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)

The effects of GM1 ganglioside administration on functional recovery and recovery of caudate nucleus dopamine levels have been assessed in cats made parkinsonian by administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cats made severely parkinsonian by MPTP administration began to show spontaneous functional recovery by the third week after MPTP, as had been observed in previous studies with this model. In contrast, cats with similar initial impairment but which received 3 weeks of GM1 ganglioside treatment (30 mg/kg, i.p. daily) showed an accelerated behavioral recovery, showing significant functional improvement after the first week of GM1 treatment and almost normal function by the end of the third week of treatment. The GM1-treated cats had caudate nucleus dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and HVA levels significantly increased above levels measured in saline-treated MPTP control cats. A second group of cats received MPTP only until the first signs of parkinsonism were observed and thus overall had a less severe initial syndrome than the cats described previously. Again, while all cats showed functional recovery over time, the recovery process was accelerated in GM1-treated cats. GM1 treatment also caused a significant increase in caudate dopamine levels in these cats. These results suggest that GM1 ganglioside administration can result in increased dopamine levels even in the heavily denervated striatum and accelerate functional recovery after an MPTP-induced lesion of the nigrostriatal dopamine system in the cat. This suggests that GM1 or other trophic factor therapies may be fruitful treatment strategies for a disorder of nigrostriatal function such as Parkinson's disease.
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PMID:MPTP-induced parkinsonism: acceleration of biochemical and behavioral recovery by GM1 ganglioside treatment. 161 17

The ability of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce parkinsonism has focused attention on potential endogenous or exogenous toxins that may follow similar uptake and conversion pathways to selectively target mitochondrial function in dopaminergic neurones. Exposure to such agents, together with a genetically determined susceptibility, is an attractive working hypothesis for the cause of Parkinson's disease. New insights into the mechanism of action of MPTP and its analogues are presented together with evidence supporting the potential role of endogenously produced toxins in the death of dopaminergic neurones in Parkinson's disease.
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PMID:MPTP and other Parkinson-inducing agents. 162 69

L-Deprenyl, the selective inhibitor of monoamine oxidase type B (MAO-B), has gained wide acceptance as a useful form of adjunct therapeutic drug in the treatment of Parkinson's disease. This review summarizes the molecular pharmacology of L-deprenyl, and the advances in our understanding of its possible mode of action in Parkinson's disease. L-Deprenyl belongs to the class of enzyme-activated irreversible inhibitors also described as 'suicide' inhibitors, because the compound acts as a substrate for the target enzyme, whose action on the compound results in irreversible inhibition. L-Deprenyl first of all forms a noncovalent complex with MAO as an initial, reversible step. The subsequent interaction of L-deprenyl with MAO leads to a reduction of the enzyme-bound flavin-adenine dinucleotide (FAD), and concomitant oxidation of the inhibitor. This oxidized inhibitor then reacts with FAD at the N-5-position in a covalent manner. The observed in vitro selectivity of L-deprenyl for MAO-B may be accounted for by differences in the affinities of the two MAO subtypes for reversible interaction with L-deprenyl, differences in the rates of reaction within the noncovalent complexes to form the irreversibly inhibited adduct, or a combination of both these factors. However, if selective inhibition is to be maintained in vivo, correct dosage schedules are critically important, since all selective MAO inhibitors described up to now lack selectivity at high doses. In experimental animals L-deprenyl is protective against the damaging effects of several neurotoxins, including the dopaminergic agents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) and the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Beside MAO-B inhibition, which above all explains the prevention of neurotoxic action of MPTP by preventing its metabolism, L-deprenyl appears to exhibit other mechanisms of action which are independent of its action on MAO-B.
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PMID:The molecular pharmacology of L-deprenyl. 163 15

We examined whether the N-methyl-D-aspartate antagonist MK-801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L-dopa in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK-801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK-801 (0.1 mg/kg) with L-dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK-801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.
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PMID:Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys. 164 62

The olfactory function of 6 patients whose parkinsonism was the result of intravenous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was compared to that of 12 age-matched patients with idiopathic Parkinson's disease (PD) and 10 age-matched normal control subjects. Unlike their PD counterparts, the olfactory test scores of patients with MPTP-induced parkinsonism did not differ significantly from those of control subjects. These findings suggest that MPTP-induced parkinsonism, unlike idiopathic PD, is unaccompanied, on average, by major alterations in the ability to smell.
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PMID:Lack of major olfactory dysfunction in MPTP-induced parkinsonism. 164 78

