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)

To examine the consequences of nigrostriatal denervation and chronic levodopa (L-DOPA) treatment on functional activity of the basal ganglia, we analyzed, using in situ hybridization, the cellular expression of the mRNA encoding for cytochrome oxidase subunit I (COI mRNA), a molecular marker for functional neuronal activity, in the basal ganglia. This analysis was performed in monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Intoxication, some of which had been receiving L-DOPA, and in patients with Parkinson's disease (PD). In MPTP-intoxicated monkeys compared with control animals, COI mRNA expression was increased in the subthalamic nucleus (STN) and in the output nuclei of the basal ganglia, i.e., the internal segment of the globus pallidus and the substantia nigra pars reticulata. This increase was partially reversed by L-DOPA treatment. COI mRNA expression remained unchanged in the external segment of the globus pallidus (GPe). In PD patients, all of whom had been treated chronically by L-DOPA, COI mRNA expression in the analyzed basal ganglia structures was similar to that in control subjects. These results are in agreement with the accepted model of basal ganglia organization, to the extent that the output nuclei of the basal ganglia are considered to be overactive after nigrostriatal denervation, partly because of increased activity of excitatory afferents from the STN. Yet, our results would also seem to contradict this model, because the overactivity of the STN does not seem to be attributable to a hypoactivation of the GPe.
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PMID:Consequences of nigrostriatal denervation on the functioning of the basal ganglia in human and nonhuman primates: an in situ hybridization study of cytochrome oxidase subunit I mRNA. 898 98

The cellular expression of cytochrome oxidase subunit I (COI) mRNA as a metabolic marker for neuronal activity has recently been used to examine the effects of nigrostriatal denervation on the functioning of the basal ganglia. However, this technique also allows functional changes to be detected in other cerebral structures in parkinsonian syndromes. Since the zona incerta has been implicated in locomotor activity and has been the site of stereotactic surgery in Parkinson's disease, the aim of our study was to determine whether changes in neuronal activity are observed in this structure during parkinsonism. Using in situ hybridization, we analyzed the expression of COI mRNA in rats with 6-hydroxydopamine unilateral lesion of the substantia nigra and sham-operated animals. A quantitative analysis showed that COI mRNA expression was increased in the zona incerta ipsilateral to the lesion 24 h and 3 days after lesion, but by day 14 had returned almost to the level observed in controls. The hyperactivity of zona incerta neurons was confirmed by single-unit electrophysiological recordings. In contrast to the COI mRNA expression, the increase in electric neuronal activity was still observed 1 month after the lesion. This increase in zona incerta neuronal activity after nigrostriatal denervation might be related to the pathophysiology of parkinsonism, at least in the early stages, in agreement with previous reports suggesting an involvement of the zona incerta in motor functions.
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PMID:Functional activity of zona incerta neurons is altered after nigrostriatal denervation in hemiparkinsonian rats. 1071 2

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinson's disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem.
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PMID:Metabolic effects of nigrostriatal denervation in basal ganglia. 1105 24

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is now recognized as an effective treatment for advanced Parkinson's disease, but the molecular basis of its effects remains unknown. This study examined the effects of unilateral STN HFS (2 hr of continuous stimulation) in intact and hemiparkinsonian awake rats on STN neuron metabolic activity and on neurotransmitter-related gene expression in the basal ganglia, by means of in situ hybridization histochemistry and immunocytochemistry. In both intact and hemiparkinsonian rats, this stimulation was found to induce c-fos protein expression but to decrease cytochrome oxidase subunit I mRNA levels in STN neurons. STN HFS did not affect the dopamine lesion-mediated overexpression of enkephalin mRNA or the decrease in substance P in the ipsilateral striatum. The lesion-induced increases in intraneuronal glutamate decarboxylase 67 kDa isoform (GAD67) mRNA levels on the lesion side were reversed by STN HFS in the substantia nigra, partially antagonized in the entopeduncular nucleus but unaffected in the globus pallidus. The stimulation did not affect neuropeptide or GAD67 mRNA levels in the side contralateral to the dopamine lesion or in intact animals. These data furnish the first evidence that STN HFS decreases the metabolic activity of STN neurons and antagonizes dopamine lesion-mediated cellular defects in the basal ganglia output structures. They provide molecular substrate to the therapeutic effects of this stimulation consistent with the current hypothesis that HFS blocks STN neuron activity. However, the differential impact of STN HFS on the effects of dopamine lesion among structures receiving direct STN inputs suggests that this stimulation may not cause simply interruption of STN outflow.
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PMID:High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat. 1207 9

