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)

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

Guinea pig brain S-adenosylmethionine (SAM)-dependent N-methyltransferase activity toward physiologically relevant beta-carboline (BC) substrates was examined with reverse-phase HPLC and radiochemical detection. Representative BCs, norharman and harmine, were enzymatically methylated on the 2[beta]-nitrogen by [3H]CH3-SAM in undialyzed homogenates to yield 2[beta]-methylated BCs and subsequently on the 9[indole]-nitrogen to generate 2,9-dimethylated BC products. This may be the first account of mammalian indole N-methyl transfer. There was no HPLC evidence for 9-methyl BC or (from carbon methylation) 2,6-dimethyl BC products. Capillary gas chromatography-mass spectrometry analysis confirmed the structures of the 2,9-dimethyl and 2-methyl products of norharman. The 2[beta]- and 9[indole]-N-methylation activities were mainly in the nuclear fractions and were negligible in undialyzed cytosol. This differs from the cytosolic SAM-dependent N-methylations reported with other azaheterocyclics, including 1,2,3,4-tetrahydro-BCs. The involvement of a single enzyme was suggested because the two N-methyl transfers with BC substrate had similar subcellular activity patterns, regional brain distributions, and Km and Vmax values. Sequential N-methylation of various BCs that have been observed in vivo may be a unique route to centrally retained N2,N9-dimethylated beta-carbolinium ions. Because they resemble the synthetic parkinsonian toxicant, N-methyl-4-phenylpyridinium, with respect to structure and neurotoxic activity, such "bioactivated" carbolinium ions could be endogenous causative factors in Parkinson's disease.
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PMID:Novel S-adenosylmethionine-dependent indole-N-methylation of beta-carbolines in brain particulate fractions. 162 24

The tetrahydro-beta-carboline derived from the condensation of N-methyltryptamine and formaldehyde, a semirigid tricyclic analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) tha has been detected in the brains of normal laboratory rats, is biotransformed in a monoamine oxidase B (MAO-B) catalyzed reaction to the corresponding dihydro compound at a rate that is approximately 0.5% of that observed with MPTP. The corresponding tetrahydroindenopyridine in which the double bond beta,gamma to the nitrogen atom retains allylic character is a somewhat better MAO-B substrate. The steric bulk of the nitrogen and methylene bridges in addition to ring strain present in the proposed carbon-centered radical intermediates derived from these types of tricyclic structures may contribute to their relatively poor MAO-B substrate properties. Although no MPTP-like neurotoxic properties were observed following acute administration of the test compounds to mice, we speculate that the chronic accumulation of beta-carbolinium type metabolites could contribute to the rate of nigrostriatal cell loss associated with idiopathic Parkinson's disease.
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PMID:Studies on semirigid tricyclic analogues of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 278 13

Studies in animals suggest that fetal neural grafts might restore lost neurological function in Parkinson's disease. In monkeys, such grafts survive for many months and reverse signs of parkinsonism, without attendant graft rejection. The successful and reliable application of a similar transplantation procedure to human patients, however, will require neural tissue obtained from human fetal cadavers, with demonstrated cellular identity, viability, and biological safety. In this report, human fetal neural tissue was successfully grafted into the brains of monkeys. Neural tissue was collected from human fetal cadavers after 9 to 12 weeks of gestation and cryopreserved in liquid nitrogen. Viability after up to 2 months of storage was demonstrated by cell culture and by transplantation into monkeys. Cryopreservation and storage of human fetal neural tissue would allow formation of a tissue bank. The stored cells could then be specifically tested to assure their cellular identity, viability, and bacteriological and virological safety before clinical use. The capacity to collect and maintain viable human fetal neural tissue would also facilitate research efforts to understand the development and function of the human brain and provide opportunities to study neurological diseases.
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PMID:Cryopreservation, culture, and transplantation of human fetal mesencephalic tissue into monkeys. 290 52

In this review, we describe the discovery of a new neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPTP, which appears to be highly selective for the substantia nigra of human and non-human primates. This compound appears to produce a "pure" parkinsonian state more consistently than most, if not all previously described neurotoxins. Identification of its unique properties has already led to the development of an animal model for Parkinson's disease in the monkey. In this paper we review the history of the compound, and describe its clinical effects in man and monkeys. Experiments are reviewed which suggest that the "4-5" double bond in the nitrogen-containing ring is key for this compound to exert its toxic effects, probably serving as a starting point for oxidation of MPTP to its quaternary amine, 1-methyl-4-phenylpyridinium ion (MPP+). MPTP appears to be rapidly converted to the latter compound in all tissues studied to date, including brain. We believe that this newly recognized nigrotoxin holds promise as a tool for the study of Parkinson's disease and the nigrostriatal dopaminergic system of the brain.
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PMID:MPTP-induced parkinsonism in human and non-human primates--clinical and experimental aspects. 633 34

1-Alkyl-4,4-diphenylpiperidines 5-23 are accessible in a simple manner and with attractive yields by regioselective reaction of piperidine derivatives like 1, 2, 3 or particularly 3-aroyl-4-aryl-4-hydroxypiperidines 4, which can be varied widely at the nitrogen atom, with benzene under Friedel-Crafts conditions. The physico-chemical parameters, which are important for the transport and the distribution of a drug in a living system, are discussed for the 1-tert-butyl derivative 13 (budipine) (pKa, partition coefficient P, saturation concentration Cs, surface activity, protein binding). Rapid absorption of this drug in man is indicated by the size of the permeability coefficient PM of the passive transport through artificial phospholipid collodium membranes as well as the invasion curves calculated from PM. According to pharmacological screening tests, most of the compounds of this class show marked antagonistic activity against experimentally generated pathological states in mice (tremorine and reserpine antagonism) which suggest their potential use in the therapy of Parkinson's disease. 13 has been selected for detailed investigations. Structure-activity analyses did not readily demonstrate the presence of a relationship between the type of alkyl substituent at the piperidine nitrogen atom and the pharmacological screening results obtained.
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PMID:[Synthesis, physical-chemical properties and pharmacologically-oriented screening studies on budipine and related 4,4-diphenylpiperidines]. 653 2

