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)

N-Methylsalsolinol, an analogue of 1,2,3,6-tetrahydropyridine, is present in the brains of patients with Parkinson's disease. To determine the metabolic pathway for the synthesis of N-Methylsalsolinol in the brain, salsolinol was perfused through the striatum or the substantia nigra of the rat brain by in vivo microdialysis. N-Methylsalsolinol was detected in the brain dialysate samples during microdialysis with salsolinol using gas chromatography-mass spectrometry with selected-ion monitoring. These results demonstrate that endogenous N-methylation of salsolinol into N-methylsalsolinol occurs in the brain in vivo.
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PMID:Endogenous synthesis of N-methylsalsolinol, an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, in rat brain during in vivo microdialysis with salsolinol, as demonstrated by gas chromatography-mass spectrometry. 140 Jul 75

The toxin N-methyl-1,2,3,6-tetrahydropyridine produces a model of neural degeneration very similar to idiopathic Parkinson disease. To understand the cellular mechanisms that modulate susceptibility to its active metabolite N-methyl-4-phenylpyridinium (MPP+), we have transfected a cDNA expression library from the relatively MPP(+)-resistant rat pheochromocytoma PC12 cells into MPP(+)-sensitive Chinese hamster ovary (CHO) fibroblasts. Selection of the stable transformants in high concentrations of MPP+ has yielded a clone extremely resistant to the toxin. Reserpine reverses the resistance to MPP+, suggesting that a transport activity protects against this form of toxicity, perhaps by sequestering the toxin within an intracellular compartment. In support of this hypothesis, dopamine loaded into the CHO transformant shows a localized distribution that is distinct from the pattern observed in wild-type cells and is also reversed by reserpine.
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PMID:Gene transfer of a reserpine-sensitive mechanism of resistance to N-methyl-4-phenylpyridinium. 140 4

Classical neurotransmitters are transported into synaptic vesicles so that their release can be regulated by neural activity. In addition, the vesicular transport of biogenic amines modulates susceptibility to N-methyl-4-phenylpyridinium (MPP+), the active metabolite of the neurotoxin N-methyl-1,2,3,6-tetrahydropyridine that produces a model of Parkinson's disease. Taking advantage of selection in MPP+, we have used gene transfer followed by plasmid rescue to identify a cDNA clone that encodes a vesicular amine transporter. The sequence predicts a novel mammalian protein with 12 transmembrane domains and homology to a class of bacterial drug resistance transporters. We have detected messenger RNA transcripts for this transporter only in the adrenal gland. Monoamine cell populations in the brain stem express a distinct but highly related protein.
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PMID:A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. 150 23

1-Methyl-3-phenyl-1,2,3,6-tetrahydropyridine (M-3-PTP) is an analogue to the Parkinson-producing dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), M-3-PTP, and simple analogues thereof, are versatile intermediates in organic synthesis. The present study was undertaken to investigate the possible dopaminergic toxicity of M-3-PTP. Male albino mice were injected with 50 mg/kg of either MPTP or M-3-PTP and dopamine (DA) and its metabolites were determined 2 hr and 7 days after the administration. Two hr after MPTP profound acute changes in brain DA metabolism were found, i.e. an approximately 50% reduction in the concentration of DA together with a 10-fold increase in the level of 3-methoxytyramine. Seven days after MPTP, DA and metabolites were markedly reduced which is consistent with a degeneration of the dopaminergic neurones. In contrast M-3-PTP produced no acute or long-term alterations in the concentrations of DA and its metabolites in mouse brain. Furthermore, in vitro experiments show that M-3-PTP does not inhibit monoamine oxidase B. Thus, the present data show that M-3-PTP is devoid of dopaminergic toxicity in mouse brain and is not likely to produce Parkinson's disease in humans. The lack of toxicity is probably explained by the low affinity of M-3-PTP for monoamino oxidase B.
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PMID:Investigation of the possible dopaminergic toxicity of 1-methyl-3-phenyl-1,2,3,6-tetrahydropyridine, an isomer to the neurotoxin MPTP. 168 9

