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)

Resident microglia are involved in immune responses of the central nervous system and may contribute to neuronal degeneration and death. Here, we tested in adult rats whether injection of bacterial lipopolysaccharide (which causes inflammation and microglial activation) just above the substantia nigra, results in the death of dopaminergic substantia nigra pars compacta neurons. Two weeks after lipopolysaccharide injection, microglial activation was evident throughout the nigra and the number of retrogradely-labeled substantia nigra neurons was reduced to 66% of normal. This suggests that inflammation and/or microglial activation can lead to neuronal cell death in a well-defined adult animal model. The opioid receptor antagonist naloxone reportedly reduces release of cytotoxic substances from microglia and protects cortical neurons in vitro. Here, a continuous two-week infusion of naloxone at a micromolar concentration close to the substantia nigra, prevented most of the neuronal death caused by lipopolysaccharide, i.e. 85% of the neurons survived. In addition, with systemic (subcutaneous) infusion of 0. 1mg/d naloxone, 94% of the neurons survived. Naloxone infusions did not obviously affect the morphological signs of microglial activation, suggesting that naloxone reduces the release of microglial-derived cytotoxic substances. Alternatively, microglia might not cause the neuronal loss, or naloxone might act by blocking opioid receptors on (dopaminergic or GABAergic) neurons.Thus, local inflammation induces and the opioid antagonist naloxone prevents the death of dopaminergic substantia nigra neurons in adult rats. This may be relevant to the understanding of the pathology and treatment of Parkinson's disease, where these neurons degenerate.
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PMID:Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. 1079 60

The hallmark of Parkinson's disease is the death of nigral dopaminergic neurons, and inflammation in the brain has been increasingly associated with the pathogenesis of this neurological disorder. Dynorphins are among the major opioid peptides in the striato-nigral pathway and are important in regulating dopaminergic neuronal activities. However, it is not clear whether dynorphins play a role in the survival of nigral dopaminergic neurons. We have recently demonstrated that lipopolysaccharide (LPS) activates the brain immune cells microglia, in vitro and in vivo, to release neurotoxic factors to degenerate dopaminergic neurons. The purpose of this study was to explore the neuroprotective effect of dynorphins in the inflammation-mediated degeneration of dopaminergic neurons in rat midbrain neuron-glia cultures. LPS-induced neurotoxicity was significantly reduced by treatment with ultra low concentrations (10(-13)--10(-15) M) of the kappa-opioid receptor agonist dynorphin A (1--17) or the receptor binding ineffective [des-Tyr(1)]dynorphin A (2--17), but not by U50488, a synthetic kappa-receptor agonist. The glia-mediated neuroprotective effect of dynorphins was further supported by the finding that femtomolar concentrations of dynorphins did not prevent the killing of dopaminergic neurons by 6-hydroxydopamine. However, ultra low concentrations of dynorphins inhibited LPS-induced production of superoxide. These results suggest a glia-mediated and conventional opioid receptor-unrelated mechanism of action for the neuroprotective effect of ultra low concentrations of dynorphins. Understanding the underlying mechanisms of action should further define the roles of dynorphins in the regulation of dopaminergic neurons and help devise novel strategies to combat neurodegenerative diseases.
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PMID:Femtomolar concentrations of dynorphins protect rat mesencephalic dopaminergic neurons against inflammatory damage. 1150 11

Long-term treatment of Parkinson's disease with levodopa is complicated by the emergence of involuntary movements, known as levodopa-induced dyskinesia. It has been hypothesized that increased opioid transmission in striatal output pathways may be responsible for the generation of dyskinesia. In this study, we have investigated the effect of blockade of opioid peptide transmission on levodopa-induced dyskinesia in a primate model of Parkinson's disease-the MPTP-lesioned marmoset. Coadministration of nonselective and mu- or delta-subtype-selective opioid receptor antagonists with levodopa resulted in a significant decrease in dyskinesia. There was no attenuation of the anti-parkinsonian actions of levodopa. These data suggest that specific mu- or delta-opioid receptor antagonists might be applicable clinically in the treatment of levodopa-induced dyskinesia in Parkinson's disease.
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PMID:Mu- and delta-opioid receptor antagonists reduce levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. 1152 Jan 28

Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, especially that of microglia that produce a variety of proinflammatory and neurotoxic factors, including cytokines, fatty acid metabolites, free radicals--such as nitric oxide (NO) and superoxide. Excessive production of NO, as a consequence of nitric oxide synthase induction in activated glia, has been attributed to participate in neurodegeneration. Using primary mixed neuron-glia cultures and glia-enriched cultures prepared from embryonic rodent brain tissues, we have systemically studied the relationship between the production of NO and neurodegeneration in response to stimulation by the inflammagen lipopolysaccharide. This review summarizes our recent findings on the kinetics of NO generation, the relative contribution of microglia and astrocytes to NO accumulation, the relationship between NO production and neurodegeneration, and points of intervention along the pathways associated with NO generation to achieve neuroprotection. We also describe our results relating to the effect of several opioid-related agents on microglial activation and neuroprotection. Among these agents, the opioid receptor antagonist naloxone, especially its non-opioid enantiomer (+)-naloxone, promises to be of potential therapeutic value for the treatment of inflammation-related diseases.
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PMID:Role of nitric oxide in inflammation-mediated neurodegeneration. 1207 84

The motor signs of Parkinson's disease have been partly attributed to an overinhibition of the external globus pallidus (GP) that results from hyperactivity of striatopallidal GABA/enkephalinergic neurons. The goals of this study were to measure basal levels of extracellular fluid GABA in the GP of normal cats, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian cats and cats spontaneously recovered from MPTP-induced parkinsonism, and to examine the effects of opioid receptor activation on potassium (K+)-evoked GABA release in the GP in these animals. Basal GP GABA levels were increased 75% from normal in parkinsonian animals 1 week after MPTP administration and returned to control levels in recovered animals 6 weeks after MPTP administration. No significant differences were observed in K+-evoked GABA release across conditions. The opioid receptor agonist [D-Ala2]-Met-Enkephalinamide (DALA) significantly attenuated K+-evoked GABA release in the GP of MPTP-treated symptomatic and recovered cats, but had no significant effect on GABA release in normal animals. These data show that basal GP GABA levels are elevated coincident with expression of parkinsonian signs and return to normal in animals that have functionally compensated for a nigrostriatal lesion. DALA-induced inhibition of pallidal GABA release after a dopamine-depleting lesion, suggests that enkephalin may attenuate GABA release in the GP specifically after striatal dopamine loss.
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PMID:GABA-opioid interactions in the globus pallidus: [D-Ala2]-Met-enkephalinamide attenuates potassium-evoked GABA release after nigrostriatal lesion. 1215 90

Previously we reported that naloxone stereoisomers, in an opioid receptor-independent manner, attenuated the inflammation-mediated degeneration of dopaminergic neurons by inhibition of the activation of microglia, the resident immune cells in the brain. Recently we discovered that beta-amyloid peptide Abeta (1-42) exhibited enhanced neurotoxicity toward both cortical and mesencephalic neurons through the activation of microglia and production of superoxide. The purpose of this study was to determine whether naloxone isomers had any effect on Abeta (1-42)-induced neurodegeneration. Pretreatment of either cortical or mesencephalic neuron-glia cultures with 1 to 10 microM (-)-naloxone, prior to treatment for up to 11 days with 0.1 to 3 microM Abeta (1-42), afforded significant neuroprotection as judged by neurotransmitter uptake, immunocytochemical analysis, and cell counting. More importantly, (+)-naloxone, the ineffective enantiomer of (-)-naloxone in binding opioid receptors, was equally effective in affording neuroprotection. Mechanistically, inhibition of Abeta (1-42)-induced production of superoxide in microglia underlay the neuroprotective effect of naloxone stereoisomers. Moreover, neuroprotection and inhibition of Abeta (1-42)-induced superoxide production was also achieved with naloxone methiodide, a charged analog with quaternary amine, suggesting that the site of action for naloxone isomers is at the cell surface of microglia. These results demonstrated that naloxone isomers, through mechanisms unrelated to the opioid receptors, were capable of inhibiting Abeta (1-42)-induced microglial activation and degeneration of both cortical and mesencephalic neurons. Combined with our previous observations with inflammagen-induced neurodegeneration, naloxone analogs, especially (+)-naloxone, may have potential therapeutic efficacy for the treatment of Alzheimer's and Parkinson's disease.
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PMID:Inhibition by naloxone stereoisomers of beta-amyloid peptide (1-42)-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons. 1218 82

