Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0233565 (bradykinesia)
 2,352 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease results from the progressive degeneration of dopamine neurons that innervate the striatum. In rodents, glial-cell-line-derived neurotrophic factor (GDNF) stimulates an increase in midbrain dopamine levels, protects dopamine neurons from some neurotoxins, and maintains injured dopamine neurons. Here we extend the rodent studies to an animal closer to the human in brain organization and function, by evaluating the effects of GDNF injected intracerebrally in rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The recipients of GDNF displayed significant improvements in three of the cardinal symptoms of parkinsonism: bradykinesia, rigidity and postural instability. GDNF administered every four weeks maintained functional recovery. On the lesioned side of GDNF-treated animals, dopamine levels in the midbrain and globus pallidus were twice as high, and nigral dopamine neurons were, on average, 20% larger, with an increased fibre density. The results indicate that GDNF may be of benefit in the treatment of Parkinson's disease.
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PMID:Functional recovery in parkinsonian monkeys treated with GDNF. 863 74

Previous studies have shown that riluzole (2-amino-6-trifluoromethoxy-benzothiazole), a drug which interferes with glutamate neurotransmission, has a neuroprotective action in rodent models of global and focal cerebral ischemia. In this pilot study, the protective and palliative effects of riluzole have been examined using an animal model of Parkinson's disease. Two monkeys were rendered hemiparkinsonian by one intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and motor signs were evaluated using clinical examination and electromyographic recordings. When riluzole (4 mg/kg) was administered before the injection of MPTP, parkinsonian motor symptoms, in particular bradykinesia and rigidity, were absent. When injected daily in one monkey which presented stable motor symptoms, bradykinesia and rigidity were significantly reduce d. Riluzole pretreatment induced a persistent increase in dopamine turnover when compared to MPTP alone. Thus, a possible neuroprotection and a facilitation of dopamine release may explain the behavioural effects reported with riluzole treatment. These preliminary results suggest that riluzole could possess neuroprotective and palliative effects in a primate model of Parkinson's disease.
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PMID:Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey: a pilot study. 866 12

The D2 dopamine agonist piribedil is not widely used in the treatment of Parkinson's disease because it was thought to be effective mainly on parkinsonian tremor and to produce a high incidence of peripheral side effects, particular nausea. In this study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates to reevaluate the antiparkinsonian ability of piribedil after its oral administration in the presence or absence of domperidone pretreatment. Adult common marmosets (Callithrix jacchus) were treated with the nigral toxin MPTP to induce a parkinsonian syndrome characterised primarily by bradykinesia and other motor deficits. Oral administration of a solution of piribedil [1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine] produced a dose-related reversal of all MPTP locomotor and behavioural deficits. However, this effect was short lived and associated with unwanted effects, particular nausea and retching, which clearly hindered locomotion. In contrast, after pretreatment with the peripheral dopamine antagonist domperidone, administration of piribedil did not induce nausea or retching in MPTP-treated marmosets. In these animals, piribedil caused a more marked and longer lasting enhancement of locomotor activity and a further reduction in behavioural deficits than that observed after administration of piribedil alone. In addition, piribedil induced increased vigilance and awareness. These data show that piribedil can reverse akinesia and rigidity in MPTP-treated primates. In addition, they show the drug to be effective without peripheral side effects when used in conjunction with domperidone. These data indicate that piribedil should be an effective monotherapy for Parkinson's disease.
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PMID:An appraisal of the antiparkinsonian activity of piribedil in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. 868 81

Experimental studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that akinesia and rigidity are linked to a hyperactivity of glutamatergic subthalamic nucleus neurons and that the lesion of this nucleus can ameliorate parkinsonian motor signs. In our study, high-frequency stimulation applied at the subthalamic level was performed on two Macaca mulatta monkeys rendered hemiparkinsonian by unilateral infusion of MPTP. Its effects on rigidity and bradykinesia have been quantified. The results exhibit an important alleviation of both symptoms during the application of subthalamic stimulation comparable to that obtained during L-Dopa treatment, but without the appearance of abnormal movements such hemiballism or dyskinesia. Our data show that subthalamic stimulation has a beneficial effect on experimental parkinsonian rigidity and bradykinesia and suggests a new therapy approach for the treatment of Parkinson's disease by using subthalamic high-frequency stimulation instead of L-Dopa treatment.
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PMID:Alleviation of experimental hemiparkinsonism by high-frequency stimulation of the subthalamic nucleus in primates: a comparison with L-Dopa treatment. 891 87

