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)

Positron emission tomography (PET) and the dopamine (DA) metabolism tracer, [18F]6-fluoro-L-m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and the clinical stage of parkinsonism monkeys following either unilateral ICA MPTP infusion or unilateral ICA MPTP infusion and subsequent varying sequential systemic doses of MPTP. Clinical stage corresponded to PET measures of striatal DA metabolism, showing the usefulness of the overlesioned hemiparkinsonian monkey as a stable model of various stages of Parkinson's disease (PD).
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PMID:A novel MPTP primate model of Parkinson's disease: neurochemical and clinical changes. 973 79

Manganese is known to induce neurological disorders similar to parkinsonisms. A dopamine deficiency has been demonstrated in Parkinson's disease and in chronic manganese poisoning, suggesting that the mechanisms underlying the neurotoxic effects of the metal ion are related to a functional abnormality of the extrapyramidal system. However, the details have yet to be elucidated. Here we report that manganese causes characteristic internucleosomal DNA fragmentation, a biochemical hallmark of apoptosis, in PC12 cells. It was transcription dependent, relatively specific for manganese, and blocked in Bcl-2-overexpressed PC12 cells. The results indicate that apoptosis may play a role in the dopaminergic neurotoxicity associated with manganese, the first metal to be reported to induce this form of cell death. The early biochemical events show the impairment of energy metabolism, and the process may require new synthesis of proteins such as c-Fos and c-Jun. In addition, manganese induces phosphorylation of c-Jun at Ser63 and Ser73 and SEK1/MKK4 (c-Jun N-terminal kinase kinase) at Thr258 and tyrosine phosphorylation of several proteins. These results indicate that manganese activates specific signal cascades including the c-Jun N-terminal kinase pathway.
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PMID:Activation of JNK pathway and induction of apoptosis by manganese in PC12 cells. 975 Nov 94

A new mechanism of oxygen radical formation in dopaminergic neurons is proposed, based on the oxidative mechanism of tyrosine hydroxylase. The cofactor (6R,6S)-5,6,7,8-tetrahydrobiopterin can rearrange in solution which allows an autoxidation reaction producing O2.-, H2O2 and HO.. The combination of tyrosine hydroxylase and the cofactor produces more oxygen radicals than does the autoxidation of the cofactor. This production of oxygen radicals could be damaging to dopaminergic neurons. In the presence of tyrosine, the enzyme produces less radicals than it does in the absence of tyrosine. Mechanisms are proposed for the generation of reactive oxygen species during the autoxidation of the cofactor and during enzymatic catalysis. The generation, by tyrosine hydroxylase, of very small amounts of oxygen radicals over the period of 65 years could contribute to the oxidative stress that causes Parkinson's disease.
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PMID:Tyrosine hydroxylase: mechanisms of oxygen radical formation. 975 25

Catechol-O-methyltransferase inhibitors have been newly introduced as adjunct drugs to the levodopa/dopa decarboxylase inhibitor therapy in Parkinson's disease. When given alone, catechol-O-methyltransferase inhibitors seem to affect behaviour. We wanted to determine whether the concentrations of free amine would be increased by catechol-O-methyltransferase inhibition with tolcapone and underpin the positive behavioural effects. To this end, dopamine and noradrenaline levels were analyzed in the microdialysis perfusion fluid collected from several brain regions in chloral hydrate anaesthetized rats. We also analyzed the turnover rate of catecholamines in the brain after single doses of tolcapone and entacapone using the alpha-methyl-p-tyrosine method. On their own, tolcapone (at 10 or 30 mg/kg) did not elevate dopamine or noradrenaline levels in any brain region studied although the formation of catechol-O-methyltransferase-dependent metabolites was strongly reduced. Neither tolcapone nor entacapone (at 30 mg/kg) affected the turnover rate of catecholamines. It seems that catechol-O-methyltransferase inhibitors do not alter behaviour by elevating extracellular levels of free catecholamines levels but other explanations are needed.
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PMID:No change of brain extracellular catecholamine levels after acute catechol-O-methyltransferase inhibition: a microdialysis study in anaesthetized rats. 977 42

