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 opioid transmitters enkephalin and dynorphin are known to regulate pallidal output and consequently cortical excitability. Indeed, abnormal basal ganglia opioid transmission has been reported in several involuntary movement disorders, including levodopa-induced dyskinesias in Parkinson's disease (PD), tardive dyskinesias/dystonia, Huntington's disease, and Tourette's syndrome. Moreover, a previous 11C-diprenorphine PET study investigating levodopa-induced dyskinesias found reduced opioid receptor availability in PD with but not without dyskinesias. We wished to investigate if a similar alteration in basal ganglia opioid binding was present in DYT1 primary torsion dystonia (PTD). Regional cerebral 11C-diprenorphine binding was investigated in 7 manifesting carriers of the DYT1 gene and 15 age-matched normal controls using a region-of-interest (ROI) approach and statistical parametric mapping (SPM). No difference in regional mean 11C-diprenorphine binding was found between DYT1-PTD and controls, and no correlation between the severity of dystonia and opioid binding was seen. We conclude that aberrant opioid transmission is unlikely to be present in DYT1-PTD and altered opioid transmission is not a common mechanism underlying all disorders of involuntary movement.
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PMID:Opioid binding in DYT1 primary torsion dystonia: an 11C-diprenorphine PET study. 1539 64

The in vivo biotransformation of dynorphin A(1-17) (Dyn A) was studied in the striatum of hemiparkinsonian rats by using microdialysis in combination with nanoflow reversed-phase liquid chromatography/electrospray time-of-flight mass spectrometry. The microdialysis probes were implanted into both hemispheres of unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats. Dyn A (10 pmol microl(-1)) was infused through the probes at 0.4 microl min(-1) for 2 h. Samples were collected every 30 min and analyzed by mass spectrometry. The results showed for the first time that there was a difference in the Dyn A biotransformation when comparing the two corresponding sides of the brain. Dyn A metabolites 1-8, 1-16, 5-17, 10-17, 7-10 and 8-10 were detected in the dopamine-depleted striatum but not in the untreated striatum. Dyn A biotransformed fragments found in both hemispheres were N-terminal fragments 1-4, 1-5, 1-6, 1-11, 1-12 and 1-13, C-terminal fragments 2-17, 3-17, 4-17, 7-17 and 8-17 and internal fragments 2-5, 2-10, 2-11, 2-12, and 8-15. The relative levels of these fragments were lower in the dopamine-depleted striatum. The results imply that the extracellular in vivo processing of the dynorphin system is being disturbed in the 6-OHDA-lesion animal model of Parkinson's disease.
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PMID:Altered extracellular striatal in vivo biotransformation of the opioid neuropeptide dynorphin A(1-17) in the unilateral 6-OHDA rat model of Parkinson's disease. 1570 26

Inflammation has been increasingly recognized to contribute to the pathogenesis of Parkinson's disease. Several compounds are neuroprotective at femtomolar concentrations through the inhibition of inflammation. However, the mechanisms mediating femtomolar-acting compounds are poorly understood. Here we show that both gly-gly-phe (GGF), a tri-peptide contained in the dynorphin opioid peptide, and naloxone are neuroprotective at femtomolar concentrations against LPS-induced dopaminergic neurotoxicity through the reduction of microglial activation. Mechanistic studies demonstrated the critical role of NADPH oxidase in the GGF and naloxone inhibition of microglial activation and associated DA neurotoxicity. Pharmacophore analysis of the neuroprotective dynorphin peptides and naloxone revealed common chemical properties (hydrogen bond acceptor, hydrogen bond donor, positive ionizable, hydrophobic) of these femtomolar-acting compounds. These results support a common high-affinity site of action for several femtomolar-acting compounds, where NADPH oxidase is the critical mechanism governing neuroprotection, suggesting a novel avenue of anti-inflammatory and neuroprotective therapy.
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PMID:Microglial NADPH oxidase is a novel target for femtomolar neuroprotection against oxidative stress. 1579 Oct 5