Effects of L-DOPA (0.1-10,000 nM) on spontaneous release (Sp), evoked release (S) and tissue content (C) of dopamine (DA) were studied comparatively in superfused striatal slices from control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black mice to obtain evidence for L-DOPA-induced facilitation of S via presynaptic beta-adrenoceptors. In control slices, isoproterenol-induced concentration-dependent increases in S were propranolol-sensitive. L-DOPA at 0.1-3 nM tended to increase the S of DA with a concomitant tendency of increases in Sp. L-DOPA at 10-1 x 10(4) nM concentration-dependently increased Sp. L-DOPA at 1-10 microM tended to increase S and 10 microM increased C. In slices from MPTP-treated mice, the absolute amounts of Sp, S and C decreased by half compared to those in control slices. L-DOPA at 3 nM facilitated S without increasing Sp. This facilitation was antagonized by propranolol at 3 nM. L-DOPA at 30 nM decreased S from the peak facilitation, which contrasted with no effect in the control slices. However, 10-100 nM L-DOPA increased Sp more markedly than that in the control slices. L-DOPA at 100 nM increased S and C, which contrasted with no effect in the control slices. In conclusion, nanomolar L-DOPA facilitates the S of DA via presynaptic beta-adrenoceptors at concentrations lower than those required to induce conversion to DA even in striatal slices from the MPTP-treated mice model for Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nanomolar L-dopa facilitates release of dopamine via presynaptic beta-adrenoceptors: comparative studies on the actions in striatal slices from control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black mice, an animal model for Parkinson's disease. 164 16

Parkinson's disease is one of the commonest neurodegenerative disorders in Western society. Although the neuropathological changes have been well documented, the underlying biochemical defect is unknown. Toxins may play a part in the aetiology of this disorder. It has been shown that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a Parkinson-like syndrome in both man and primates and 1-methyl-4-phenylpyridine (MPP+), a metabolite of MPTP, inhibits NADH-ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain. We studied mitochondrial respiratory chain function in skeletal muscle from patients with Parkinson's disease because, like brain, it has a high dependence on oxidative metabolism. Our results show low activity in all complexes studied (I, II and IV). The implications of these findings are discussed in relation to the aetiology of Parkinson's disease.
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PMID:Respiratory chain abnormalities in skeletal muscle from patients with Parkinson's disease. 165 41

Abnormally increased subthalamic nucleus output to the internal pallidal segment and the reticular part of the substantia nigra plays a critical pathophysiological role in the development of parkinsonism. Because synaptic transmission of subthalamic output is glutamatergic and mediated, in part, by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, AMPA receptor antagonists may possess antiparkinsonian properties. We report that in monoamine-depleted rats, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) (Novo-Nordisk, Copenhagen, Denmark)--a selective antagonist of the AMPA subtype of glutamate receptor--suppressed muscular rigidity but had no effect on akinesia. NBQX microinjected into the subthalamic nucleus, internal pallidal segment, and reticular part of the substantia nigra, but not into the laterodorsal neostriatum of the rats, stimulated locomotor activity and reduced muscular rigidity. In aged Rhesus monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills. NBQX also potentiated the antiparkinsonian effects of L-3,4-dihydroxyphenylalanine in both rats and monkeys. Blockade of excitatory synaptic transmission by AMPA receptor antagonists may provide a new therapeutic strategy for Parkinson's disease (PD).
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PMID:The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys. 166 77

These studies characterise the pharmacology of ropinirole, a selective D-2 agonist. High-affinity human caudate binding revealed a Ki for D2 receptors of 2.9 x 10(-8) M with no affinity for D1 at 10(-4) M in the rat. Ropinirole was weakly active at alpha 2-adrenoceptors and 5-HT2 receptors but inactive at 5-HT1, benzodiazepine and gamma-aminobutyric acid receptors or alpha 1 and beta-adrenoceptors. In rodents, ropinirole, like apomorphine, caused biphasic spontaneous locomotor activity and contralateral circling in 6-OHDA-lesioned mice with no tolerance to the latter after 14 days treatment. Amphetamine caused ipsilateral responses in the lesioned mice. Ropinirole did not cause marked stereotypies. In marmosets ropinirole (0.05-1.0 mg/kg SC or 0.1 mg/kg PO) reversed all motor and behavioural deficits induced by MPTP. This response started 10-20 minutes after dosing, and exceeded 2 hours. No tolerance was seen following chronic b.i.d. treatment. Similar results were obtained with 1-dopa plus benserazide; however, 1-dopa always caused emesis, whereas beneficial effects were shown with ropinirole in the absence of this side effect. These results support the continued clinical assessment of ropinirole for the treatment of Parkinson's disease.
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PMID:Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist. 167 48

The study attempted to verify whether activation of locus coeruleus neurons by alpha 2 antagonists might improve parkinsonian signs. Treatment with the racemic alpha 2 antagonist R 47 243 of a monkey with MPTP-induced parkinsonian signs normalized blink rate, reduced resting tremor, and improved several other parkinsonian signs. In a second experiment, the (-)-isomer R 62 651 produced a gradual change in tremor which was the inverse of the mannner in which tremor had become installed as the result of progression earlier upon the MPTP challenge. It is proposed that further research be conducted to determine whether alpha 2 antagonists may beneficially influence the progression of Parkinson's disease.
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PMID:Effects of an alpha 2 antagonist in a 20-year-old Java monkey with MPTP-induced parkinsonian signs. 167 7


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