The present study examined the effects of the antiparkinsonian drug budipine on dopamine synthesis and release from L-DOPA in the substantia nigra of reserpine-treated rats. Budipine (at 100 microM, but not 10 microM) applied by reverse dialysis to the nigra caused a small and significant rise in dopamine recovery in normal rats, but not in rats pretreated with reserpine (4 mg/kg i.p. for 18 hours) and alpha-methyl-p-tyrosine (alpha-MPT; 200 mg/kg i.p. for 1 hour to limit dopamine synthesis to L-DOPA). L-DOPA applied to the nigra by reverse dialysis in reserpine + alpha-MPT-treated rats, increased the recovery of dopamine when applied at 5 or 10 microM, but not at 2 microM. Coadministration of budipine (10 microM) significantly enhanced L-DOPA-induced dopamine (and DOPAC) release with 5 microM L-DOPA, but not with 2 or 10 microM L-DOPA. This potentiation was even more pronounced when the budipine concentration was raised to 100 microM (equivalent to approximately 10 microM extracellularly). Pretreating rats with budipine (5, 12.5, or 20 mg/kg i.p.) for 1 hour significantly raised the activity of the enzyme L-aromatic amino acid decarboxylase in the striata and nigras of intact rats, as well as in rats pretreated with reserpine alone (5 mg/kg i.p.), without altering tissue levels of dopamine or its metabolites. It is suggested that the beneficial effects of budipine, when used as an adjunct to L-DOPA therapy of Parkinson's disease, may be due to an increase in the bioconversion of L-DOPA with a consequent rise in synaptic dopamine. These actions of budipine may be related to its weak NMDA receptor antagonist property.
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PMID:The antiparkinsonian drug budipine stimulates the activity of aromatic L-amino acid decarboxylase and enhances L-DOPA-induced dopamine release in rat substantia nigra. 977 34

Sensitization of striatal N-methyl-D-aspartate receptors (NMDAR) has been linked to events leading to the motor response changes associated with the administration of dopaminomimetics to parkinsonian animals and patients. To determine whether tyrosine phosphorylation of NMDAR subunits contributes to the apparent long-term enhancement in synaptic efficacy of these receptors, we examined the effect of unilateral nigrostriatal dopamine system ablation with 6-hydroxydopamine followed by twice-daily treatment with l-DOPA on the phosphorylation state of rat striatal NR2A and NR2B subunits. Three weeks of intermittent l-DOPA administration produced a shortening in the duration of the rotational response to dopaminergic challenge and other changes mimicking those occurring in patients with Parkinson's disease. Concurrently, tyrosine phosphorylation of NR2A and especially of NR2B subunits increased ipsilateral to the lesion (20+/-5% and 46+/-7% of intact striatum, respectively; p<0.01) without attendant changes in subunit protein levels. Selective blockade of NR2B subunits with ACEA 10-1244, but not of NR2A subunits with MDL 100,453, reversed the l-DOPA-induced response alterations. The intrastriatal injection of a tyrosine kinase inhibitor, genistein, at a dose (2.0 microg) that normalized the response shortening, attenuated the NR2A and NR2B phosphorylation increase by about 12% and 24%, respectively (p<0.01). Taken together, these results suggest that augmented tyrosine phosphorylation of NR2B subunits, alone or in combination with the smaller rise in NR2A subunit phosphorylation, contributes to the apparent enhancement in striatal NMDAR sensitivity and thus to the plastic alterations in dopaminergic responses in l-DOPA-treated parkinsonian rats.
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PMID:Enhanced tyrosine phosphorylation of striatal NMDA receptor subunits: effect of dopaminergic denervation and L-DOPA administration. 982 89

Embryonic day 14 rat midbrain cultures were kept for 7 days in vitro and then intoxicated with radical donors iron and sodium-nitroprusside for 24 h. Tyrosine-hydroxylase positive neurons in cultures which were additionally treated with growth/differentiation factor-5 (GDF-5) survived to a significantly higher percentage as compared to sister cultures without factor supplementation. Since the degeneration of TH positive cells is a key feature in Parkinson's disease, GDF-5 might be a putative therapeutical agent for this disorder.
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PMID:Midbrain dopaminergic neurons are protected from radical induced damage by GDF-5 application. Short communication. 1022 34

The identification of novel factors that promote neuronal survival could have profound effects on developing new therapeutics for neurodegenerative disorders. Glial cell line-derived neurotrophic factor (GDNF) is a novel protein purified and cloned based on its marked ability to promote dopaminergic neuronal function. GDNF, now known to be the first identified member of a family of factors, signals through the previously known receptor tyrosine kinase, Ret. Unlike most ligands for receptor tyrosine kinases, GDNF does not bind and activate Ret directly, but requires the presence of GPI-linked coreceptors. There are several coreceptors with differing affinities for the GDNF family members. The profile of coreceptors in a cell may determine which factor preferentially activates Ret. In vivo differences in localization of the GDNF family members, its coreceptors and Ret suggest this ligand/receptor interaction has extensive and multiple functions in the CNS as well as in peripheral tissues. GDNF promotes survival of several neuronal populations both in vitro and in vivo. Dopaminergic neuronal survival and function are preserved by GDNF in vivo when challenged by the toxins MPTP and 6-hydroxydopamine. Furthermore, GDNF improves the symptoms of pharmacologically induced Parkinson's disease in monkeys. Several motor neuron populations isolated in vitro are also rescued by GDNF. In vivo, GDNF protects these neurons from programmed cell death associated with development and death induced by neuronal transection. These experiments suggest that GDNF may provide significant therapeutic opportunities in several neurodegenerative disorders.
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PMID:GDNF: a novel factor with therapeutic potential for neurodegenerative disorders. 1032 71

