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)

Degeneration of dopaminergic nigrostriatal neurons in primate models of Parkinson's disease (PD) leads to an overactivity of excitatory glutamatergic projections from the subthalamic nucleus (STN) to the output nuclei of the basal ganglia resulting in rigidity and akinesia. The selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist 6-nitro-sulfamoyl-benzo-quinoxaline-dione (NBQX) and the competitive N-methyl-D-aspartate (NMDA) antagonist 3-carboxy-piperazin-propyl phosphonic acid (CPP) ameliorate parkinsonian symptomatology when co-administered with threshold doses of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets and induce rotations in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra (SN). Here we report that in the 6-OHDA-lesioned rat NBQX and CPP induce contralateral rotations when combined with threshold doses of the direct dopamine agonists lisuride or apomorphine. AMPA antagonists and competitive NMDA antagonists may therefore be suitable as adjuvants for the treatment of PD.
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PMID:NBQX (6-nitro-sulfamoyl-benzo-quinoxaline-dione) and CPP (3-carboxy-piperazin-propyl phosphonic acid) potentiate dopamine agonist induced rotations in substantia nigra lesioned rats. 128 Jul 93

1-Methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), a metabolic product of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has been shown to generate superoxide radicals during its autoxidation process. The generation of superoxide radicals was detected as a 5,5-dimethyl-1-pyrroline-N-oxide (DMPO).O2- spin adduct by spin trapping in combination with EPR techniques. The rate of formation of spin adduct was dependent not only on the concentrations of MPDP+ and oxygen but also on the pH of the system. Superoxide dismutase inhibited the spin adduct formation in a dose-dependent manner. The ability of DMPO to trap superoxide radicals, generated during the autoxidation of MPDP+, and of superoxide dismutase to effectively compete with this reaction for the available O2-, has been used as a convenient competition reaction to quantitatively determine various kinetic parameters. Thus, using this technique the rate constant for scavenging of superoxide radical by superoxide dismutase was found to be 7.56 x 10(9) M-1 s-1. The maximum rate of superoxide generation at a fixed spin trap concentration using different amounts of MPDP+ was found to be 4.48 x 10(-10) M s-1. The rate constant (K1) for MPDP+ making superoxide radical was found to be 3.97 x 10(-6) s-1. The secondary order rate constant (KDMPO) for DMPO-trapping superoxide radicals was found to be 10.2 M-1 s-1. The lifetime of superoxide radical at pH 10.0 was calculated to be 1.25 s. These values are in close agreement to the published values obtained using different experimental techniques. These results indicate that superoxide radicals are produced during spontaneous oxidation of MPDP+ and that EPR spin trapping can be used to determine the rate constants and lifetime of free radicals generated in aqueous solutions. It appears likely that the nigrostriatal toxicity of MPTP/MPDP+ leading to Parkinson's disease may largely be due to the reactivity of these radicals.
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PMID:EPR kinetic studies of superoxide radicals generated during the autoxidation of 1-methyl-4-phenyl-2,3-dihydropyridinium, a bioactivated intermediate of parkinsonian-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 133 Oct 93

Dopamine-stimulated adenylyl cyclase activity was measured in striatal homogenates of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys and humans with idiopathic Parkinson's disease and compared with the activity in control tissue. No differences between parkinsonian and control tissue were found in the presence of 20 mM NaCl. However, when 120 mM NaCl was included in the assay medium, a significantly higher increase in the Vmax of dopamine-stimulated adenylyl cyclase activity was observed in the caudate of MPTP-parkinsonian rhesus monkeys and the putamen of patients with idiopathic Parkinson's disease. No such sensitization was seen in the MPTP-treated rhesus putamen or human Parkinson's disease caudate tissue. A role of D2 receptors in this sensitization could be ruled out by the concomitant use of the D2 antagonist l-sulpiride and by [3H]spiperone saturation analysis of the D2 receptor density, which was found at control level in the caudate tissue of MPTP-treated rhesus monkeys. Similarly, on the basis of saturation binding with the D1 selective ligand 125I-SCH 23982, there was no difference in caudate nucleus D1 receptor densities between control and MPTP-treated monkeys. Our results point to a region-specific functional sensitization of D1 receptors as a consequence of severe dopaminergic denervation of the striatum and suggest the possibility of a therapeutic potential of a D1 agonist with full intrinsic activity in Parkinson's disease.
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PMID:Sensitization of dopamine-stimulated adenylyl cyclase in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys and patients with idiopathic Parkinson's disease. 134 41

Following the demonstration of an anti-tremor effect of ethosuximide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model, we have tested the effect of this drug in 10 patients with typical parkinsonian tremor. Six patients suffered from Parkinson's disease with prominent, relatively drug-resistant rest tremor. The other four patients had a drug-induced parkinsonian tremor due to neuroleptic agents taken for a psychiatric condition. Five of the six parkinsonian patients and three of the four psychiatric patients reported within a few days a marked and intolerable exacerbation of their tremor. One patient in each group was improved, and this improvement was verified in repeated examinations. Thus, for unknown reasons, the effect of ethosuximide was not as predicted by the monkey model. Among possible explanations is the fact that we had chosen patients with drug-resistant tremor.
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PMID:Ethosuximide and tremor in Parkinson's disease: a pilot study. 135 60

