acid tyrosine-rich peptide. It is one of the most abundant and widely distributed neuropeptides known today within the central nervous system with particularly high concentrations in the hypothalamus and in several limbic regions. 2. NPY seems to coexist with other on neurotransmitters like somatostatin, galanin, GABA and the catecholamines noradrenaline and adrenaline in discrete brain regions. 3. NPY binding sites are widely distributed in the brain. However they do not always overlap with the distribution of NPY-like immunoreactivity. 4. NPY is suggested to be involved in a large number of neuroendocrine functions, stress responses, circadian rhythms, central autonomic functions, eating and drinking behaviour, and sexual and motor behaviour. 5. Psychotropic drugs and neurotoxins can alter the NPY concentrations in discrete brain regions. 6. It is possible that NPY is related to various neurological and psychiatric illnesses, like Huntington's chorea, Alzheimer's disease, Parkinson's disease, eating disorders, and major depressive illness.
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PMID:Neuropeptide Y (NPY) and the central nervous system: distribution effects and possible relationship to neurological and psychiatric disorders. 266 85

In Parkinson's disease the progressive loss of nigrostriatal dopamine neurons leads to striatal dopamine deficiency and correlates with the severity of parkinsonian disability. The findings concerning dopamine receptors both in vitro and in vivo are not consistent, possibly reflecting differences in patient populations, but the presynaptic defect in dopaminergic neurotransmission is greater than that seen in postsynaptic receptor binding studies. The cholinergic neurons in the extrapyramidal nuclei are relatively well preserved, but subcortico-cortical and -hippocampal cholinergic neurons degenerate in relation to the degree of dementia. The decreased GABA receptor binding in the parkinsonian substantia nigra possibly reflects the loss of nigral dopamine neurons, since nigral GABA receptors are located on these neurons. Of the various neuropeptides, the concentration of met- and leu-enkephalin seems to be reduced in the striatum. In the substantia nigra the concentration of substance P decreases, together with the met-enkephalin and cholecystokinin levels. The concentration of somatostatin decreases in the frontal cortex and hippocampus of demented patients. With the exception of the association between cortical somatostatin deficiency and intellectual deterioration, the role of the neuropeptides in the pathophysiology and clinical features of Parkinson's disease are not yet fully understood.
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PMID:Chemical neurotransmission in the parkinsonian brain. 282 31

The study of neurotransmitter receptors aids in the understanding of the normal anatomy, pharmacology, therapeutics and pathophysiology of disease processes involving the basal ganglia. Receptors may be studied in vitro by homogenate binding experiments, enzyme analysis or quantitative autoradiography and in vivo with positron emission tomography. In the substantia nigra (SN), receptors have been identified for somatostatin, neurotensin, substance P, glycine, benzodiazepine and GABA, opiates, dopamine, angiotensin converting enzyme (ACE) and serotonin. The striatum has receptors for dopamine, GABA and benzodiazepines, acetylcholine, opiates, substance P, glutamate and cholecystokinin. GABA and benzodiazepine receptors are also located in the globus pallidus. In Parkinson's disease, striatal dopamine D-2 receptors are elevated in patients that have not received L-DOPA therapy. This supersensitivity is reversed with agonist therapy. Muscarinic binding to cholinergic receptors seems to correlate with dopamine receptors. Delta opiate receptors are increased in the caudate and mu binding is reduced in the striatum. In the SN of patients with Parkinson's disease, there is reduced binding of somatostatin, neurotensin, mu and kappa opiates, benzodiazepine and GABA and glycine. In Huntington's disease, there is reduced binding of GABA and benzodiazepines, dopamine, acetylcholine, glutamate and CCK. There is increased binding of GABA in both the SN and globus pallidus. Glycine binding is increased in the substantia nigra and ACE is reduced.
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PMID:Receptors in the basal ganglia. 282 9


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