Glial cell line-derived neurotrophic factor (GDNF) was first discovered as a potent survival factor for midbrain dopaminergic neurons and was then shown to rescue these neurons in animal models of Parkinson's disease. GDNF is a more potent survival factor for dopaminergic neurons and the noradrenergic neurons of the locus coeruleus than other neurotrophic factors, and an almost 100 times more efficient survival factor for spinal motor neurons than the neurotrophins. The members of the GDNF family, GDNF, neurturin (NTN), persephin (PSP), and artemin (ART), have seven conserved cysteine residues with similar spacing, making them distant members of the transforming growth factor-beta (TGF-beta) superfamily. Like the members of the neurotrophin family, the GDNF-like growth factors belong structurally to the cysteine knot proteins. Like neurotrophins, GDNF family proteins are responsible for the development and maintenance of various sets of sensory and sympathetic neurons but, in addition, GDNF and NTN are also responsible for the development and survival of the enteric neurons, and NTN for parasympathetic neurons. All neurotrophins bind to the p75 low-affinity receptor, but their ligand specificity is determined by trk receptor tyrosine kinases. GDNF, NTN, PSP, and ART mediate their signals via a common receptor tyrosine kinase, Ret, but their ligand specificity is determined by a novel class of glycosylphosphatidylinositol (GPI)-anchored proteins called the GDNF family receptor alpha (GFR alpha). GDNF binds preferentially to GFR alpha1, NTN GFR alpha2, ART GRF alpha3, and PSP GFR alpha4 as a co-receptor to activate Ret. GFR alpha4 has until now been described only from chicken. Although the GDNF family members signal mainly via Ret receptor tyrosine kinase, there is recent evidence that they can also mediate their signals via GFR alpha receptors independently of Ret. The GDNF family of growth factors, unlike neurotrophins, has a well-defined function outside the nervous system. Recent transgenic and organ culture experiments have clearly demonstrated that GDNF is a mesenchyme-derived signaling molecule for the promotion of ureteric branching in kidney development. NTN, ART, and PSP are also expressed in the developing kidney, and NTN and PSP induce ureteric branching in vitro, but their true in vivo role in kidney morphogenesis is still unclear.
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PMID:Other neurotrophic factors: glial cell line-derived neurotrophic factor (GDNF). 1038 22

The catecholaminergic cell groups in the human brain, denominated from A1 to A17, display some striking anatomical differences with those described in the rodent. These differences are essentially observed in the extent of the dopaminergic neurons and especially their axonal fields in the telencephalon. Immunocytochemistry for tyrosine-hydroxylase and dopamine-ss-hydroxylase allowed the visualization of the precocious human catecholaminergic groups as early as 4.5 postovulatory weeks. Maps of tyrosine-hydroxylase positive neurons generated in the different rhombomeres, midbrain, and prosomeres are shown following the prosomeric model introduced by Puelles and Rubenstein [(1993) Trends Neurosci. 16:472-476]. Such a description is convenient to compare catecholaminergic systems in different mammalian species and provide clear anatomical landmarks of the embryonic substantia nigra (midbrain and prosomeres 1 and 2), that are necessary for transplantation of neural tissue in Parkinson's disease. The development and early specification of the dopaminergic neurons expressing calbindin D28K phenotype in the substantia nigra and in the ventral tegmental area are described. The catecholaminergic axons enter the anlage of the cerebral cortex just after the formation of the cortical plate, from 7 postovulatory weeks on. They invade the subplate layer where they wait for 4 weeks before penetrating the cortical plate. At midgestation, the different areas and layers of the frontal cerebral wall are invaded by the catecholaminergic axons, before the layering of the cortex is completed, in a pattern of fiber distribution similar to that described in the adult human brain. The early pattern of development of the catecholamine systems appeared to be phylogenetically well preserved in mammals, but specific features emerging during the differentiation period are unique to humans.
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PMID:Distribution of the catecholaminergic neurons in the central nervous system of human embryos and fetuses. 1040 70


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