1 A number of aromatic-N-propargyl (acetylenic) compounds and indoleamines were tested for their inhibitory action on monoamine oxidase (MAO) type A and type B using the substrates 5-hydroxytryptamine (5-HT), beta-phenylethylamine (PEA) and dopamine. 2 Structure activity studies with aromatic-N-propragyl (acetylenic) derivatives have shown that MAO inhibitory potency is least dependent on the aromatic portion of the compounds. N-methylated propargyl derivatives are the most active and replacement of the methyl group with a higher alkyl or aromatic group results in significant reduction of activity. The triple bond in the N-propargyl portion is absolutely essential for activity and must be beta-to the nitrogen. It is the acetylenic group that gives these compounds their irreversible MAO inhibitory property. 3 The present study has indicated that since the acetylenic compounds resemble the enzyme substrates the distance between the aromatic ring and the N-propargyl terminal is crucial in designating the type A or type B MAO inhibitory property. For MAO type A inhibition, a distance equivalent to at least three carbon units is required, while for the inhibition of the B type enzyme this distance can be 1 or 2 carbon units. 4 The compounds AGN-1133 and AGN-1135 show most promise in Parkinson's disease or as anti-depressants because of their irreversible selective type B MAO inhibition in vitro and in vivo. 5 A number of indoleamine derivatives were found to be reversible selective type A inhibitors.
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PMID:Selective acetylenic 'suicide' and reversible inhibitors of monoamine oxidase types A and B. 728 98

Although intracerebral grafting has become a new strategy for the treatment of Parkinson's disease, many problems related to the grafts remain. We focused on primary skin fibroblasts as grafts. Rat primary skin fibroblasts were transfected with a retrovirus vector containing the cDNA of human tyrosine hydroxylase (TH) (pLTHSNL) or cytomegalovirus promoter (pCTHSNL) as a foreign promoter, and catecholamine production and release by these genetically modified fibroblasts, were analyzed in vitro immunocytochemically and by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The cells were supplemented with biopterin (BH4; (6R)-L-erythro-tetrahydrobiopterin), a cofactor required for TH activity, and they produced and released L-DOPA into the culture medium. When exposed to the combination of a foreign promoter and BH4, L-DOPA production increased in a time-dependent manner, and was unaffected by the number of cell-passages or the duration of liquid-nitrogen freezing. This suggests that the foreign gene (THcDNA)-containing retrovirus vector had integrated into the chromosomal DNA of the target cells (fibroblasts). Primary fibroblasts can be easily obtained and cultured. Thus, genetically modified primary skin fibroblasts transfected with THcDNA using this retrovirus vector system appear to be a promising graft for transplantation and gene therapy of Parkinson's disease in the future.
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PMID:[L-DOPA-producing primary fibroblasts genetically modified with a retrovirus vector system]. 754 38

Oxygen-based free radicals have been shown to play a major role in the acute destruction of neurons following cerebral ischemia and may be involved in the chronic neurodegeneration seen in Parkinson's disease, Alzheimer's disease, and other conditions characterized by the progressive death of neurons in the central nervous system. Drugs belonging to a group of antioxidant compounds, collectively known as the lazaroids, have strong neuroprotective effects in experimental models of acute ischemia. However, the specific mechanisms by which these drugs reduce the harmful actions of free radicals have not been established. Using electron paramagnetic resonance (EPR) spectroscopy with spin trapping, we investigated the interaction of U-74500A, a first-generation lazaroid, and U-78517F, a second-generation lazaroid, with two species of oxygen-based free radicals in aqueous solution and with the stable nitrogen-based free radical diphenylpicrylhydrazyl in dimethyl sulfoxide. Superoxide radicals were generated by the action of xanthine oxidase on hypoxanthine. Hydroxyl radicals were generated by the Fenton reaction involving aqueous ferrous iron and hydrogen peroxide. Both lazaroids reduce the EPR signal of all three radicals, but the drugs differ in potency and relative radical selectivity. These observations are consistent with the lazaroids being scavengers of oxygen-based and nitrogen-based free radicals and suggest that the neuroprotective actions of the lazaroids in cerebral ischemia may involve direct interactions of the lazaroids with several different species of free radicals.
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PMID:An in vitro EPR study of the free-radical scavenging actions of the lazaroid antioxidants U-74500A and U-78517F. 763 55

The significance of restrictions on protein for patients with Parkinson's disease is reviewed. Large neutral amino acids and levodopa share the same saturated carrier system through the blood-brain-barrier. Fluctuating patients are sensitive to a decreased supply of levodopa from the blood, and clinical studies show that an increased concentration of large neutral amino acids in the blood decreases mobility and reduces "on-time". A reduction of protein intake to 0.75-0.8 g/kg body weight/day has been recommended. A protein redistribution diet implying that less than 10% of the daily protein is taken in daytime and the rest in the evening, gives best results. However, in the elderly, protein restrictions may lead to a lasting negative nitrogen balance, and even in younger patients the supply of certain minerals and vitamins may become too low or marginally adequate. The diet must therefore be used with caution.
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PMID:[Diet therapy in Parkinson disease]. 775 95


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