Intermittent oral doses of levodopa (L-DOPA) are routinely used to treat Parkinson's disease, but with prolonged use can result in adverse motor complications, such as dyskinesia. Continuous administration of L-DOPA achieves therapeutic efficacy without producing this effect, yet the molecular mechanisms are unclear. This study examined, by in situ hybridization histochemistry, the effects of continuous or intermittent L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Results were compared to 6-OHDA-treated rats receiving vehicle. Our results provide original evidence that continuous L-DOPA normalizes the 6-OHDA-lesion-induced increase in mRNA levels encoding for the 67 kDa isoform of glutamate decarboxylase in neurons of the globus pallidus and cytochrome oxidase subunit I mRNA levels in the subthalamic nucleus. The extent of normalization did not differ between the continuous and intermittent groups. In addition, intermittent L-DOPA induced an increase in the mRNA levels encoding for the 65 kDa isoform of glutamate decarboxylase in globus pallidus neurons ipsilateral to the lesion and a bilateral increase in c-fos mRNA expression in the subthalamic nucleus. These results suggest that continuous L-DOPA tends to normalize the 6-OHDA-lesion-induced alterations in cell signaling in the pallido-subthalamic loop. On the other hand, we propose that chronic intermittent L-DOPA exerts a dual effect by normalizing cell signaling in a subpopulation of neurons in the globus pallidus and subthalamic nucleus while inducing abnormal signaling in another subpopulation.
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PMID:Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion. 1282 44

This study examined the cellular correlates of the akinetic deficits produced in Wistar rats by discrete bilateral 6-hydroxydopamine (6-OHDA) striatal infusions in the dorsolateral striatum, mimicking the preferential denervation of the motor striatal territory in early symptomatic stage of Parkinson's disease (PD). Intraneuronal gene expression of cytochrome oxidase subunit I (COI), a metabolic index of neuronal activity, was increased in the subthalamic nucleus, substantia nigra pars reticulata and decreased in frontal cortical areas, but paradoxically unchanged in the striatum, globus pallidus, entopeduncular nucleus and ventrolateral thalamic nucleus. Neither preproenkephalin A nor preprotachykinin mRNA expression, markers of striatal projection neurons, were modified in the denervated striatal area despite 90% loss of dopamine (DA) terminals. Preproenkephalin A mRNA expression was however, decreased in the nondepleted striatal region, suggesting compensatory increase of dopamine tone from those spared areas. A chronic treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethylnyl)-pyridine (MPEP), which alleviated the akinetic disorders produced by the lesion, reversed the lesion-induced variations of COI gene expression, moderately increased this marker in the structures unaffected by the lesion and did not modify the striatal neuropeptides gene expression. These data suggest that the expression of akinetic deficits in early parkinsonism is associated with focused metabolic changes in the cortico-basal ganglia-cortical loop downstream of the striatum and pallidal complex.
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PMID:Dysfunction of the cortico-basal ganglia-cortical loop in a rat model of early parkinsonism is reversed by metabotropic glutamate receptor 5 antagonism. 1632 10

The pedunculopontine nucleus is a mesencephalic nucleus that has widespread and reciprocal connections with the basal ganglia. It has been implicated in the physiopathology of akinesia, rigidity, gait failure and sleep disorders associated with Parkinson's disease. In this study, in situ hybridization was used to examine the changes in neuronal metabolic activity (measuring cytochrome oxidase subunit I) and in the level of acetylcholine and Substance P synthesis in the pedunculopontine nucleus of monkeys chronically treated with MPTP. Significant reductions were observed in cytochrome oxidase subunit I (p = 0.001), choline acetyl transferase (p = 0.003) and substance P (p = 0.006) mRNA expression in parkinsonian animals compared with controls, indicating that pedunculopontine cholinergic neurons activity decreases with parkinsonism.
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PMID:Changes in the neuronal activity in the pedunculopontine nucleus in chronic MPTP-treated primates: an in situ hybridization study of cytochrome oxidase subunit I, choline acetyl transferase and substance P mRNA expression. 1698 96