Nineteen Macaca fascicularis monkeys were divided into four different groups: Group A (n = 3), control; Group B (n = 3), monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Group C (n = 8), animals treated with MPTP in which the subthalamic nucleus (STN) was unilaterally lesioned by kainic acid injection; in Group D (n = 5), the STN was lesioned prior to MPTP administration. Subthalamotomy resulted in a bilateral improvement of tremor, spontaneous activity, bradykinesia (evaluated by a manual motor test) and freezing in Group C. All these monkeys developed hemichorea contralateral to the lesion. The improvement was maintained and the hemichorea continued until death. The monkeys in group D showed severe hemiballism which persisted throughout MPTP administration and developed parkinsonian signs mainly on the side ipsilateral to the lesion. Analysis of the in situ hybridization of the mRNA coding for glutamic acid decarboxylase (GAD) of MPTP monkeys showed a significant increase in the mean density of silver grains over every labelled neuron in the globus pallidum lateralis (56.8% over control) as well as the globus pallidus medialis (GPM) (45.7% over control) and the substantia nigra reticulata (SNR) (35.8% over control). No significant change was observed in the thalamic nucleus reticularis. Subthalamotomy (Groups C and D) produced a significant reduction in mRNA GAD expression on the side of the lesion in the GPM and the SNR (34% and 42.3%, respectively) with respect to the ipsilateral (non-lesioned) side and also when compared with parkinsonian monkeys. These results confirm and expand, at the cellular level, the paramount role of STN hyperactivity in the pathophysiology of parkinsonism. The therapeutic consequences of these findings for surgical treatment of Parkinson's disease are discussed.
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PMID:Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis. 893 92

Animal models are an important aid in experimental medical science because they enable one to study the pathogenetic mechanisms and the therapeutic principles of treating the functional disturbances (symptoms) of human diseases. Once the causative mechanism is understood, animal models are also helpful in the development of therapeutic approaches exploiting this understanding. On the basis of experimental and clinical findings. Parkinson's disease (PD) became the first neurological disease to be treated palliatively by neurotransmitter replacement therapy. The pathological hallmark of PD is a specific degeneration of nigral and other pigmented brainstem nuclei, with a characteristic inclusion, the Lewy body, in remaining nerve cells. There is now a lot of evidence that degeneration of the dopaminergic nigral neurones and the resulting striatal dopamine-deficiency syndrome are responsible for its classic motor symptoms akinesia and bradykinesia. PD is one of many human diseases which do not appear to have spontaneously arisen in animals. The characteristic features of the disease can however be more or less faithfully imitated in animals through the administration of various neurotoxic agents and drugs disturbing the dopaminergic neurotransmission. The cause of chronic nigral cell death in PD and the underlying mechanisms remain elusive. The partial elucidation of the processes underlie the selective action of neurotoxic substances such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has however revealed possible molecular mechanisms that give rise to neuronal death. Accordingly, hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD. The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of PD. The currently most important animal models (e.g. the reserpine model, neuroleptic-induced catalepsy, tremor models, experimentally-induced degeneration of nigrostriatal dopaminergic neurons with 6-OHDA, methamphetamine, MPTP, MPP+, tetrahydroisoquinolines, beta-carbolines, and iron) critically reviewed next, and are compared with the characteristic features of the disease in man.
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PMID:Animal models of Parkinson's disease: an empirical comparison with the phenomenology of the disease in man. 901 91

Studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in monkeys suggest that excessive inhibitory outflow from the internal segment of the globus pallidus (GPi) suppresses the motor thalamus, which reduces activation of the cerebral cortex motor system, resulting in the slowness and poverty of movement of Parkinson's disease (PD). This hypothesis is supported by reports of high rates of spontaneous neuronal discharges and hypermetabolism in GPi (ref. 4-7) and impaired activation of the supplementary motor area (SMA) and dorsolateral prefrontal regions in PD patients. Furthermore, lesion or chronic high-frequency electrical (likely inactivating) stimulation of GPi (ref. 10-14) is associated with marked improvements in akinesia and rigidity, and the impaired activation of SMA is reversed when the akinesia is treated with dopamine agonists. To test whether improvement in motor function with pallidal surgery can be attributed to increased activity in premotor cortical regions, we assessed the changes in regional cerebral blood flow (rCBF) and parkinsonian symptoms during disruption of GPi activity with high-frequency stimulation delivered through implanted brain electrodes. Positron emission tomography (PET) revealed an increase in rCBF in ipsilateral premotor cortical areas during GPi stimulation, which improved rigidity and bradykinesia. These results suggest that disrupting the excessive inhibitory output of the basal ganglia reverses parkinsonism, via a thalamic relay, by activation of brain areas involved in the initiation of movement.
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PMID:Globus pallidus stimulation activates the cortical motor system during alleviation of parkinsonian symptoms. 917 79

