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)

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeated l-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However, de novo administration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenkephalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenkephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A1-17 and B1-13, leucine-enkephalin, and alpha-neoendorphin) in striatal output pathways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. Expression was assessed following repeated L-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal ganglia circuitry into anatomically discrete parallel circuits, we investigated alterations in peptide expression with reference to the detailed topography of the striatum. Following repeated L-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. This became markedly enhanced with repeated treatment. We have previously characterized the pharmacology of this enhanced response and have suggested that it is a useful model for the elucidation of the cellular and molecular mechanisms underlying L-DOPA- and dopamine agonist-induced dyskinesia. In contrast to l-DOPA, de novo administration of bromocriptine (1 or 5 mg/kg, b.d., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animals, PPE-A expression was elevated rostrally and dorsally, while PPE-B expression was reduced in the striatum at all rostrocaudal levels. Repeated l-DOPA administration was accompanied by elevations in striatal PPE-B mRNA levels and a further elevation, above lesion-induced levels, in PPE-A expression. This further elevation was restricted to the dorsolateral striatum. However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B levels may, through decreasing GABA and glutamate release, respectively, in output nuclei of the basal ganglia, play a role in the development of L-DOPA- and dopamine-agonist induced dyskinesia in Parkinson's disease. These studies suggest that anti-parkinsonian treatments which are not associated with an elevation in PPE-B and/or normalize elevated PPE-A precursor expression, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor agonists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson's disease.
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PMID:Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat. 1007 96

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.
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PMID:Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with L-DOPA. 1076 40

We investigated the role of dopamine neurons in the manifestation of levodopa-induced dyskinesia in a rat model of Parkinson's disease. Daily treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movements (AIM) in 6-hydroxydopamine-lesioned rats, which included stereotypy and contraversive rotation. After 4 weeks of levodopa treatment, rats with mild and severe AIM were assigned to two treatment subgroups. The graft subgroup received embryonic ventral mesencephalic tissue into the striatum, whilst the sham-graft subgroup received vehicle only. Rats continued to receive levodopa treatment for 3 months post-graft. Brain sections at the level of the basal ganglia were processed for autoradiography using a ligand for dopamine transporter, and in situ hybridization histochemistry for mRNAs encoding postsynaptic markers. Levodopa-induced AIM significantly improved in grafted rats. The severity of AIM correlated inversely with the density of dopamine nerve terminals in the striatum (P < 0. 001), with almost no AIM when the density of dopamine nerve terminals was >10-20% of normal. Embryonic dopamine neuronal grafts normalized not only mRNA expression for preproenkephalin (PPE) in the indirect pathway, but also mRNA expression for prodynorphin (PDyn) in the direct pathway, which was upregulated by levodopa treatment. AIM scores correlated linearly with expression of PPE mRNA in the indirect pathway (P < 0.001) and also with PDyn mRNA in the direct pathway (P < 0.001). We conclude that embryonic dopamine neuronal grafts may improve levodopa-induced dyskinesia by restoring altered activities of postsynaptic neurons, resulting not only from dopamine denervation, but also from levodopa therapy, provided that the density of striatal dopaminergic nerve terminals is restored above a 'threshold' level.
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PMID:Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease. 1086 49

GABA and enkephalin-utilizing efferents from the striatum to the external segment of the pallidal complex (GPe) are thought to be overactive in Parkinson's disease (PD). This overactivity is generally held to play a major role in the genesis of parkinsonian symptoms, which are thought to appear when dopaminergic neuronal death exceeds a critical threshold. Little is known, however, regarding the activity of this pathway during disease progression and more particularly, prior to the emergence of parkinsonian symptoms. In order to test the hypothesis that an upregulation of striatal preproenkephalin-A (PPE-A) mRNA levels occurs before the appearance of parkinsonian motor disabilities, the present study assessed PPE-A mRNA expression and striatal dopamine (DA) content following a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration protocol in monkeys that produces a progressive parkinsonian state. Groups ranged from normal to full parkinsonian through asymptomatic lesioned monkeys. The key finding of this study is that PPE-A expression is already upregulated in asymptomatic-lesioned monkeys showing a marked DA depletion (56%). Importantly, this up-regulation is restricted to motor regions of the basal ganglia circuitry. The increased PPE-A mRNA expression observed in asymptomatic, but DA-depleted animals, supports our initial hypothesis of such an upregulation occurring before the appearance of parkinsonian motor disabilities. Furthermore, when considered with recent electrophysiological and histochemical data, these findings question the functional significance of upregulated enkephalin transmission in the indirect striatopallidal pathway.
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PMID:Upregulation of striatal preproenkephalin gene expression occurs before the appearance of parkinsonian signs in 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine monkeys. 1130 Jul 29

