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)

After administration of tyrosine, total concentration of biopterin, the cofactor for tyrosine hydroxylase, was increased in the striatum, adrenal glands, and serum of rats, and in the serum of humans. Serum biopterin is lower in patients with Parkinson's disease than in normal controls. After oral administration of tyrosine, the increase in serum biopterin concentration was smaller in patients with Parkinson's disease (less than twofold) than in healthy controls (three-to sevenfold). These results suggest that tyrosine may have a regulatory role in biopterin biosynthesis and that patients with Parkinson's disease may have some abnormality in the regulation of biopterin biosynthesis.
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PMID:Effects of tyrosine administration on serum biopterin in normal controls and patients with Parkinson's disease. 684 20

The release of 3H-dopamine (DA) continuously synthesized from 3H-tyrosine was measured in the caudate nucleus (CN) and in the substantia nigra (SN) in both sides of the brain during electrical stimulation of the superficial radial nerve in cats lightly anaesthetized with halothane. Use of appropriate electrophysiologically controlled stimulation led to selective activation of low threshold afferent fibers whereas high stimulation activated all cutaneous afferents. Results showed that low threshold fiber activation induced a decreased dopaminergic activity in CN contralateral to nerve stimulation and a concomitant increase in dopaminergic activity on the ipsilateral side. Stimulation of group I and threshold stimulation of group II afferent fibers induced changes in the release of 3H-DA mainly on the contralateral CN and SN and in the ipsilateral CH. High stimulation was followed by a general increase of the neurotransmitter release in the four structures. This shows that the nigro-striatal dopaminergic neurons are mainly--if not exclusively--controlled by cutaneous sensory inputs. This control, primarily inhibitory in the side contralateral to the stimulation, seems rather non-specific when high threshold cutaneous fibers are also activated. Such activations could contribute to reestablish sufficient release of DA when the dopaminergic function is impaired as in Parkinson's disease.
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PMID:Effect of superficial radial nerve stimulation on the activity of nigro-striatal dopaminergic neurons in the cat: role of cutaneous sensory input. 707 12

Tyrosine and tryptophan have been assayed spectrofluorometrically in postmortem human brain areas of patients with Parkinson's disease treated orally with or without 3,4-dihydroxyphenylalanine (L-dopa) plus the peripherally acting decarboxylase inhibitor benserazide. Tyrosine as well as tryptophan decrease significantly after treatment with L-dopa, thus showing a competitive action of L-dopa to other aromatic amino acids on human brain uptake. It is suggested that some of the side effects of L-dopa treatment in Parkinson's disease are due to a disturbance in the brain and neural uptake of other, specially aromatic and branched-chain amino acids. An influence of L-dopa administration on protein synthesis also cannot be excluded.
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PMID:L-dopa competes with tyrosine and tryptophan for human brain uptake. 721 1

Several studies suggest that nitric oxide (NO.) contributes to cell death following activation of NMDA receptors in cultured cortical, hippocampal, and striatal neurons. In the present study we investigated whether 7-nitroindazole (7-NI), a specific neuronal nitric oxide synthase inhibitor, can block dopaminergic neurotoxicity seen in mice after systemic administration of MPTP. 7-NI dose-dependently protected against MPTP-induced dopamine depletions using two different dosing regimens of MPTP that produced varying degrees of dopamine depletion. At 50 mg/kg of 7-NI there was almost complete protection in both paradigms. Similar effects were seen with MPTP-induced depletions of both homovanillic acid and 3,4-dihydroxyphenylacetic acid. 7-NI had no significant effect on dopamine transport in vitro and on monoamine oxidase B activity both in vitro and in vivo. One mechanism by which NO. is thought to mediate its toxicity is by interacting with superoxide radical to form peroxynitrite (ONOO-), which then may nitrate tyrosine residues. Consistent with this hypothesis, MPTP neurotoxicity in mice resulted in a significant increase in the concentration of 3-nitrotyrosine, which was attenuated by treatment with 7 NI. Our results suggest that NO. plays a role in MPTP neurotoxicity as well as novel therapeutic strategies for Parkinson's disease.
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PMID:Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. 753 Feb 97

