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)

The aim of the present study was to examine the effects of neurotensin in an animal model of Parkinson's disease (PD). Bilateral administration of 6-OHDA in the medial forebrain bundle at the level of the posterolateral hypothalamus of rats resulted in the appearance of the 3 principal neurological signs of PD: hypokinesia, rigidity and tremor. These symptoms were accompanied by severe losses of dopamine and its main metabolites in terminal regions of well-known dopamine pathways. Norepinephrine concentrations were also decreased in several regions but to a lesser extent than dopamine. Intracerebroventricular administration of neurotensin, in doses ranging from 7.5 to 120.0 micrograms, resulted in dose related attenuations of both muscular rigidity and tremors of animals. However, hypokinesia, defined as decreased motor activity was not significantly affected by the peptide. Administration of 120.0 micrograms of [Ala]NT, an inactive analogue of neurotensin, failed to alter any of the 3 neurological signs. Together, these results reveal selective antiparkinson-like effects of neurotensin in an animal model. The theoretical significance of these findings is discussed.
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PMID:Antiparkinson-like effects of neurotensin in 6-hydroxydopamine lesioned rats. 190 4

DL-threo-3,4-dihydroxyphenylserine (DL-threo-DOPS) was administered during 10 days to 4 patients with longstanding Parkinson's disease in addition to their treatment with L-3,4-dihydroxyphenyl-L-alanine (L-DOPA)-carbidopa (Sinemet). All patients tended to improve in their symptoms freezing, all day life activity and mood. There were no improvements in rigidity, tremor, and akinesia (in general). During the DL-threo-DOPS-treatment cerebrospinal fluid (CSF), serum and urine concentrations of catecholamines were measured. The results show that DL-threo-DOPS is transported to the brain and CSF in a way comparable with L-DOPA. However, no measurable increase of 3-methoxy-4-hydroxyphenylethyleneglycol (MOPEG) in CSF could be demonstrated. This suggests that the synthesis of noradrenaline from DL-threo-DOPS in the brain is doubtful. In addition measurements in urine reveals that at the dose used Sinemet prevents peripheral decarboxylation of DL-threo-DOPS into noradrenaline. Other possible metabolic pathways of DL-threo-DOPS are discussed.
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PMID:Catecholamine metabolism during additional administration of DL-threo-3,4-dihydroxyphenylserine to patients with Parkinson's disease. 247 57

Repeated dietary consumption of the neurotoxic amino acid beta-N-methylamino-L-alanine (BMAA), found in the seeds of Cycas circinalis, has been postulated as causing both amyotrophic lateral sclerosis (ALS) and the parkinsonism-dementia syndrome (PD) that were formerly very prevalent among the indigenous people of the Marianas Islands. Cynomolgus monkeys fed BMAA have been reported to develop behavioral and neuropathological changes like those found in human ALS. We gave large amounts of BMAA, totaling 15.5 g/kg of the L-isomer, by gavage to mice over 11 weeks without observing any behavioral abnormalities. When killed, these animals showed none of the neurochemical or neuropathological changes that would be expected in ALS or Parkinson's disease. Their striatal dopamine contents were normal, and there were no reductions in the contents of glutamate and aspartate in cerebral cortex like those encountered in sporadic human ALS. The results of this experiment do not support chronic ingestion of BMAA as the causative factor for Guamanian ALS or PD.
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PMID:Beta-N-methylamino-L-alanine. Chronic oral administration is not neurotoxic to mice. 261 65

L-3-(3-Hydroxy-4-pivaloyloxyphenyl)alanine (1, NB-355) is a novel L-dopa prodrug. After oral administration with carbidopa in rats, 1 demonstrated 2.3 times longer duration (MRT) and 1.4 times larger bioavailability (AUC) on plasma L-dopa concentrations than those of L-dopa itself. Similar results were obtained in dogs. The prolonged profile of L-dopa was parallel to that of carbidopa, and the intact ester was undetectable in rat plasma. After intravenous administration in rats, 1 was converted quickly and completely to L-dopa in the systemic circulation. It was also noted that the oral LD50 value of 1 was greater than 6 g/kg in mice. These data suggest that 1 will offer long-lasting L-dopa therapy for the treatment of Parkinson's disease with little concern about toxicity.
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PMID:A new potential prodrug to improve the duration of L-dopa: L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine. 277 50

The incorporation of labelled carbon from glucose U-14C into CSF amino acids was investigated in three patients with Parkinson's disease and in three control persons with comparable age and physical stature. Comparing the specific radioactivities of serum and CSF one can postulate that the labelled amino acids found in the CSF are synthesized mainly by brain tissue. The resorption of glucose into the CNS and therefore the synthesis of amino acids from glucose was more rapid in controls; labelled alanine and glutamine appeared later in the CSF of the patients. As expected, in the controls the specific radioactivity of glutamic acid was found to be higher than that of glutamine, in patients the labelling of glutamine was higher as was that of serine, glycine, aspartic acid and asparagine. From our knowledge concerning the compartmentation of the metabolism of glutamate, we assume that in Parkinsonism the metabolic activity of neurons is reduced but that of astroglia is enhanced.
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PMID:[Biosynthesis of amino acids from glucose in the central nervous system in the Parkinson syndrome]. 665 3

Mitochondrial targeting sequence (MTS) has a common property to form an amphiphilic helical structure which is essential for its effective transport of mitochondrial protein. Natural polymorphism in human MTS which affects its mitochondrial transport ability has not been reported. Furthermore, no structural polymorphism for manganese superoxide dismutase (MnSOD) gene has been studied in human population. We here identify diallelic polymorphism (Ala-9Val) in the MTS of human MnSOD in a Japanese population. Calculation of a helix forming potential predicted the typical amphiphilic helical structure in -9Ala allele and its disruption in -9Val allele. We here suggest that this mutation may reflect functional polymorphism of mitochondrial transport of human MnSOD. An association study using this polymorphism showed significant allelic deviation for -9Ala allele (12.1% vs. 19.3%) in Parkinson's disease.
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PMID:Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease. 880 73