The oxidation of opioid peptides by tyrosinase in the presence of an excess of a thiol gives rise to cysteinyldopa derivatives. The major products arising from the reaction between Leu-enkephalin and cysteine are represented by 5-S-cysteinyldopaenkephalin (5-CDenk) and 2-S-cysteinyldopaenkephalin (2-CDenk). The interaction of 5-CDenk and 2-CDenk with reactive oxygen species (ROS) has been studied. These compounds are able to scavenge superoxide anion, hydroxyl and peroxyl radicals as well as to reduce the lipid peroxidation rate induced by ABAP. The scavenging activities in all instances are dose-dependent. In some cases CDenks are more active than compounds recognized as strong radical scavengers, such as Trolox and mannitol. As a result of the action of the Fenton system, the CDenks (as well as the Enks) are oxidized into pigmented derivatives. The possible implications of the interaction of CDenks and Enks with ROS on melanization process in Parkinson's disease are discussed.
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PMID:Interaction of enkephalin derivatives with reactive oxygen species. 1134 52

Destruction of the nigro-striatal pathway in Parkinson's disease and treatment with L-DOPA lead to persistent alterations in basal ganglia output pathways that are poorly characterised. Differential display mRNA analysis was used to study the effects of 6-hydroxydopamine-induced lesions of the medial forebrain bundle on gene expression in the rat striatum. One up-regulated cDNA identified in two independent groups of 6-hydroxydopamine-lesioned animals was cloned and sequence analysis showed 97% homology to secretogranin II. Differential up-regulation of secretogranin II following 6-hydroxydopamine lesioning was confirmed in a further group of 6-hydroxydopamine-lesioned rats using TaqMan real time quantitative reverse transcription-polymerase chain reaction. Following chronic L-DOPA treatment of 6-hydroxydopamine-lesioned rats, secretogranin II mRNA was further up-regulated to a similar degree to that observed for preproenkephalin A mRNA expression. Immunohistochemical analysis confirmed the increase in secretogranin II peptide levels in striatal neurones in 6-hydroxydopamine-lesioned rats following chronic L-DOPA treatment. The increase in secretogranin II mRNA occurring following destruction of the nigro-striatal pathway and chronic L-DOPA treatment may result in an increase in secretoneurin levels, which could be important for the regulation of striatal output pathways.
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PMID:Up-regulation of secretoneurin immunoreactivity and secretogranin II mRNA in rat striatum following 6-hydroxydopamine lesioning and chronic L-DOPA treatment. 1167 3

Current knowledge of the molecular changes induced by dopamine denervation and subsequent treatment with L-DOPA is based on studies performed on relatively acute and young animal models of parkinsonism. It is highly warranted to ask how well these models simulate the state of chronic denervation and sustained L-DOPA pharmacotherapy which are typical of advanced Parkinson's disease. This study investigates the effects of time postdenervation and L-dopa treatment duration on the striatal expression of opioid precursor mRNAs and FosB/DeltaFosB-related proteins. Unilaterally 6-hydroxydopamine-lesioned rats were treated with therapeutical doses of L-DOPA for one year (long-term group) or a few weeks (short-term group). Age-matched lesioned rats received injections of vehicle or bromocriptine, an antiparkinsonian compound which does not produce dyskinesia when administered de novo. The lesion-induced up-regulation of preproenkephalin mRNA expression persisted at more than one year postlesion, and was unaffected by the pharmacological treatments applied. L-DOPA, but not bromocriptine, induced high striatal levels of FosB/DeltaFosB immunoreactivity and prodynorphin mRNA, and these did not differ between short-term and long-term L-DOPA-treated rats. The present data provide the first demonstration that L-DOPA maintains high striatal levels of fosB and prodynorphin gene expression during a prolonged course of treatment, which simulates the clinical practice in Parkinson's disease more closely than the short-treatment paradigms studied thus far.
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PMID:Persistent changes in striatal gene expression induced by long-term L-DOPA treatment in a rat model of Parkinson's disease. 1168 9

