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)

1. Benserazide and carbidopa, decarboxylase inhibitors used in the treatment of Parkinson's disease, have been shown to inhibit the enzyme kynurenine hydrolase in rat and mouse liver. This results in reduced synthesis of nicotinamide coenzymes from tryptophan, and hence an increased reliance on dietary niacin. 2. Pellagra might be expected as a result of this inhibition of endogenous synthesis of nicotinamide nucleotides, but has not been reported in patients treated with either drug. 3. The urinary excretion of N1-methyl-nicotinamide, a product of nicotinamide nucleotide metabolism, is considerably reduced in patients treated with dopa alone or in combination with an inhibitor of peripheral dopa decarboxylase, to as low as 40% of the control value. This means that many of these patients could be classified as 'at risk' of niacin deficiency, even if not frankly deficient. 4. Patients treated with dopa plus a decarboxylase inhibitor, but not those treated with dopa alone, also show a reduced excretion of xanthurenic acid, and an increased excretion of kynurenine, as would be expected after inhibition of the kynurenine pathway, and possibly indicative of marginal vitamin B6 deficiency.
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PMID:Niacin depletion in Parkinsonian patients treated with L-dopa, benserazide and carbidopa. 47 87

Bromocriptine (CB-154) is regarded as a dopamine agonist, hence is used in the treatment of Parkinson's disease. In the paper presented a possibility of the influence of bromocriptine on central serotonin neurons has been studied. It was demonstrated that CB-154, like tryptophan, 5-hydroxytryptophan, LSD or fenfluramine in previous experiments, potentiates the flexor reflex of the spinal rat, and this effect of CB-154 is prevented by serotonin antagonists--cryproheptadine and danitracen. CB-154, like fenfluramine used as a comparative serotonergic agent, rises the body temperature in rabbits. The hyperthermic effect of CB-154 is prevented by cyproheptadine, danitracen and mianserin. Haloperidol prevents the hyperthermia caused by a lower dose of CB-154 or on fenfluramine-induced hyperthermia. The results obtained indicate that CB-154, besides a dopaminomimetic action, possesses central serotonin actions as well.
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PMID:The influence of bromocriptine on serotonin neurons. 92 86

Mental symptoms increased in frequency among 100 patients with parkinsonism treated with levodopa. Dementia was found in about one-third of patients throughout the 6-year treatment period. Thirteen patients became demented during the study, and dementia worsened severely in seven others. Agitated confusion became increasingly frequent and was observed in 60 percent of patients taking levodopa for 6 years. Withdrawal from levodopa decreased agitation, but not dementia. Ten patients received L-tryptophan along with levodopa, but no change in mentation was observed. In view of previous studies of mentation in Parkinson's disease and reports of widespread neuronal changes in the brain of autopsied patients with parkinsonism, our results suggest that the high incidence of dementia in patients with Parkinson's disease who take levodopa reflects prolongation of the course of the illness rather than a direct effect of the medication.
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PMID:Mental symptoms in Parkinson's disease during chronic treatment with levodopa. 94 87

The behaviour of some urinary metabolites of tryptophan/nicotinic acid pathway was studied in 7 patients with Parkinson's disease during a 24-day period of levodopa treatment. Corresponding to the appearance of side-effects (agitation, anorexia, dysphagia, glossitis, abdominal pains) in 5 patients there was an increase in urinary Ky, AA, AAG, o-AHA, and 3-HK, while 3-HAA excretion fell. Since no other drugs were given, it was presumed that this effect was due to levodopa administration.
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PMID:Tryptophan/nicotinic acid pathway during levodopa treatment of Parkinsonism. 124 93

Animal data indicate that serotonin (5-HT) is a major neurotransmitter involved in the control of numerous central nervous system functions including mood, aggression, pain, anxiety, sleep, memory, eating behavior, addictive behavior, temperature control, endocrine regulation, and motor behavior. Moreover, there is evidence that abnormalities of 5-HT functions are related to the pathophysiology of diverse neurological conditions including Parkinson's disease, tardive dyskinesia, akathisia, dystonia, Huntington's disease, familial tremor, restless legs syndrome, myoclonus, Gilles de la Tourette's syndrome, multiple sclerosis, sleep disorders, and dementia. The psychiatric disorders of schizophrenia, mania, depression, aggressive and self-injurious behavior, obsessive compulsive disorder, seasonal affective disorder, substance abuse, hypersexuality, anxiety disorders, bulimia, childhood hyperactivity, and behavioral disorders in geriatric patients have been linked to impaired central 5-HT functions. Tryptophan, the natural amino acid precursor in 5-HT biosynthesis, increases 5-HT synthesis in the brain and, therefore, may stimulate 5-HT release and function. Since it is a natural constituent of the diet, tryptophan should have low toxicity and produce few side effects. Based on these advantages, dietary tryptophan supplementation has been used in the management of neuropsychiatric disorders with variable success. This review summarizes current clinical use of tryptophan supplementation in neuropsychiatric disorders.
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PMID:L-tryptophan in neuropsychiatric disorders: a review. 130 30

