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)

Benzodiazepine receptors have been characterized in human brain. They have been localized mainly in the cerebral cortex and a synaptosomal enrichment was observed after brain fractionation by differential centrifugation. Benzodiazepine receptors were studied in Parkinson's disease and in progressive supranuclear palsy (PSP). In both diseases, the [3H]flunitrazepam specific binding was unchanged when compared to control groups (Bmax and KD values) except in the caudate nucleus of parkinsonian patients where an increase of the specific binding was observed. The subcellular distribution profile of benzodiazepine receptors in Parkinson's disease was similar to that of controls. gamma-Aminobutyric acid (GABA) still enhanced the [3H]flunitrazepam-specific binding (increase of binding affinity), indicating that the functional link between GABA and benzodiazepine receptors remained intact in Parkinson's disease. The present results suggest that benzodiazepine receptors in human striatum are localized on neuronal elements which do not degenerate in Parkinson's disease and PSP.
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PMID:Benzodiazepine receptors in normal human brain, in Parkinson's disease and in progressive supranuclear palsy. 283 33

Parkinson's disease is characterized especially by a degeneration of pigmented brain regions, like substantia nigra. These changes are accompanied by a variety of biochemical disturbances of dopaminergic and noradrenergic systems. Also the reduction of serotonin can be related to degenerative processes occurring in subareas of the raphe. Furthermore amino acid transmitters like GABA and a variety of peptidergic neuromodulators are changed. Additional cholinergic hypofunction due to degeneration of the nucleus basalis Meynert is able to impair the quality of life due to loss of intellectual capacity. A variety of biochemical mechanisms compensate for a long time the progression of neuronal loss. Modern treatment strategies (combined L-dopa therapy, dopaminergic agonists, MAO-B inhibitors, amantadine) are able to substitute the deficiency especially of the catecholamines. For the development of more causal therapies, a new animal model has been developed 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism after peripheral administration and leads to denervation of the dopaminergic nigrostriatal system. It is the hope that this new model, which is described here in detail, will lead to decisive data underlying the cause of Parkinson's disease.
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PMID:[Neurobiologic and pharmacologic studies on the pathogenesis of Parkinson disease]. 287 40

Guided and reflex eye movements were studied in cats trained to make orienting saccades toward visual and auditory targets. Injections of a GABA-agonist (Muscimol) or GABA-antagonists (Bicuculline and Picrotoxin) were made in the Substantia Nigra pars reticulata (SNpr). Bicuculline and Picrotoxin, whether unilaterally or bilaterally injected had no effect on the posture nor the oculomotor performance of the animals. Neck muscle activity remained symmetrical. Unilateral injections of Muscimol produced oro-facial akinesia, reduction of the number of eye movements, contralateral head turning, visual neglect mostly (but not only) for ipsilateral visual space. Balance between the gains of the vestibulo-ocular reflex (VOR) in the two directions of movement was changed. Gain was decreased for the ipsilateral rotation. The optokinetic nystagmus (OKN) was not affected. Contralateral neck muscles were hypertonic. After bilateral injections of Muscimol, the cats did not orient. The VOR was normal when the injections induced no postural asymmetry. Hypertony was bilateral. Implications of these results for the role of the basal ganglia in motor control are discussed. We suggest that in Parkinson's disease the fixed inhibitory drive of the SNpr on the tectum and on the thalamus is disrupted.
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PMID:Role of the cat substantia nigra pars reticulata in eye and head movements. II. Effects of local pharmacological injections. 298 33

