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)

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces certain clinical, pathological, and neurochemical features of Parkinson's disease. MPTP is metabolized by monoamine oxidase Type B to 1-methyl-4-phenylpyridine (MPP+), which is selectively accumulated by high-affinity uptake mechanisms into dopaminergic neurons. Lyden et al. described low-affinity binding of MPTP to synthetic and retinal melanin. We showed that MPP+ binds to neuromelanin with high affinity, suggesting that in MPTP neurotoxicity, MPP+ enters nigral neurons by the dopamine uptake system and binds to neuromelanin, which serves as a depot, continuously releasing MPP+ until it destroys the cells. This model predicts that agents which compete with MPP+ binding to neuromelanin should partially protect the dopamine neurons from MPTP-induced toxicity. The most potent identified competitor for MPP+ binding to melanin is the antimalarial drug chloroquine, which has a high affinity for melanins. In the present study, chloroquine, administered to monkeys in conventional anti-malarial doses before MPTP, protects them from MPTP-induced parkinsonian motor abnormalities, dopamine depletion in the striatum, and neuropathological changes in the substantia nigra.
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PMID:Evidence for neuromelanin involvement in MPTP-induced neurotoxicity. 288 68

We studied the effect of intracerebroventricular infusion of dopamine and dopamine agonists in rat and primate models of Parkinson's disease as an experimental approach to the treatment of levodopa-induced fluctuations. The infusion of dopamine, lisuride, and pergolide into the ventricle ipsilateral to the lesion, by 6-hydroxydopamine, of the nigrostriatal pathway induced a contralateral rotation which was maximal 24-48 h after infusion and whose intensity progressively decreased over the period of 1 week. [3H]Spiperone binding was decreased by the infusion of dopamine but the responses to subcutaneous apomomorphine were unchanged. The infusion of dopamine also restored the levels of monoamines in the rat brain. In chronic reserpized rats, the infusion of dopamine restored brain levels of dopamine but did not reverse akinesia unless monoamine oxidase inhibitors were simultaneously administered, either systemically or intracerebroventricularly. Lisuride and pergolide proved much weaker than dopamine in reversing the effects of reserpine. Intracerebroventricular infusion of dopamine plus deprenyl reversed MPTP induced akinesia in monkeys but the pump used for the delivery was not well tolerated, because of its size, by the animals.
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PMID:Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson's disease. 290 48

The authors investigated the effects of chronic intracerebroventricular (ICV) infusion of dopamine (DA) and DA agonists in animal models of DA deficiency in rodents and primates. Rats with unilateral nigrostriatal lesions induced by 6-OH-DA received infusions of DA, pergolide, lisuride, and (+)-4-propyl-9-hydroxynaphthoxacine (PHNO) for from 1 to 2 weeks through a catheter implanted into the cerebral ventricle ipsilateral to the lesion and connected to an osmotic minipump filled with the active substance. The infused animals had persistent contralateral rotation during the period of infusion. The DA infusion restored DA levels in lesioned animals. In animals treated chronically with reserpine, the ICV DA infusion restored DA levels in the brain, but akinesia was not reversed unless monoamine oxidase inhibiters were also given, intraperitoneally or ICV, with the DA infusion. An ICV infusion of PHNO reversed reserpine-induced akinesia. The infusion of DA or PHNO restored normal patterns of behavior in monkeys made akinetic by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but the infusion was complicated by intolerance to the pump or frequent disconnection of the catheter. An ICV infusion of PHNO may be an alternative experimental approach to the treatment of fluctuations in patients with Parkinson's disease.
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PMID:Intracerebroventricular infusion of dopamine and its agonists in rodents and primates. An experimental approach to the treatment of Parkinson's disease. 290 93

Parkinson disease is characterized by a major loss (approximately 80% or more) of dopaminergic nigrostriatal neurons and by an increased turnover of neurotransmitter by surviving neurons of the nigrostriatal tract. In theory, increased turnover of dopamine should be associated with an oxidative stress derived from increased production of hydrogen peroxide. The peroxide is formed during the oxidative deamination of dopamine by monoamine oxidase. In experiments with mice, increased presynaptic turnover of dopamine was evoked by injection of reserpine, which interferes with the storage of dopamine in synaptic vesicles. Loss of dopamine and formation of deaminated metabolites were accompanied by a significant rise (87.8%) in the level of oxidized glutathione in brain. This change was observed in the striatum, which is richly innervated by dopamine terminals, but not in the frontal cortex, which receives a much sparser innervation by catecholamine nerve terminals. The rise in oxidized glutathione was seen even though dopamine terminals constitute only 1% or less of the mass of the striatum. Clorgyline, an inhibitor of monoamine oxidase type A, blocked the formation of oxidized glutathione. These observations confirm that a selective increase in neurotransmitter turnover within nigrostriatal nerve terminals can evoke a change in cellular redox status. We suggest that an oxidative stress may play a role in the natural history of Parkinson disease.
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PMID:Dopamine turnover and glutathione oxidation: implications for Parkinson disease. 291 85

The effects of a COMT-inhibitor, U-0521, and a MAO-B-inhibitor, 1-deprenyl, on L-dopa-induced circling behaviour were compared in 6-OHDA-lesioned rats. The actions of U-0521 and 1-deprenyl on the anti-cataleptic effect of L-dopa were also studied. Both U-0521 and 1-deprenyl were found to potentiate L-dopa-induced circling behaviour and anti-cataleptic effect of L-dopa. In both test systems the L-dopa potentiation of 1-deprenyl was longer-lasting than that caused by U-0521. Thus inhibition of COMT, like inhibition of MAO, is able to enhance the central effects of L-dopa. This principle might be beneficial in the treatment of Parkinson's disease especially if COMT-inhibitors with greater performance can be developed.
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PMID:Potentiation of central effects of L-dopa by an inhibitor of catechol-O-methyltransferase. 296 Jul 78