The expression of preproenkephalin messenger RNA was studied in the brain of Parkinson disease (PD) patients using in situ hybridization. All these patients were treated with levodopa (LD) and the development of motor complications was recorded. Eleven normal controls and 14 PD patients were used, of which 4 developed dyskinesias, 3 developed wearing-off, 3 developed both dyskinesias and wearing-off, and 4 developed no adverse effect following dopaminomimetic therapy. Nigrostriatal denervation was similar between the subgroups of PD patients as assessed using 125I-RTI-specific binding to the dopamine transporter and measures of catecholamine concentrations by HPLC. A significant increase of preproenkephalin messenger RNA levels was observed in the lateral putamen of dyskinetic patients in comparison to controls (+210%; p < 0.01) and in comparison to nondyskinetic patients (+112%; p < 0.05). No change was observed in medial parts of the putamen or in the caudate nucleus. No relationship between preproenkephalin messenger RNA levels and other clinical variables such as development of wearing-off, age of death, duration of disease, or duration of LD therapy was found. These findings suggest that increase synthesis of preproenkephalin in the medium spiny output neurons of the striatopallidal pathway play a role in the development of dyskinesias following long-term LD therapy in Parkinson disease.
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PMID:Increase of preproenkephalin mRNA levels in the putamen of Parkinson disease patients with levodopa-induced dyskinesias. 1185 20

Changes in preproenkephalin expression in the caudate and putamen have been linked to the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in primate models of Parkinson's disease, although not all investigators have been able to confirm this association. Because nigrostriatal damage per se is associated with increases in striatal preproenkephalin mRNA levels, it is difficult to know if changes in transcript levels are a result of lesioning or concurrent L-DOPA treatment and resulting dyskinesias. To circumvent these difficulties, we measured striatal preproenkephalin mRNA levels in monkeys with L-DOPA-induced dyskinesias both with and without lesions of the nigrostriatal system. The latter model is not confounded by morphological and biochemical changes resulting from nigrostriatal damage. Monkeys were gavaged with L-DOPA (15 mg/kg) twice daily for a 2-week period and killed 3 days after treatment. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment alone resulted in an increase in preproenkephalin mRNA levels as previously shown. However, striatal transcript levels were similarly elevated in dyskinetic MPTP-lesioned animals treated with L-DOPA. In unlesioned animals, preproenkephalin mRNA levels were also similar in control and L-DOPA-treated dyskinetic monkeys. Because drug-induced changes in mRNA may not be sustained for a prolonged period after treatment, a second series of experiments were done in which animals were killed 3-4 h after the last dose of L-DOPA, but the results were similar to those obtained after 3 days. These data show that, while elevations in striatal preproenkephalin mRNA levels are associated with nigrostriatal damage, they are not linked to the development of L-DOPA-induced dyskinesias. These results thus question the importance of preproenkephalin mRNA in the pathogenesis of this disabling complication of L-DOPA therapy in Parkinson's disease.
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PMID:Increases in striatal preproenkephalin gene expression are associated with nigrostriatal damage but not L-DOPA-induced dyskinesias in the squirrel monkey. 1212 99

Post-mortem studies in human brain of patients with Parkinson's disease have greatly contributed to our understanding of the disease. However, few human brain studies have focused on levodopa-induced dyskinesias, which considerably limit the beneficial effect of levodopa (LD) in the treatment of Parkinson's disease. We have taken advantage of the fact that some patients develop dyskinesias and other do not to compare biochemical markers between them. In post-mortem samples from LD-treated parkinsonian patients, increased preproenkephalin expression in the putamen and increased GABA(A) receptors content in the internal globus pallidus (GPi) are found in dyskinetic parkinsonian patients compared to non-dyskinetic patients. These data are consistent with previous observations in MPTP monkeys developing dyskinesias following LD or dopamine agonist treatment. This combination of data in an animal model and in humans strongly suggests that increased enkephalinergic activity in the putamen and increased sensitivity of GABA(A) receptors in the GPi are implicated in the pathogenesis of LD-induced dyskinesias in Parkinson's disease.
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PMID:Levodopa response motor complications--GABA receptors and preproenkephalin expression in human brain. 1221 34


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