Nitric oxide, produced following activation of N-methyl-D-aspartate (NMDA) receptors, may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity since NMDA receptor antagonists have been shown to prevent MPTP induced nigral cell loss in primates. Common marmosets were treated with either saline or MPTP or L-NGnitro arginine methyl ester (L-NAME) or MPTP and L-NAME. MPTP-treated common marmosets showed motor deficits including bradykinesia, rigidity, and tremor accompanied by a marked loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta and of [3H]-mazindol binding in the caudate-putamen. MPTP treatment also caused an increase in glial fibrillary acidic protein (GFAP) staining in the substantia nigra compared to controls. However, MPTP treatment did not alter the number of constitutive nitric oxide synthase-immunoreactive neurones in the caudate-putamen. Furthermore, neurones or glial cells immunoreactive for inducible nitric oxide synthase were not observed in the substantia nigra pars compacta following MPTP treatment. L-NAME treatment alone did not produce any behavioural changes in marmosets and did not alter the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta, the number of constitutive nitric oxide synthase-immunoreactive neurones or [3H]-mazindol binding in the caudate-putamen compared to saline-treated control animals. Furthermore, L-NAME did not affect the motor deficits, loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta, loss of [3H]-mazindol binding in the caudate-putamen, or the increase in GFAP staining in the substantia nigra induced by MPTP treatment of common marmosets. The failure of L-NAME to protect against MPTP-induced toxicity in the marmoset suggests that nitric oxide does not play a major role in such toxicity and casts doubt over the involvement of the NMDA:nitric oxide system in neurodegeneration in MPTP-treated primates.
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PMID:Nitric oxide synthase inhibition and MPTP-induced toxicity in the common marmoset. 918 19

The pathophysiology of dystonia is unclear, but several clues implicate striatal dopamine dysfunction. In contrast, the causal relationship between striatal dopamine deficiency and parkinsonism is well defined. We now suggest that parkinsonism or dystonia may occur following striatal dopamine deficiency. Baboons treated with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed transient hemidystonia prior to hemiparkinsonism. The day after MPTP treatment, most animals had spontaneous ipsilateral turning. Within a few days, all developed contralateral hemidystonia, with the arm and leg extended and externally rotated. This transient dystonia preceded hemiparkinsonism with flexed posture, bradykinesia, and postural tremor that persisted for up to 1.5 years. Dystonia corresponded temporally with a decreased striatal dopamine content and a transient decrease in D2-like receptor number. The time course of dystonia and parkinsonism is analogous to lower limb dystonia as the first, frequently transient, symptom of Parkinson's disease in humans. The association of striatal dopamine deficiency with dystonia and parkinsonism implies that other factors influence clinical manifestations.
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PMID:MPTP induces dystonia and parkinsonism. Clues to the pathophysiology of dystonia. 937 34

Carbon disulfide toxicity is well characterized. The principal target organ is the nervous system, although cardiovascular, reproductive, ophthalmologic, and other effects are also recognized. The neurotoxicity manifests in three ways: encephalopathy, peripheral and cranial nerve dysfunction, and movement abnormalities. This report describes a case of olivopontocerebellar atrophy, a form of multiple system atrophy, developing in an adult after over 30 years of occupational exposure to carbon disulfide. The patient presented with the insidious onset of balance problems, impotence, and irritability, without tremor, cogwheel rigidity, bradykinesia, or changes in facial expression. Over the next few years severe ataxia developed, and the clinical diagnosis was confirmed with computed tomography and magnetic resonance imaging scans. The patient experienced multiple medical complications and died approximately 9 years after diagnosis. This case is consistent with a large body of clinical and experimental literature, much of it 50 years old, showing that carbon disulfide can cause movement disorders. It also serves as a reminder that movement disorders, ranging from parkinsonism to dystonia, are associated with a variety of toxic exposures such as manganese, carbon monoxide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and medications.
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PMID:Multiple system atrophy following chronic carbon disulfide exposure. 1070 37


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