Early gene induction by L-DOPA in the striatum of dopamine denervated rats represents a useful way to study long-term modifications produced by this drug. The effects of acute and subchronic L-DOPA administration on zif-268 mRNA expression were compared in 6-hydroxydopamine-lesioned rats. Rats received a subchronic intermittent L-DOPA (6 mg/kg) treatment, which produces behavioural sensitization, a correlate of dyskinetic movements. Three days after interruption of subchronic treatment, zif-268 mRNA was evaluated after an L-DOPA challenge. Zif-268 mRNA levels increased in the lesioned dorsolateral striatum after either acute or subchronic L-DOPA administration. Double labelling of striatal cells with zif-268 and enkephalin or dynorphin mRNA probes was performed to assess neuronal activation in the indirect and direct output pathway. Single acute L-DOPA significantly increased zif-268 in all striatal neurons reflecting a hyperresponsiveness of dopamine-depleted striatum. After subchronic L-DOPA, zif-268 mRNA labelling was still increased in the striatonigral pathway, limited to dynorphin(+) neurons, whereas in all other neurons it was similar to the control value. Results suggest that striatal neurons responding to acute L-DOPA differ from those responding to subchronic L-DOPA. L-DOPA-induced behavioural sensitization was associated to a down-regulation in the responsiveness of striatopallidal and striatonigral dynorphin(-) neurons, whereas in striatonigral neurons containing dynorphin a hyperresponsiveness to L-DOPA was observed. High levels of zif-268, together with a persistent hyperresponsiveness of striatonigral dymorphinergic neurons and hyporesponsiveness of striatopallidal neurons, by creating an unbalanced state of striatal efferent neurons, may be implicated in dyskinetic movements observed in Parkinson's disease (PD).
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PMID:Different responsiveness of striatonigral and striatopallidal neurons to L-DOPA after a subchronic intermittent L-DOPA treatment. 1581 29

Marked fluctuation of dopamine concentration in the striatum following long-term L-DOPA administration contributes to the development of L-DOPA-induced motor complications including L-DOPA-induced dyskinesias and wearing-off in patients with Parkinson's disease. We have shown that pretreatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A (5-hydroxytryptamine) receptor agonist, alleviates fluctuation of dopamine levels in the dopamine-denervated striatum of 6-hydroxydopamine-lesioned (hemiparkinsonian) rats after L-DOPA treatment. To determine whether co-administration of 8-OH-DPAT with L-DOPA prevents L-DOPA-induced motor complications, we examined rotation behavior and levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the striatum of 6-hydroxydopamine-lesioned rats treated with L-DOPA alone or L-DOPA + 8-OH-DPAT, twice daily, for 2 weeks. Co-administration of 8-OH-DPAT inhibited an increase of rotation behavior to L-DOPA and L-DOPA-induced increases in levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the dopamine-denervated striatum, both of which are established indices of L-DOPA-induced motor complications. These results suggest that pharmaceutical products that stimulate 5-HT1A receptors could prove useful in prevention of the development of L-DOPA-induced motor complications in patients with Parkinson's disease.
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PMID:A serotonin 5-HT1A receptor agonist prevents behavioral sensitization to L-DOPA in a rodent model of Parkinson's disease. 1589 79

Motor complications induced through repeated L-DOPA treatment in patients with Parkinson's disease are thought to be the consequence of molecular adaptations that occur in response to repeated dopamine receptors stimulation. Here, we studied the molecular changes taking place in the denervated striatum of unilaterally 6-OHDA-lesioned rats repeatedly treated with L-DOPA alone or combined to the D1 receptor antagonist SCH23390. We looked at the territorial patterns of expression of neurotensin (NT), dynorphin (DYN), enkephalin (ENK) and Nur77 (also known as NGFI-B) mRNA expression in the striatum and contrasted these with markers of glutamatergic transport and dopaminergic receptor functions. The denervation process induced NT and Nur77 mRNA expression in ENK-positive cells. Subsequent repeated L-DOPA treatment led to a sensitization of L-DOPA-induced rotational response and produced a second surge of NT induction, this time limited to DYN-positive cells and preferentially restricted to the lateral striatum. In this specific territory, the number of Nur77-positive cells was decreased, in response to L-DOPA, when compared to the medial part of the lesioned striatum. L-DOPA treatment increased dopamine D3 receptor and glutamate transporter 1 (GLT1) mRNA expression in the lesioned striatum and that, specifically in an area overlapping one of Nur77 decrease and of NT/DYN induction. The concomitant administration of SCH23390 with repeated L-DOPA treatment blocked the development of behavioral sensitization and the appearance of all L-DOPA-induced molecular reorganizations reported above. Our results showed that repeated L-DOPA treatment produces, in a denervated striatum, a complex pattern of genes regulation in both the direct and the indirect striatal output pathways. This phenomenon is located preferentially in a striatal area receiving converging inputs from the thalamus and sensorimotor cortex and is dependent upon D1 receptor stimulation.
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PMID:Denervation and repeated L-DOPA induce complex regulatory changes in neurochemical phenotypes of striatal neurons: implication of a dopamine D1-dependent mechanism. 1589 73