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes a Parkinson's disease-like syndrome in man, monkeys, and mice. We studied the effects of MPTP and its metabolite, MPP+, on neuronal properties and synaptic transmission in isolated slices of guinea-pig hippocampus using intra- and extracellular recording methods. Addition of MPTP to the superfusate (50 to 100 microM) produced the following effects: Excitatory postsynaptic potentials and extracellularly recorded population spikes, evoked by stimulation of the Schaffer collaterals were increased in amplitude during the application period (30 min). Within 30 min of washing in normal solution, synaptic transmission was blocked, although axonal population action potentials could still be elicited. The block of synaptic transmission was prevented by prior incubation in pargyline, an inhibitor of monoamine oxidase. The membrane potential and resistance of single pyramidal neurons were virtually unaffected; action potentials elicited by depolarizing intracellular current pulses were also unchanged. MPP+ (50 microM) blocked synaptic transmission during the application period by a pargyline-in-sensitive mechanism. These results suggest that MPP+ blocks synaptic transmission in the hippocampus at a presynaptic site. This effect may be relevant for the acute action of MPTP and may provide some insight into its chronic action on nigrostriatal neurons.
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PMID:Actions of MPTP and MPP+ on synaptic transmission in guinea-pig hippocampal slices. 303 64

Depression and suicide are significant problems in the elderly, both in terms of their severity and their prevalence. It is particularly difficult to distinguish depression from early dementia, since elderly depressed patients often deny mood disorder and focus on their memory problems. This differential diagnostic dilemma is further complicated by the fact that 20 percent of Alzheimer-type dementia patients have moderate to severe depression. An even higher prevalence of depression can be seen in elderly patients with stroke or Parkinson's disease. Most all of the depressive disorders of the elderly are amenable to one form or combination of therapies: pharmacologic, electro-convulsive, or psychotherapy. Tricyclic antidepressants are often associated with adverse drug reactions in the elderly, so alternatives such as MAO inhibitors, alprazolam, bupropion and psychostimulants are currently being explored in this patient population.
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PMID:Diagnosis and treatment of depression in the elderly. 306 74

MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elicits selective destruction of nigrostriatal dopamine neurons in humans and animals along with clinical symptoms of parkinsonism. Recent studies clarify mechanisms accounting for this neurotoxicity. MPTP binds with high affinity to monoamine oxidase, which transforms it to the pyridinium MPP+ . MPP+ is selectively concentrated by the dopamine neuronal uptake system. In nigral cells, binding by melanin of MPP+ affords a "depot" release mechanism to maintain prolonged high intracellular concentrations sufficient to destroy cells. PC-12 cells provide a model catecholamine cell culture for screening environmentally occurring substances that may be relevant in the etiology of idiopathic Parkinson's disease.
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PMID:MPTP: a neurotoxin relevant to the pathophysiology of Parkinson's disease. The 1985 George C. Cotzias lecture. 308 Jun 96

The potential of a new, potent, irreversible and selective inhibitor of monoamine oxidase type B, (E)-2-(3,4-dimethoxyphenyl)-3-fluorallyamine (MDL 72145), to augment the effects of L-DOPA in an animal model which reproduces the biochemical defect of Parkinson's disease has been evaluated. In rats bearing unilateral 6-hydroxydopamine lesions of the nigro-striatal dopamine pathways, both MDL 72145 and clorgyline, a selective inhibitor of MAO A, augmented the contralateral turning response to L-DOPA combined with carbidopa. The potential of inhibitors of MAO to interact adversely in the periphery with L-DOPA was investigated in the pithed rat; L-DOPA was given either intravenously or intraduodenally. Clorgyline consistently potentiated L-DOPA when given 18 h before testing. Neither MDL 72145 nor the selective inhibitor of MAO B, L-deprenyl, augmented the cardiovascular effects of intraduodenally administered L-DOPA. The data provide no reason to suppose that MDL 72145 would be very different in clinical use from L-deprenyl which is both effective and well-tolerated as an adjunct to the L-DOPA-based therapy of Parkinson's disease.
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PMID:Selective inhibition of monoamine oxidase type B by MDL 72145 increases the central effects of L-dopa without modifying its cardiovascular effects. 308

A multicenter trial was conducted at 9 Neurology Departments to evaluate the action of L-Deprenyl, a specific monoamine oxidase-B inhibitor, combined with L-Dopa in the treatment of Parkinson disease. In all, 76 patients were treated, 33 women and 43 men, on stable treatment with L-Dopa+ aromatic decarboxylase inhibitors (DI) for at least 6 months. After a 50% reduction of the L-Dopa dose, all received L-Deprenyl 5 mg twice daily for 35 day. The combined treatment resulted in a definite improvement in rigidity, bradykinesia and, most of all, tremor. Further, at the end of treatment fewer patients had depressive symptoms and the total daily number of hours of wellbeing and normal movement increased. 12 patients presented modest side effects, in no case serious enough to warrant suspension of treatment. The trial shows that with the L-Deprenyl + L-Dopa combination the dose of L-Dopa needed to control the disease can be drastically reduced.
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PMID:Multicenter trial of L-Deprenyl in Parkinson disease. 308 93


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