The major neuropathology of Parkinson's disease (PD) is the degeneration of nigrostriatal dopamine (DA), resulting in a deficiency of DA, and of the enzyme tyrosine hydroxylase (TH), which catalyzes the synthesis of L-dopa. The symptomatic treatment of PD consists of replenishing DA by administering L-dopa, which is enzymatically converted to DA in the striatum. The increase of TH activity by modification of the enzyme leads to an increased synthesis of striatal L-dopa, and thereby replenishes the missing DA more efficiently. The activity of TH is increased by protein kinase-dependent phosphorylation of the enzyme or by inhibition of dephosphorylation with specific phosphatase inhibitors. Thus, modification of TH results in an activated form of the enzyme, which might provide a basis for developing new strategies in the treatment of PD. The extraneuronal enzyme, catechol-O-methyl transferase (COMT), inactivates catecholamines by O-methylation, and its inhibition leads to increased levels of striatal DA. The availability of selective and nontoxic COMT inhibitors makes it possible to assess their therapeutic role in treatment of PD. The intraneuronal enzymes, monoamine oxidase (MAO)-A and MAO-B, inactivate catecholamines and other biogenic amines, such as serotonin, by deamination. Inhibition of these enzyme activities leads to increased levels of striatal DA. The irreversible MAO-B inhibitor selegiline was shown to exert antiparkinsonian activity, especially in the early stages of parkinsonism. Selegiline also prevents the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in MPTP-treated mice and monkeys. Its role in the prevention of the disease is under investigation in several clinical centers.
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PMID:The role of the regulatory enzymes of catecholamine synthesis in Parkinson's disease. 834 92

A parkinsonian syndrome can be produced in nonhuman primates by administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Parkinsonian-like symptoms induced acutely by MPTP were ameliorated after treatment with GM1 ganglioside, a substance shown to have neurotrophic effects on the damaged dopamine system in rodents. Treatment with GM1 ganglioside also increased striatal dopamine and metabolite levels and enhanced the dopaminergic innervation of the striatum as demonstrated by tyrosine hydroxylase immunohistochemistry. These results suggest that GM1 ganglioside may hold promise as a therapeutic agent for the treatment of Parkinson's disease.
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PMID:Recovery from experimental parkinsonism in primates with GM1 ganglioside treatment. 135 Mar 79

Stimulation of D1 striatal receptors has been proposed as the main mechanism mediating levodopa-induced dyskinesia in Parkinson's disease. We used (+)-PHNO, a selective D2 agonist, as the only treatment in 6 cynomolgus monkeys made parkinsonian by repeated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. All animals developed choreic dyskinesia after a mean treatment period of 12.8 days (range, 1-29). Administration of the D1 antagonist SCH-23390 1 hour before administration of (+)-PHNO did not change the dyskinesia. These results indicate that drug-induced dyskinesia in a primate model of Parkinson's disease is not solely induced by D1 receptor activation.
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PMID:Selective D2 receptor stimulation induces dyskinesia in parkinsonian monkeys. 135 Jul 18

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.
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PMID:Terguride stimulates locomotor activity at 2 months but not 10 months after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets. 135 Sep 96

Computer imaging and immunohistochemical staining techniques were used to determine which midbrain dopaminergic (DA) cells are spared in Parkinson's disease (PD), and in animals treated with the DA neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and whether the spared cells contain the calcium-binding protein, calbindin-D28k (CaBP). The PD patients had more than 55% fewer midbrain DA neurons than age-matched normal subjects. The cell loss occurred within the combined substantia nigra and retrorubral area (greater than 61%; DA nuclei A9 and A8, respectively), and the ventral tegmental area (greater than 42%; DA nucleus A10). The cell loss was greatest within the ventral portion of the nucleus A9. A similar pattern of DA cell loss was observed in MPTP-treated Macaca fascicularis monkeys. The CaBP-containing cells were located specifically in the cell regions spared by PD and by MPTP-treatment in both monkeys and C57BL/6 mice. These data suggest that PD and MPTP both destroy the same population of midbrain DA neurons within nuclei A8, A9, and A10, and that perhaps CaBP protects the DA neurons from cell death caused by both PD and MPTP.
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PMID:Midbrain dopaminergic cell loss in Parkinson's disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells. 135 37

We studied how stimulation of protein kinase C and cAMP-dependent protein kinases affect the development of mesencephalic dopaminergic neurons in primary cell cultures derived from fetal rats at embryonic day E14. The effects of compounds which activate these second messenger systems were compared to those of basic fibroblast growth factor (bFGF) and insulin-like growth factor I (IGF-I). In mesencephalic cultures, there was a continuous loss of dopaminergic neurons. Despite this decline in cell number, neurotransmitter uptake per neuron increased with time, indicating that the surviving dopaminergic neurons continued their biochemical differentiation while others degenerated. IGF-I and bFGF did not affect the number of dopaminergic neurons. However, dopamine uptake per neuron was significantly higher in bFGF and IGF-I treated cultures, suggesting that these factors stimulated differentiation. Protein kinase C and cAMP-dependent protein kinases were not involved in mediating the effects of bFGF and IGF-I. Treatment of cultures with phorbol esters did not affect dopamine uptake, whereas elevated levels of intracellular cAMP resulted in an increase in dopamine uptake which was additive to that elicited by bFGF or IGF-I. Further analysis revealed that exposure of mesencephalic cultures to dibutyryl cAMP (dbcAMP) during the first 3 days after plating increased the survival of dopaminergic neurons, whereas prolonged treatment attenuated the development of the dopamine uptake system. Moreover, cyclic AMP, but not bFGF, was able to prevent the degeneration of dopaminergic neurons induced by 1-methyl-4-phenyl-pyridinium ion (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results suggest that increased intracellular levels of cAMP protect dopaminergic neurons in situations of stress like the process of dissociation and plating or the exposure to neurotoxic compounds. Our results reveal novel possibilities for the treatment of Parkinson's disease.
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PMID:Cyclic AMP, but not basic FGF, increases the in vitro survival of mesencephalic dopaminergic neurons and protects them from MPP(+)-induced degeneration. 135 86


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