The present study examined neurochemical, morphological and functional markers of the nigrostriatal dopamine system in young, intermediate-aged and old squirrel monkeys. Striking reductions in motoric activity were observed with advancing age. significant age-related loss of dopamine occurred in the substantia nigra (70%) and the putamen (30%) but not in the caudate. There was a strong correlation between the reductions in motoric activity and the loss of putamen dopamine. However, nigrostriatal dopamine loss did not appear to be the consequence of age-related loss of dopaminergic nigral neurons since the number of tyrosine immunoreactive cells was not significantly different among the three age groups. These results suggest that the aging squirrel monkey demonstrates the age-related loss of nigrostriatal dopamine thought to occur in humans and identify this non-human primate as a useful model to further investigate the underlying mechanism(s) and functional consequences of age-related decline of the nigrostriatal dopamine system. In addition, the selective loss of dopamine in the putamen but not the caudate parallels the regional vulnerability observed in Parkinson's disease, an age-related neurodegenerative disorder, raising the possibility of a relationship between normal aging and the development of this disease. Finally, because the number of tyrosine hydroxylase (TH) positive cells remains constant with age, these results raise the possibility that therapeutic strategies aimed at increasing dopamine concentrations may benefit elderly individuals.
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PMID:Aging and the nigrostriatal dopamine system: a non-human primate study. 753 Nov 6

Clinical studies suggest that gut disorders are common in Parkinson's disease, but the morphological basis is unknown. Depletion of dopamine-containing neurons in the central nervous system is a basic defect in Parkinson's disease. We compared colonic tissue from 11 patients with advanced Parkinson's disease, 17 with adenocarcinoma (normal tissue was studied), and five who underwent colectomy for severe constipation. Immunohistochemistry was used to stain myenteric and submucosal neurons for dopamine, tyrosine hydroxylase, and vasoactive intestinal polypeptide (VIP). Each class of neurons was quantified as a percentage of the total neuronal population stained for the marker protein gene product 9.5. Nine of the 11 Parkinson's disease patients had substantially fewer dopaminergic myenteric neurons than the other subjects (mean 0.4 [SE 0.2] vs 6.9 [2.3] in controls and 5.7 [2.0] in constipated subjects). There was very little difference between the groups in numbers of tyrosine-hydroxylase and VIP neurons. Two Parkinson's disease patients had similar distributions of all types of neurons, including dopaminergic myenteric neurons, to the controls. High-performance liquid chromatography showed lower levels of dopamine in the muscularis externa (but not mucosa) in four Parkinson's disease patients than in four controls (7.3 [5.1] vs 24.2 [4.6] nmol per g protein), but levels of dopamine metabolites were similar in the two groups. The identification of this defect of dopaminergic neurons in the enteric nervous system in Parkinson's disease may lead to better treatment of colorectal dysfunction in this disease.
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PMID:Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation. 756 69

Positron tomography, using [18F]6-fluoro-L-dopa as a tracer, has been used for the study of Parkinson's disease. Unfortunately, the analysis of data obtained with this agent is bedeviled because it readily forms labeled methylated metabolites that enter the brain. We have evaluated [18F]6-fluoro-L-m-tyrosine (FmT) as an alternative tracer to study intracerebral dopamine metabolism with positron tomography. Imaging studies in humans showed specific accumulation of this tracer in the dopamine-rich striatal regions. Reduced striatal uptake of the tracer was demonstrated in a patient suffering from Parkinson's disease. Increased retention of the tracer was demonstrated in a subject pretreated with the peripheral decarboxylase inhibitor carbidopa. Analysis of plasma samples for labeled metabolites of FmT revealed no methylated metabolites. Results of compartmental analysis showed that a two-compartment three rate constant model described adequately the time course of radioactivity in the striatum after an injection of FmT. The FmT decarboxylation rate constant (k21) was found to be 0.0108 min-1. Because the peripheral metabolism of FmT is simpler than that of [18F]6-fluoro-L-dopa, we propose FmT as a superior agent with which to study intracerebral dopamine metabolism in health and disease in humans.
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PMID:A probe for intracerebral aromatic amino-acid decarboxylase activity: distribution and kinetics of [18F]6-fluoro-L-m-tyrosine in the human brain. 765 47