Current symptomatic treatments for Parkinson's disease are based largely on dopamine replacement therapies; however, the fact that these treatments are characterized by many long-term side effects has led to widespread interest in nondopaminergic therapies. To date, a nondopaminergic therapy with comparable efficacy to dopamine replacement has not been devised. Here the authors discuss recent findings that systemic administration of a selective delta-opioid receptor agonist has powerful antiparkinsonian effects in rodent and primate models of Parkinson's disease that are equivalent to those of dopamine replacement. delta-Opioid receptor agonists may prove to be useful for the symptomatic treatment of Parkinson's disease in humans.
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PMID:Delta-opioid receptor agonists as a therapeutic approach in Parkinson's disease. 1293 40

The dihydroxylated tetrahydroisoquinoline derivative, 2(N)-methyl-norsalsolinol (NMNorsal), was identified in L-DOPA-treated patients with Parkinson's disease and proposed to be responsible for behavioral changes. In the present study, we investigated the effect of NMNorsal on serotonin and opioid receptors gene expression in caudate nucleus of Wistar rats. Using RT-PCR, serotonin 5-HT2A, micro- and delta-opioid receptor mRNA levels were determined after NMNorsal administration (40 mg/kg, i.p.). There was a marked increase of 5-HT2A and delta-opioid receptor mRNA levels with a maximum after 48 h. In contrast, micro-opioid receptor mRNA levels were significantly decreased to 10% after 24 h and 21% after 48 h, respectively. Our present results demonstrate for the first time that the atypical heterocylic L-DOPA/dopamine metabolite NMNorsal is able to modify long-term regulation of serotonin and opioid receptor expression in striatum. Since the occurrence of hallucinosis or psychosis following L-DOPA treatment is related to the serotonergic system, these results probably reflect a link between NMNorsal and L-DOPA side effects in Parkinson's disease. However, further experiments are needed.
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PMID:Modulation of striatal serotonin and opioid receptor mRNA expression following systemic N-methyl-norsalsolinol administration. 1460 11

The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), remains the most common treatment for Parkinson's disease. However, following long-term treatment, disabling side effects, particularly L-DOPA-induced dyskinesias, are encountered. Conversely, D2/D3 dopamine receptor agonists, such as ropinirole, exert an anti-parkinsonian effect while eliciting less dyskinesia when administered de novo in Parkinson's disease patients. Parkinson's disease and L-DOPA-induced dyskinesia are both associated with changes in mRNA and peptide levels of the opioid peptide precursors preproenkephalin-A (PPE-A) and preproenkephalin-B (PPE-B). Furthermore, a potential role of abnormal opioid peptide transmission in dyskinesia is suggested due to the ability of opioid receptor antagonists to reduce the L-DOPA-induced dyskinesia in animal models of Parkinson's disease. In this study, the behavioural response, striatal topography and levels of expression of the opioid peptide precursors PPE-A and PPE-B were assessed, following repeated vehicle, ropinirole, or L-DOPA administration in the 6-OHDA-lesioned rat model of Parkinson's disease. While repeated administration of L-DOPA significantly elevated PPE-B mRNA levels (313% cf. vehicle, 6-OHDA-lesioned rostral striatum; 189% cf. vehicle, 6-OHDA-lesioned caudal striatum) in the unilaterally 6-OHDA-lesioned rat model of Parkinson's disease, ropinirole did not. These data and previous studies suggest the involvement of enhanced opioid transmission in L-DOPA-induced dyskinesia and that part of the reason why D2/D3 dopamine receptor agonists have a reduced propensity to elicit dyskinesia may reside in their reduced ability to elevate opioid transmission.
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PMID:Ropinirole versus L-DOPA effects on striatal opioid peptide precursors in a rodent model of Parkinson's disease: implications for dyskinesia. 1469 17

Opioid peptide transmission is enhanced in the striatum of animal models and Parkinson's disease (PD) patients with levodopa-induced motor complications. Opioid receptor antagonists reduce levodopa-induced dyskinesia in primate models of PD; however, clinical trials to date have been inconclusive. A double-blind, placebo controlled, crossover design study in 14 patients with PD experiencing motor fluctuations was carried out, using the non-subtype-selective opioid receptor antagonist naloxone. Naloxone did not reduce levodopa-induced dyskinesia. The duration of action of levodopa was increased significantly by 17.5%. Non-subtype-selective opioid receptor antagonism may prove useful in the treatment of levodopa-related wearing-off in PD but not in dyskinesia.
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PMID:Non-subtype-selective opioid receptor antagonism in treatment of levodopa-induced motor complications in Parkinson's disease. 1513 20


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