A rodent model of Parkinson's disease, the 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine treated mouse, was used to determine whether striatal dopamine levels recover following grafting adrenal medulla into the striatum. Four types of grafts were performed: 1) adult mouse adrenal medulla, 2) adult adrenal medulla that had been freeze-thawed to kill viable cells, 3) postnatal day 7 adrenal medulla, and 4) sham grafts lacking tissue. At 1 month after grafting, only postnatal day 7 grafts contained surviving cells. However, all three types of tissue grafts promoted a unilateral recovery of host dopaminergic fibers on the side of the graft. In striking contrast to the unilateral recovery of the dopaminergic fibers, striatal dopamine levels were increased bilaterally in all tissue grafted mice. These observations suggest that adrenal tissue grafted into the striatum, whether it remains viable or not, has more widespread biochemical effects on the host dopaminergic system than previously recognized. Moreover, these observations bear on mechanisms that may underlie the general recovery of motor disturbances reported in human Parkinson's disease patients who have received a striatal graft of adrenal tissue.
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PMID:Bilateral recovery of striatal dopamine after unilateral adrenal grafting into the striatum of the 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP)-treated mouse. 196 70

The nigrostriatal neurotoxin N-methyl-1,2,3,6-tetrahydropyridine (MPTP) causes Parkinsonism in humans and laboratory animals. MPTP neurotoxicity is dependent on its oxidation to N-methyl-4-phenylpyridine (MPP+). The mechanism by which MPP+ causes destruction of dopamine-containing nigrostriatal cells is unknown. Here we show that MPP+ but not MPTP is taken up by energized mitochondria. MPP+ in the presence of dopamine and particularly of 6-hydroxydopamine stimulates Ca2+ release from mitochondria. Ca2+ release is accompanied by hydrolysis of intramitochondrial pyridine nucleotides. Our findings suggest that the MPTP-induced model of Parkinson's disease may be due to a disturbed Ca2+ homeostasis in dopamine neurons.
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PMID:N-methyl-4-phenylpyridine (MMP+) together with 6-hydroxydopamine or dopamine stimulates Ca2+ release from mitochondria. 308 73

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration leads to the selective destruction of the dopaminergic neurons of the nigrostriatal pathway in experimental animals including monkeys and mice. The neurotoxicity of MPTP is dependent upon its monoamine oxidase-B (MAO-B)-catalyzed conversion to the 1-methyl-4-phenylpyridinium species (MPP+). A methylated analog of MPTP. A methylated analog of MPTP, namely 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'Me-MPTP), is a more potent dopaminergic neurotoxin than MPTP in mice. Although the selective inhibition of MAO-B is sufficient to protect mice against MPTP-induced neurotoxicity, it is reported here that complete inhibition of MAO-B failed to prevent 2'Me-MPTP-induced dopaminergic neurotoxicity. However, the neurotoxicity of 2'Me-MPTP was completely prevented and 2'Me-MPP+ formation was markedly attenuated in mice in which both MAO-A and MAO-B were almost totally inhibited. This information about the role of MAO-A in the bioactivation of 2'Me-MPTP may be of relevance to those who speculate that the MAO-B catalyzed bioactivation of MPTP or a similar compound may be the cause of idiopathic Parkinson's disease.
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PMID:Role for monoamine oxidase-A (MAO-A) in the bioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTP analog, 2'Me-MPTP. 313 Nov 49