6R-L-erythro-5, 6, 7, 8-Tetrahydrobiopterin (6R-BH4) is known as a cofactor for the hydroxylases of phenylalanine, tyrosine and tryptophan and also as a cofactor for nitric oxide synthase. Recently, a novel function of 6R-BH4 has been found: that is, 6R-BH4 acts on specific membrane receptors to directly stimulate the release of monamine neurotransmitters such as dopamine and serotonin, independently of its cofactor activity. In addition, it indirectly stimulates the release of non-monoamine neurotransmitters such as acetylcholine and glutamate, through activation of monoaminergic systems. In this paper, we briefly review recent experimental data, which provide new insights into the role of 6R-BH4 as a regulator of neuronal function. We also discuss the possibility of treatment by 6R-BH4 of neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, depression and infantile autism.
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PMID:[A novel function of tetrahydrobiopterin]. 136 Nov 76

Huntington's disease (HD) is characterized by gradually evolving selective neuronal death. Several lines of evidence suggest that an excitotoxic mechanism may play a role. Tryptophan metabolism leads to production of quinolinic acid, an N-methyl-D-aspartate (NMDA) receptor agonist, and to kynurenic acid, an antagonist at these same receptors. We recently found increased kynurenine to kynurenic acid ratios in HD postmortem putamen and decreased kynurenic acid concentrations in cerebrospinal fluid, consistent with decreased formation of kynurenic acid in HD brain. In the present study we used HPLC with 16 sensor coulometric electrochemical detection to measure kynurenic acid and 18 other electrochemically active compounds in 6 cortical regions, caudate and cerebellum from controls, HD, Alzheimer's disease (AD), and Parkinson's disease (PD) patients. Significant reductions in kynurenic acid concentrations were found in 5 of 6 cortical regions examined. Smaller reductions of kynurenic acid in the caudate, cerebellum and frontal pole were not significant. No significant reductions were found in the AD and PD patients. Both uric acid and glutathionine were significantly reduced in several regions of HD cerebral cortex, which could signify abnormal energy metabolism in HD. Since kynurenic acid is an antagonist of excitatory amino acid receptors, a deficiency could contribute to the pathogenesis of neuronal degeneration in HD.
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PMID:Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex. 136 87

A 55-year-old man presented with a 5-year history of Parkinson's disease and a 6-month history of major depression. The patient's depressive symptoms responded to treatment with fluvoxamine, a selective and potent serotonin reuptake inhibitor. Tryptophan depletion testing, which acutely lowers central serotonin levels, caused a brief exacerbation of the depressive illness, which resolved upon tryptophan repletion. Serotonergic dysfunction may be an etiologic factor in depression that occurs in Parkinson's disease.
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PMID:Serotonergic dysfunction in depression associated with Parkinson's disease. 835 Oct 31

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

N-Methyl-4-phenylpyridinium ion (MPP+), a highly toxic metabolite produced in the brain from a street drug contaminant, is selectively taken up by nigrostriatal dopaminergic neurons and accumulated intraneuronally in mitochondria. There it inhibits respiration, causes neuronal death and, in primates, provokes a parkinsonian condition. It has been suggested that endogenously generated or activated agents resembling MPP+ may contribute to the development of Parkinson's disease. We report here that simple beta-carbolines derived from tryptophan or related open chain indoles, when specifically methyl-substituted on both (2[beta] and 9[indole]) available nitrogens, display mitochondrial inhibitory potencies and neurotoxic effects in vitro (PC12 cultures) and in vivo (striatal microdialysis) which approach or even surpass MPP+. These results take on physiological significance with our finding that brain enzyme activity catalyzes S-adenosylmethionine-dependent methylations of the beta- and indole-nitrogens in beta-carbolines that have been detected in vivo. The unusual 9[indole]-N-methyl transfer, previously unrecognized in animals, apparently requires prior methylation of the 2[beta]-nitrogen. Sequential di-N-methylation of endogenous or xenobiotic beta-carbolines to form unique, neurotoxic 2,9-N,N'-dimethyl-beta-carbolinium ions may serve as a brain bioactivation route in chronic neurodegenerative conditions such as Parkinson's disease.
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PMID:Indole-N-methylated beta-carbolinium ions as potential brain-bioactivated neurotoxins. 161 7


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