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)

Dopamine appears to be of less importance in the regulation of psychomotor functions than was previously thought. A central dopaminergic-glutamatergic balance may be important for both akinetic motor disorders and psychosis. In Parkinson's disease glutamate antagonists may counteract central glutamatergic hyperactivity and may be of value as anti-parkinsonian drugs. An increase of dopaminergic activity and/or a reduction of glutamatergic activity may contribute to the development of paranoid hallucinatory psychosis in schizophrenic patients and of pharmacotoxic psychosis in Parkinson's disease. Because of possibly severe side-effects of glutamatergic antagonists and agonists in the treatment of akinesia and psychosis, the development of partial glutamate agonists/antagonists could be an alternative strategy capable of producing antipsychotic or anti-kinetic effects with only mild adverse reaction.
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PMID:Glutamatergic-dopaminergic balance in the brain. Its importance in motor disorders and schizophrenia. 135 Jan 97

Ultrastructural and biochemical properties of caudate nucleus (CN) biopsies in two patients with advanced Parkinson's disease (PD) were compared with three CN specimens removed during surgery for intracranial tumors. An additional two specimens from neurologically intact patients (59 and 86 years old) were removed during autopsy (performed 3 and 4 h post mortem, respectively) for electron microscopic studies. Dopamine levels in PD were reduced to less than 15% of control values. Both PD patients showed frequent dystrophic neurites and transsynaptic degeneration of neurons and neuritic processes. These changes were not found in CN from the four control individuals. Only a few dystrophic neurites were noticed in one 67-year-old control patient. The development of neuroaxonal dystrophy in CN is consistent with a dying-back process, probably accompanying abnormalities of axonal transport in PD. Transsynaptic degeneration of neurons in CN very likely represents a morphological marker of disease severity. The occurrence of this change may account for the poor clinical response of patients with advanced PD to intracerebral implantation of dopaminergic tissues.
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PMID:Caudate nucleus pathology in Parkinson's disease: ultrastructural and biochemical findings in biopsy material. 137 3

A hypothesis implicating dopamine in depression was proposed over 15 years ago (Randrup et al 1975). The identification of multiple new subtypes of dopamine receptors and evolving views regarding the function of the dopamine systems in the brain require a reexamination of this hypothesis. Results from studies in depression, Parkinson's disease, and animal models of depression suggest a deficiency of dopamine in depression. Dopamine precursors, dopamine agonists, and dopamine reuptake inhibitors show therapeutic efficacy in depression. Electroconvulsive therapy (ECT) and standard pharmacological antidepressants enhance dopamine function. Studies using receptor-specific drugs in clinical trials and neuroimaging studies are needed to further clarify the role of dopamine in depression.
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PMID:Role of the dopaminergic system in depression. 139 Dec 89

Two major pharmacological classes of dopamine receptors exist in the central nervous system. These receptors have been designated as D1 or D2 based upon their differing pharmacology and influence on the cyclic AMP second messenger system. Different genes for the D1 and D2 dopamine receptors have been isolated and are found to be expressed in high abundance. Within the neostriatum, however the cellular distribution of the dopamine receptors is equivocal. Dopamine receptors are the targets for drugs used to treat neurological dysfunctions such as Parkinson's disease and schizophrenia, and thus knowledge of their specific cellular location is important for devising future therapeutic manipulations. Using retrograde labeling methods combined with immunofluorescence of various receptor amino acid sequences, this study has examined the postsynaptic distribution of striatal D2 dopamine receptors. We have found that the D2 dopamine receptor can be visualized on a minimum of 60% of the neurons projecting from the neostriatum to the substantia nigra. However, some 65% of all D2 receptor positive cells are represented by other intrinsic neurons of this basal ganglia nucleus.
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PMID:D2 dopamine receptor localization on striatonigral neurons. 143 5

Dopamine-glutamate interactions contribute to normal striatal function and have been implicated in neurotoxicity at nigrostriatal dopamine (DA) terminals. The present study examined the striata of idiopathic Parkinson's disease (PD) patients and age-matched controls for regional differences in the DA transporter and binding to N-methyl-D-aspartate (NMDA) receptors. [3H]Mazindol labeling of the DA transporter was reduced by 70-80% in the caudate and putamen of PD patients, with reductions being more extensive dorsally than ventrally. In contrast, L-[3H]glutamate binding to NDMA-sensitive receptors was 20-40% higher in PD cases than in controls. These findings raise the possibility that modifications occur within corticostriatal glutamate synapses of PD patients, possibly as a consequence of reduced nigrostriatal DA activity.
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PMID:Elevated NMDA receptors in parkinsonian striatum. 148 68

Iron-induced oxidant stress has been implicated in the pathogenesis of Parkinson's disease. An increasing body of evidence now indicates that in Parkinson's disease the environment within the substantia nigra is conducive to the formation of cytotoxic free radicals and cell degeneration. Dopamine neurons may be particularly vulnerable because of the oxidative metabolism of dopamine and the potential of neuromelanin to promote the site-specific accumulation and reduction of iron. This hypothesis has attracted considerable attention because it opens the way for employing antioxidant strategies as possible neuroprotective treatment for Parkinson's disease. Although the concept is appealing, free radicals have not yet been proven to play a role in Parkinson's disease, and many important issues remain to be resolved before the oxidative hypothesis can ultimately be confirmed or refuted.
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PMID:An introduction to the free radical hypothesis in Parkinson's disease. 151 Mar 76