MK-801, a non-competitive antagonist of NMDA receptors, is known to exhibit a beneficial action in many animal models of Parkinson's disease. The aim of this study was to examine the influence of MK-801 on the reserpine-induced muscle rigidity. The rigidity was estimated by a direct mechanomyographic method. This method consists in successive bending and straightening of a rat's hind foot in the ankle joint and measuring the resistance of the foot to passive movements. Reserpine in doses of 5-10 mg/kg ip, given alone or in combination with alpha-methyl-p-tyrosine (alpha MT, 250 mg/kg ip), induced rigidity. The strongest muscle rigidity was induced by 10 mg/kg of reserpine 1 hour after administration. MK-801 (0.32-1.28 mg/kg sc) injected 70 min after reserpine (10 mg/kg ip) decreased the rigidity induced by the latter compound. Similarly, MK-801 (1.28 mg/kg sc), administered 27 h 40' after joint treatment with reserpine (10 mg/kg ip) and alpha MT (250 mg/kg ip), strongly inhibited the reserpine-induced muscle rigidity. The obtained results show that the glutamatergic hyperactivity plays a significant role in the reserpine-induced rigidity. As the reserpine-induced motor disturbances are commonly accepted to be an animal model of parkinsonian symptoms, it may be assumed that the NMDA receptor blocking component may contribute substantially to the therapeutic action of antiparkinsonian drugs.
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PMID:Antiparkinsonian action of MK-801 on the reserpine-induced rigidity: a mechanomyographic analysis. 771 Jun 66

Some treatments used for Parkinson's disease attenuate locomotor depression in rats treated with reserpine and alpha-methyl-p-tyrosine. In the present study memantine (2.5, 5.0 mg/kg), amantadine (10, 20 mg/kg) (both uncompetitive NMDA antagonists), and L-deprenyl (1.0, 5.0 mg/kg; MAO-B inhibitor) were tested for possible synergistic interactions with the dopamine agonists: bromocriptine (2.5, 5.0 mg/kg) and L-dopa (50, 100 mg/kg, +benserazide, 100 mg/kg). At higher doses, memantine (10 mg/kg), amantadine (40 mg/kg), bromocriptine (5 and 10 mg/kg) and L-dopa (100, 200 mg/kg) but not L-deprenyl (up to 10 mg/kg) produced a pronounced increase in locomotor activity when given alone. The combination of memantine, amantadine and L-deprenyl with bromocriptine did not result in synergism of action and, at best, an additive effect was seen. On the other hand the combination of these agents with L-dopa produced a pronounced synergistic effect. Hence, the clinical observation that coadministration of L-dopa with either memantine or amantadine results in enhancement of their action is also reflected in an animal model of Parkinson's disease. Such a combination therapy should allow the use of lower doses of both drugs which may reduce the occurrence of side effects and may also be predicted to have additional benefits related to the neuroprotective properties of memantine, amantadine, and L-deprenyl.
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PMID:Memantine, amantadine, and L-deprenyl potentiate the action of L-dopa in monoamine-depleted rats. 771 Jul 39

To gain insight into the antiparkinsonian effects of selective D1 and D2 dopamine receptor stimulation, we examined the ability of D1 (SKF 38393) and D2 (quinpirole) agonists to reverse catalepsy induced by the combined administration of reserpine and alpha-methyl-p-tyrosine (AMPT) in rats. Catalepsy, the failure to correct an externally imposed posture, is a measure of akinesia and was assessed using the bar test. Rats injected with reserpine alone (2.5 mg/kg i.p.) developed akinesia and ptosis within 60-90 min. The D1 agonist SKF 38393 (30 mg/kg i.v.) rapidly reversed ptosis and restored near-normal mobility when administered 24 h after reserpine and AMPT; catalepsy was reversed for 90 min, after which the drug effect wore off. Quinpirole (1 mg/kg i.v.) reversed catalepsy for the duration of the test period (4 h) but did not consistently reverse ptosis or promote normal mobility; the rats continued to exhibit kyphotic postures with little spontaneous locomotion. These results indicate that selective D1 stimulation is sufficient to reverse reserpine-induced akinesia and highlight the need for the development of potent selective D1 agonists for clinical trial in Parkinson's disease. In severe dopamine depletion, D2 stimulation alone appears to be insufficient to restore normal movement. Quinpirole, but not SKF 38393, elicited paroxysmal limb/body jerking in reserpine-AMPT-treated rats, providing further evidence that atypical jerking can be elicited by D2 stimulation in the complete absence of D1 stimulation. This laboratory observation suggests that some jerking dyskinesias seen in treated parkinsonian patients may be mediated by an imbalance in D1-D2 receptor stimulation.
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PMID:Reversal of reserpine-induced catalepsy by selective D1 and D2 dopamine agonists. 790 61


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