From the data discussed in this review it appears that GABA receptor agonists exhibit a variety of actions in the central nervous system, some of which are therapeutically useful (Table V). GABA receptor agonists, by changing the firing rate of the corresponding neurons accelerate noradrenaline turnover without changes in postsynaptic receptor density and diminish serotonin liberation with an up-regulation of 5HT2 receptors. These effects differ from those of tricyclic antidepressants which primarily block monoamine re-uptake and cause down-regulation of beta-adrenergic and 5HT2 receptors. The GABA receptor agonist progabide has been shown to exert an antidepressant action which is indistinguishable from that of imipramine in patients with major affective disorders. The fact that: (a) GABA receptor agonists and tricyclic antidepressants affect noradrenergic and serotonergic transmission differently; and (b) tricyclic antidepressants alter GABA-related parameters challenges the classical monoamine hypothesis of depression and suggests that GABA-mediated mechanisms play a role in mood disorders. Decreases in cellular excitability produced by GABAergic stimulation leads to control of seizures in practically all animal models of epilepsy. GABA receptor agonists have a wide spectrum as they antagonize not only seizures which are dependent on decreased GABA synaptic activity but also convulsant states which are apparently independent of alterations in GABA-mediated events. These results in animals are confirmed in a wide range of human epileptic syndromes. GABA receptor agonists decrease dopamine turnover in the basal ganglia and antagonize neuroleptic-induced increase in dopamine release. On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics. Behaviorally, GABA receptor agonists diminish the stereotypies induced by apomorphine or L-DOPA suggesting that GABAergic stimulation results also in an antidopaminergic action which is exerted beyond the dopamine synapse. These effects of GABA receptor agonists may represent the basis of the antidyskinetic action of these compounds which, however, remains to be fully confirmed. GABA receptor agonists reduce striatal acetylcholine turnover, an effect which occurs at doses much lower than those which affect dopamine neurons. Since hyperactivity of cholinergic neurons plays a determinant role in the pathogenesis of some parkinsonian symptoms, it is conceivable that GABAergic stimulation is effective in ameliorating Parkinson's disease.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:GABA receptor agonists: pharmacological spectrum and therapeutic actions. 298 90

Recent morphologic and functional techniques for the study of nerve cells, such as intracellular injection and neurotransmitter immunohistochemistry, allow a new approach to the functional architecture of the retinal circuitry. Two types of dopaminergic cells are described: amacrine cells and interplexiform cells. These latter cells, which send processes to both the inner and outer plexiform layers, form a feedback loop acting at the level of horizontal cell coupling. Two molecules localized in such cells, dopamine and GABA, have antagonistic effects on horizontal cell coupling and regulate the diameter of their receptive fields which code for contrast. Changes in the ERG, VEPs and contrast sensitivity occur in Parkinsonian patients and are identical to those observed in animal models whose dopaminergic retinal system has been destroyed, thus suggesting a degenerative process of this system in Parkinson's disease. The observation of dopamine neurons, labelled by their tyrosine hydroxylase immunoreactivity, in the retina of 5 patients, led to the observation of reduced dopamine innervation in the central retina of Parkinsonian patients.
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PMID:Functional neuroarchitecture of the retina: hypothesis on the dysfunction of retinal dopaminergic circuitry in Parkinson's disease. 313 18

The alteration of amino acids in cerebrospinal fluids (CSF) from 14 cases of Parkinson's disease, five cases of cerebellar degeneration and five cases of headache (control) was studied using high performance liquid chromatography. In patients with Parkinson's disease, it was found that the CSF level of GABA showed a significant decrease, while that of taurine had an increase. The degree of disability in Parkinson's disease and the decreased GABA levels had a positive correlation, especially at its advanced stages. In patients with cerebellar degeneration, it was also found that there was a significant decrease in CSF GABA. The present results suggest that the CSF level of GABA may be a good indicator of the severity of Parkinson's disease as well as the presence of cerebellar degeneration. Possible involvement of the increase of CSF taurine in the pathogenesis of Parkinson's disease is also suggested.
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PMID:Alteration of amino acids in cerebrospinal fluid from patients with Parkinson's disease and spinocerebellar degeneration. 370 20