Male retired breeder C57/Bl and CD-1 mice were treated with either MPTP or its vehicle. At 7-10 days post-treatment, catecholamine concentrations within the olfactory bulbs (OB) and hypothalamus were determined. Norepinephrine concentrations within the OB were significantly decreased in MPTP-treated mice. These effects were more pronounced in the CD-1 (50% reduction) compared to the C57/Bl (20% reduction) strain. No effects of MPTP were observed on norepinephrine concentrations within the hypothalamus. Dopamine concentrations in the OB and hypothalamus did not differ between MPTP- and vehicle-treated mice in either strain. Overall, catecholamine concentrations within the OB, but not the hypothalamus, were significantly greater in C57/Bl compared to CD-1 mice. The reduction in OB norepinephrine concentration in the MPTP-treated animals may be related to the olfactory deficits which accompany Parkinson's disease.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reduces norepinephrine concentrations in the olfactory bulbs of male mice. 151 43

We measured metabolites of tyrosine and tryptophan (TRP) in the frontal cortex, putamen (PT), and pars compacta of the substantia nigra (SN) of control and Parkinson's disease (PD) brain tissues. Dopamine concentrations were significantly decreased in the PT and SN of PD tissue, regardless of L-dopa therapy. However, 3-O-methyldopa (3OMD) concentration showed a significant increase in each region of the PD group treated with L-dopa (PD[+]) as compared with both the control group and the PD group without L-dopa therapy (PD[-]). Therefore, 3OMD concentration appears to be a reliable marker of L-dopa therapy. Serotonin concentration was lower in each region of the PD groups than in the control group. Although the magnitude of decrease was greater in the PD(+) group, there was no statistical significance between the two PD groups. The same patterns of decrease were present in kynurenine (KYN) and kynurenic acid (KYA) concentrations, but the molar ratios of TRP to KYN and KYN to KYA were unchanged among three groups. In contrast, 3-hydroxykynurenine (3OHKY) concentration was increased in the PT PD(-) group and in three regions of the PD(+) group. Since the KYN pathway leads to formation of nicotinamide-adenine dinucleotide (NADH), the present results may be a further indication of a defect in NADH:ubiquinone oxidoreductase (complex I) in mitochondria in PD.
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PMID:Kynurenine pathway abnormalities in Parkinson's disease. 151 57

Dopamine is a neurotransmitter found in the retina. Delays in the visual evoked responses and abnormalities in contrast sensitivity occur in patients with Parkinson's disease. Improvement in the P100 has followed L-dopa therapy. Suspected abnormalities at the retinal level in Parkinson's disease are observed in reductions in photopic, scotopic, and pattern-derived electroretinograms. We studied 35 patients with Parkinson's disease and 26 controls of comparable age and visual acuities using visual evoked responses, color vision, and contrast sensitivity testing. Contrast sensitivity thresholds were significantly different at most frequencies tested, using both stationary and temporally modulated sinusoidal gratings. The total error score of the Farnsworth-Munsell 100 Hue Test revealed significant differences between the patients and controls. The contrast thresholds derived from certain spatial frequencies and the total error in color score were significantly related to the duration of disease. A stepwise discriminant analysis correctly identified 94% of the patients and 94% of the controls. The significant error in chromatic discrimination observed in Parkinson's disease patients may be due to altered intraretinal dopaminergic synaptic activity in these patients.
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PMID:Abnormalities in color vision and contrast sensitivity in Parkinson's disease. 156 48

Dopamine (DA) is a neurotransmitter which modulates the transfer of information along fast-conducting pathways at the level of two main nodal points: the ventral striatum, composed by limbic areas (nucleus accumbens, tuberculum olfactorium) and the dorsal striatum, composed by extrapyramidal nuclei (caudate-putamen). These two subdivisions of the enlarged basal ganglia, are provided with different functions; accordingly, limbic DA plays an active role in goal-oriented (motivated) behaviour; instead, extrapyramidal DA is essential for execution of learned motor programs and its impairment results in the symptoms of Parkinson's disease. Various centrally acting drugs are able to interfere with DA transmission or with other neurotransmitter systems which interact with DA. Drugs of abuse owe their incentive properties to a preferential stimulation of DA transmission at the level of the limbic dopaminergic areas. On the other hand, drugs able to block glutamatergic transmission on NMDA receptors are able to selectively potentiate the action of DA at the level of a specific type of DA-receptors, the D-1 type. Knowledge of the role of DA in the brain can provide the basis not only for understanding the mechanism of drug action but also for developing new strategies for the treatment of drug abuse and extrapyramidal disorders.
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PMID:Functions of dopamine in the extrapyramidal and limbic systems. Clues for the mechanism of drug actions. 158 94


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