A motor disorder similar to idiopathic Parkinson's Disease develops in rhesus monkeys after several daily repeated doses of N-methyl-4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP). The concentrations of peptides derived from proenkephalin A, proenkephalin B, substance P and somatostatin were measured by specific radioimmunoassays in the basal ganglia of MPTP-treated monkeys. In MPTP-treated monkeys, dynorphin B concentration was reduced in the caudate. In the putamen, the concentrations of peptides derived from both proenkephalin A and proenkephalin B were decreased. In the globus pallidus, the concentrations of all opioid peptides tend to be increased, reaching significance only for alpha-neo-endorphin. In the substantia nigra, only Met-enkephalin concentration was reduced, while other peptides derived from either proenkephalin A or proenkephalin B were not changed. Substance P and somatostatin were not changed in any brain area examined. Some of the symptoms associated with Parkinson's Disease may be related to altered activity of endogenous opiates in basal ganglia.
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PMID:Primate model of Parkinson's disease: alterations in multiple opioid systems in the basal ganglia. 615 Jul 50

A major theory regarding the mechanism of neuronal degeneration in several movement disorders is that mitochondrial defects may play a role. Biochemical studies in Parkinson's disease, Huntington's disease, multiple system atrophy, and idiopathic dystonia have shown defects in enzymes of oxidative phosphorylation in postmortem brain tissue, platelets, muscle, or lymphocytes. The basal ganglia and substantia nigra are also particularly susceptible to the accumulation of age-dependent mitochondrial DNA deletions, which may contribute to the delayed onset of movement disorders. The 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine model of Parkinson's disease involves conversion to 1-methyl-4-phenylpyridinium, which then inhibits complex I of the electron transport chain. Our studies show that the complex II inhibitor 3-nitropropionic acid can closely replicate the neurochemical, histologic, and clinical features of Huntington's disease. The mechanism of neuronal death in both these models may be slow excitotoxicity. Both direct biochemical studies and animal models of movement disorders therefore suggest that mitochondrial dysfunction may play a direct role in their pathogenesis.
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PMID:Mitochondrial dysfunction in movement disorders. 795 42

The question has been raised as to whether neuromelanin, a by-product of catecholamine metabolism which accumulates during aging in primate midbrain neurons, contributes to the selective vulnerability of subgroups of dopaminergic neurons in Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP+) a metabolite of 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) is toxic to dopaminergic neurons, particularly in primates, producing a motor syndrome similar to that observed in Parkinson's disease. To test whether this neurotoxin preferentially affects melanized neurons, the survival of melanized and non-melanized catecholaminergic neurons was analysed after MPTP intoxication in the midbrain of the cynomolgus monkey (Macaca fascicularis). Experiments were performed on six animals chronically treated with MPTP (two were severely disabled, four moderately affected) and two age-matched control monkeys. Two populations of neurons were examined on regularly spaced sections throughout the midbrain: catecholaminergic neurons, identified by tyrosine hydroxylase immunohistochemistry and neuromelanin-containing neurons, visualized by Masson's method. The total number of neurons of each type was estimated in the different midbrain catecholaminergic cell groups using computer assisted image analysis. In the midbrains of control animals not all catecholaminergic neurons contained neuromelanin. The percentage of melanized neurons compared to the total population of tyrosine hydroxylase-positive neurons was high in the substantia nigra pars compacta (81.5%) and in the locus coeruleus (98%), intermediate in the substantia nigra pars lateralis (70%), in the catecholaminergic cell group A8 (50%), and in the ventral tegmental area (41.5%) and almost nil in the central gray substance. In MPTP-treated monkeys, the severity of the loss of catecholaminergic neurons was variable within the different midbrain cell groups, though of similar intensity in severely and mildly disabled monkeys. A relationship was found between the loss of dopaminergic neurons in the different mesencephalic cell groups of MPTP-intoxicated animals and the percentage of melanized neurons they normally contain (r = 0.98; P = 0.04). The percentage loss of catecholaminergic neurons in the locus coeruleus, the only noradrenergic cell group studied, was lower than expected from the correlation curve obtained for dopaminergic cell groups. Altogether, these findings indicate: (i) that dopaminergic neurons are more vulnerable to MPTP-toxicity than noradrenergic neurons; and (ii) that among dopaminergic neurons, those containing neuromelanin are more susceptible, indicating a possible role of neuromelanin in MPTP-toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP? 824 75


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