There is accumulating evidence that the centre median-parafascicular (CM/Pf) complex of the thalamus is implicated in basal ganglia-related movement disorders and notably in Parkinson's disease. However, the impact of the changes affecting CM/Pf on the pathophysiological functioning of basal ganglia in parkinsonian state remains poorly understood. To address this issue, we have examined the effects of excitotoxic lesion of CM/Pf and of 6-hydroxydopamine-induced lesion of nigral dopamine neurons, separately or in association, on gene expression of markers of neuronal activity in the rat basal ganglia (striatal neuropeptide precursors, GAD67, cytochrome oxidase subunit I) by quantitative in situ hybridization histochemistry. CM/Pf lesion prevented the changes produced by the dopamine denervation in the components of the indirect pathway connecting the striatum to the output structures (striatopallidal neurons, globus pallidus, subthalamic nucleus), and among the output structures, in the entopeduncular nucleus. Preliminary data on the effects of deep brain stimulation of CM/Pf in rats with nigral dopamine lesion show that this surgical approach produces efficient anti-akinetic effect associated with partial reversal of the dopamine lesion-induced increase in striatal preproenkephalin A mRNA levels, a marker of the striatopallidal neurons. These data, which provide substrates for the potential of CM/Pf surgery in the treatment of movement disorders, are discussed in comparison with the effects of lesion or deep brain stimulation of the subthalamic nucleus, the currently preferred target for the surgical treatment of PD.
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PMID:Impact of surgery targeting the caudal intralaminar thalamic nuclei on the pathophysiological functioning of basal ganglia in a rat model of Parkinson's disease. 1879 21

The thalamic centromedian-parafascicular (CM/Pf) complex, mainly represented by Pf in rodents, is proposed as an interesting target for the neurosurgical treatment of movement disorders, including Parkinson's disease. In this study, we examined the functional impact of subchronic high-frequency stimulation (HFS) of Pf in the 6-hydroxydopamine-lesioned hemiparkinsonian rat model. Pf-HFS had significant anti-akinetic action, evidenced by alleviation of limb use asymmetry (cylinder test). Whereas this anti-akinetic action was moderate, Pf-HFS totally reversed lateralized neglect (corridor task), suggesting potent action on sensorimotor integration. At the cellular level, Pf-HFS partially reversed the dopamine denervation-induced increase in striatal preproenkephalin A mRNA levels, a marker of the neurons of the indirect pathway, without interfering with the markers of the direct pathway (preprotachykinin and preprodynorphin). Pf-HFS totally reversed the lesion-induced changes in the gene expression of cytochrome oxidase subunit I in the subthalamic nucleus, the globus pallidus, and the substantia nigra pars reticulata, and partially in the entopeduncular nucleus. Unlike HFS of the subthalamic nucleus, Pf-HFS did not induce per se dyskinesias and directly, although partially, alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced forelimb dyskinesia. Conversely, L-DOPA treatment negatively interfered with the anti-parkinsonian effect of Pf-HFS. Altogether, these data show that Pf-DBS, by recruiting a large basal ganglia circuitry, provides moderate to strong anti-parkinsonian benefits that might, however, be affected by L-DOPA. The widespread behavioral and cellular outcomes of Pf-HFS evidenced here demonstrate that CM/Pf is an important node for modulating the pathophysiological functioning of basal ganglia and related disorders.
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PMID:Deep brain stimulation of the center median-parafascicular complex of the thalamus has efficient anti-parkinsonian action associated with widespread cellular responses in the basal ganglia network in a rat model of Parkinson's disease. 2066 Feb 74

Activation of group III metabotropic glutamate (mGlu) receptors has been recently highlighted as a potential approach in the treatment of Parkinson's disease (PD). This study evaluates the antiparkinsonian action of systemic administration of the broad-spectrum agonist of group III mGlu receptors, 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), and investigates its site of action within the basal ganglia circuitry. Acute injection of ACPT-I reverses haloperidol-induced catalepsy, an index of akinesia in rodents. In a rat model of early PD based on partial bilateral nigrostriatal lesions, chronic (2weeks) administration of ACPT-I is required to efficiently alleviate the akinetic deficit evidenced in a reaction time task. This treatment counteracts the post-lesional increases in the gene expression of cytochrome oxidase subunit I, a metabolic marker of neuronal activity, in the overall subthalamic nucleus and in the lateral motor part of the substantia nigra pars reticulata (SNr) but has no effect in the globus pallidus. Paradoxically, ACPT-I administration in sham animals impairs performance and induces overexpression of cytochrome oxidase subunit I mRNA in the lateral SNr, and has no effect in the subthalamic nucleus or globus pallidus. Altogether, our results provide new evidence for the antiparkinsonian efficiency of group III mGlu receptor agonism, point to the regulation of the overactive subthalamo-nigral connection as a main site of action in an early stage of PD and underline the complex interplay between these receptors and the dopaminergic system to regulate basal ganglia function in control and PD conditions.
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PMID:Antiparkinsonian action of a selective group III mGlu receptor agonist is associated with reversal of subthalamonigral overactivity. 2224 62


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