In Parkinson's disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved.
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PMID:Neuroprotection induced by the adenosine A2A antagonist CSC in the 6-OHDA rat model of parkinsonism: effect on the activity of striatal output pathways. 1596 57

Although oral administration of L-Dopa remains the best therapy for Parkinson disease, its long-term administration causes the appearance of abnormal involuntary movements such as dyskinesia. Although persistent striatal induction of some genes has already been associated with such pathologic profiles in hemiparkinsonian rats, molecular and cellular mechanisms underlying such long-term adaptations remain to be elucidated. In this study, using a rat model of L-Dopa-induced dyskinesia, we report that activity regulated cytoskeletal (Arc)-associated protein is strongly upregulated in the lesioned striatum and that the extent of its induction further varies according to the occurrence or absence of locomotor sensitization. Moreover, Arc is preferentially induced, along with FosB, nur77, and homer-1a, in striatonigral neurons, which express mRNA encoding the precursor of dynorphin. Given the likely importance of Arc in the regulation of cytoskeleton during synaptic plasticity, its upregulation supports the hypothesis that a relationship exists between cytoskeletal modifications and the longlasting action of chronically administrated L-Dopa.
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PMID:Coordinated and spatial upregulation of arc in striatonigral neurons correlates with L-dopa-induced behavioral sensitization in dyskinetic rats. 1625 88

Preferential neurodegeneration of dopaminergic neurons in the ventral substantia nigra of the midbrain is a hallmark of Parkinson's disease. The homeobox transcription factor Pitx3 is similarly and selectively expressed in the same neurons. Pitx3 deficiency in a natural mouse mutant, the aphakia mouse, was correlated with the loss of these neurons and with a deficit in locomotor activity. We now report that the locomotor deficit of aphakia mice is established by 40 days of age and that it can be rescued by injection of l-dopa. We further show that downstream striatal correlates of the midbrain neuronal losses in aphakia mice, as assessed by dopamine transporter binding and expression of dopamine receptors, enkephalin, dynorphin and neurotensin, are highly similar to neuroadaptive responses observed following rapid neurodegeneration induced by neurotoxin administration in adult animals or following the progressive neurodegenerative processes as seen in Parkinson patients. Taken collectively, these data support the idea that the aphakia mice represent a selective model of dopaminergic deficiency that closely resembles the midbrain and striatal neuropathology associated with Parkinson's disease, and this suggests that these mice are a good model to assess therapies for Parkinson's disease as well as to understand the susceptibility of these neurons to neurodegeneration.
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PMID:Striatal neuroadaptation and rescue of locomotor deficit by L-dopa in aphakia mice, a model of Parkinson's disease. 1626 7

Unregulated microglial activation has been implicated as a pivotal factor contributing to Parkinson's disease. Using mesencephalic neuron-glia cultures, we address the novel possibility that peptides endogenous to the substantia nigra (SN), substance P and dynorphin (10(-13)-10(-14) M), are opposing mediators of microglial activation and consequent DA neurotoxicity. Here, we identify that substance P (10(-13)-10(-14) M) is selectively toxic to DA neurons in a microglia-dependent manner. Mechanistically, substance P (10(-13)-10(-14) M) activated microglial NADPH oxidase to produce extracellular superoxide and intracellular reactive oxygen species (ROS). Neuron-glia cultures from mice lacking a functional NADPH oxidase complex (PHOX-/-) were insensitive to substance P (10(-13)-10(-14) M) -induced loss of DA neuron function. Mixed glia cultures from (PHOX-/-) mice failed to show a significant increase in intracellular ROS in response to substance P compared with control cultures (PHOX+/+). Further, dynorphin (10(-14) M) inhibited substance P (10(-13) M) -induced loss of [3H] DA uptake. Here we demonstrate a tightly regulated mechanism governing microglia-derived oxidative stress, where the neuropeptide balance of dynorphin and substance P is critical to DA neuron survival.
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PMID:Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival: substance P vs. dynorphin. 1644 97


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