We studied the characterization of cabergoline, a new ergot alkaloid derivative and a selective dopamine D2 receptor agonist, in comparison to bromocriptine and pergolide in reserpine-treated rodents. Cabergoline (0.25-1.0 mg/kg, s.c.) improved dose-dependently the reserpine-induced akinesia that was assessed on the locomotor activity, and the efficacy lasted longer than those of bromocriptine (1.25-5.0 mg/kg, s.c.) or pergolide (0.0625-0.5 mg/kg s.c.). Cabergoline (ED50 = 1.10 mg/kg, at 4 h after the administration of drugs) also reversed catalepsy, the failure to correct an externally imposed posture, and its efficacy was stronger and longer than bromocriptine (ED50 = 4.65 mg/kg, at 4 h). Further, reserpine-induced rigidity was improved equally by cabergoline (0.125-1.0 mg/kg, i.v) and bromocriptine (1.0 mg/kg, i.v.). When cabergoline was administered together with 3(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), the effects were additive. Our results indicate that the long-lasting effects of cabergoline could be beneficial for treating Parkinson's disease.
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PMID:Effect of cabergoline, a long-acting dopamine D2 agonist, on reserpine-treated rodents. 895 Nov 72

We measured the CSF levels of 21, and the plasma levels of 26, amino acids in 31 patients with Parkinson's disease (PD) and in 45 matched controls. We used an ion-exchange chromatography method. When compared to controls, PD patients had lower CSF levels of taurine, alanine, valine, leucine, isoleucine, ethanolamine, citrulline, ornithine, lysine, histidine, arginine, and alpha-aminobutyric acid. PD patients not treated with levodopa or with dopamine agonists had higher CSF tyrosine and phenylalanine levels than those not treated with these drugs and also than controls. PD patients had higher plasma levels of phosphoserine, threonine, methionine, tyrosine, sarcosine and alpha-aminoadipic acid, and lower plasma levels of valine, leucine, and tryptophan, than controls. The CSF/plasma ratio of many of these amino acids was significantly lower in PD patients than those of controls, suggesting that PD patients might have a dysfunction in the transport of neutral and basic amino acids across the blood-brain barrier.
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PMID:Decreased cerebrospinal fluid levels of neutral and basic amino acids in patients with Parkinson's disease. 926 38

Rats were treated intraperitoneally with a mixture of 250 mg/kg L-DOPA and 40 mg/kg carbidopa or with vehicle and sacrificed 30 min later. Plasma, heart and cortex, midbrain, brainstem and cerebellum were removed from each animal and assayed by HPLC for L-DOPA and a large number of amino acids and related amino compounds. L-DOPA levels increased from undetectable (<0.2 nmol/ml or g) to 1,146, 1,007, 399, 376, 368 and 850 nmol/ml or g in the above tissues. In addition, several amino compounds were significantly affected by L-DOPA/carbidopa (p < or = 0.01). Plasma concentrations of phosphoserine, oxidized glutathione, citrulline, phenylalanine, tyrosine and 1-methylhistidine increased and arginine, glutamic acid and lysine decreased. In the heart, concentrations of phosphoserine, taurine, reduced glutathione, threonine, serine, glutamine, glycine, alanine, valine, GABA, ethanolamine, ammonia and arginine decreased. In the cortex, camosine and homocarnosine increased. In the midbrain, valine increased and leucine, ornithine and oxidized glutathione decreased. In the cerebellum, citrulline increased. In the brainstem, threonine, serine, asparagine, glutamine, oxidized glutathione, alanine, and leucine decreased. In the brainstem, arginine was slightly decreased with a concomitant increase in citrulline (p < 0.05), indicative of nitrous oxide formation. These results show that administration of L-DOPA/ carbidopa not only raises dopamine levels but can also affect other biochemicals and that the observed changes in amino acids and related compounds can perhaps contribute to the beneficial and/or adverse effects of L-DOPA/carbidopa therapy of Parkinson's disease.
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PMID:Effects of L-DOPA/carbidopa administration on the levels of L-DOPA, other amino acids and related compounds in the plasma, brain and heart of the rat. 934 99

We report Mn superoxide dismutase (SOD) protein and activity in a patient with familial autosomal recessive Lewy body-negative parkinsonism in comparison with patients with sporadic Parkinson's disease (PD) and controls. We recently proved linkage of this family with markers of chromosome 6 at 6q25.2-27, which included the Mn SOD gene. We used a novel polymorphic mutation at -9 position of the signal peptide of the Mn SOD precursor protein, which caused valine to alanine substitution. All the affected members of this family showed homozygosity for alanine, whereas nonaffected members, sporadic PD patients, and the control subjects studied showed either heterozygosity of alanine and valine or homozygosity of valine. The Mn SOD activity of this familial patient was the highest among the PD patients and the control subjects studied, and an abundant expression of Mn SOD was found in the substantia nigra. The molecular weight of Mn SOD protein by Western blotting of this patient was essentially similar to that of PD patients and the control subjects. High Mn SOD activity may constitute a genetic risk factor in this familial patient. The difference in the signal peptide sequence may affect the expression of Mn SOD within mitochondria; however, it is unlikely that loss of function type Mn SOD mutation is the cause of this familial parkinsonism. Mn SOD in sporadic PD patients was similar to that in controls.
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PMID:Mn SOD activity and protein in a patient with chromosome 6-linked autosomal recessive parkinsonism in comparison with Parkinson's disease and control. 937 4


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