Parkinson's disease is characterized by a deficiency of dopamine in the nigrostriatal system. However, changes in dopamine neurons were found also outside the extrapyramidal system, showing that there is a more general brain defect than just the loss of substantia nigra dopamine neurons. With regard to the behavior of striatal D-2 receptors it was possible to divide parkinsonian patients into two subgroups, because either a decrease or an increase in the number of D-2 receptors was found. Clinically, the patients with a decreased number of striatal D-2 receptors were more disabled and had lost the beneficial response to levodopa. D-3 receptor binding sites were decreased in the parkinsonian striatum. Changes in the cholinergic-muscarinic receptors in the striatum seem to be related to changes in D-2 receptors, and muscarinic receptor supersensitivity was found in cortical areas. GABA receptor binding was decreased in the substantia nigra. In the parkinsonian brain there seems to be supersensitivity of a population of enkephalin receptors (delta) in the striatum and in the limbic system and also a loss of others (mu) in the striatum. Furthermore, the Met-enkephalin content was decreased in the parkinsonian substantia nigra. A decreased concentration of substance P was found in the substantia nigra of all parkinsonian patients and in the putamen of those patients who had not received levodopa treatment. The somatostatin level was decreased in the frontal cortex in relation to dementia. There are thus multiple neuronal disturbances in the parkinsonian brain, although those of the nigrostriatal dopamine neurons seem to be the greatest and are more closely related to parkinsonian clinical features and to treatment responses.
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PMID:Brain neurotransmitters and neuropeptides in Parkinson's disease. 609 88

Professor Johnston has alluded earlier in this volume to the complexity of the GABA-activated systems. Although considerably less well understood, it is probable that the glutamate-aspartate receptors will prove to be as complicated and as diverse as those activated by GABA, and as quantitatively important. Given these indications, their involvement in the etiology of Parkinson's disease and other neurological disorders is eminently probable.
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PMID:Excitatory amino acid receptors. 611 78

From binding studies using 3H-GABA and 3H-strychnine in dissected human brain material, inhibitory amino acid neurotransmitter receptors have a widespread distribution in the human CNS. Generally GABA receptors are predominant in the forebrain and upper brainstem whereas glycine receptors are more localized in the lower brainstem and spinal cord. Some areas (eg. the substantia nigra) have appreciable quantities of both receptors. Although glycine receptors are altered in some pathological conditions (eg. in Parkinson's disease, in the substantia nigra) the neuropharmacology of the glycine system is still poorly understood. On the other hand the GABA system has been intensively studied. Dysfunction of GABA receptors occurs in various neurological states, as epilepsy, Parkinson's disease and Huntington's chorea. Furthermore GABA agonists are active in animal models for dyskinesia, epilepsy and depression, amongst others. Clinical studies with progabide confirm these findings in animal models, and suggest that low-medium affinity GABA agonists are more appropriate clinical agents than are high or very high affinity GABA agonists. From these and many other findings there appears to be a very large potential for creating new pharmacological agents for different neuropsychiatric disorders based on agonist activity at inhibitory amino-acid receptors. From the example of progabide these compounds can be made not only specific for the receptor involved, but also to have a lower incidence of neurotoxic effects than presently available drugs.
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PMID:Neurochemical and neuropharmacological indications for the involvement of GABA and glycine receptors in neuropsychiatric disorders. 613 47

The literature is reviewed on the afferents and efferents of the caudate/putamen, globus pallidus and substantia nigra, and on the neurotransmitters occurring in the various tracts. Emphasis is placed upon the diverse roles played by GABA and glutamate as transmitters in motor pathways and upon the probability that the substantia nigra pars reticulata plays a pivotal role in the output of the basal ganglia. Excessive stimulation of the projection from the pedunculopontine tegmental area to the substantia nigra is shown to cause destruction of dopaminergic neurons in the latter nucleus, suggesting another possible mechanism for cell death in Parkinson's disease.
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PMID:Neurotransmitters in the basal ganglia. 614 12


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