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)

The dopaminergic projection from the substantia nigra to the patch and matrix compartments of the caudate-putamen undergoes a spontaneous, early postnatal degeneration in mice which carry the weaver gene. The projection to nucleus accumbens is relatively spared. Dopaminergic afferents have been shown to be important modulators of striatal opioid receptor expression. In the present study, opioid receptor localization in the caudate-putamen and nucleus accumbens of control and weaver mice was examined by quantitative autoradiography. Mu, delta and kappa opioid receptors were differentially distributed in nucleus accumbens and in patch and matrix compartments of the caudate-putamen. In animals which were homozygous for the weaver gene, the density of mu opioid receptors in both patch and matrix compartments was unchanged with respect to control mice. In contrast, the density of delta and kappa opioid receptors was significantly decreased in weaver caudate-putamen and nucleus accumbens. The significance of these results with respect to opioid receptor expression and Parkinson's disease is discussed.
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PMID:Opioid receptor changes in weaver mouse striatum. 132 69

The clinical differentiation of Parkinson's disease from the striatonigral degeneration (SND) type of multiple system atrophy (MSA) and Steele-Richardson-Olszewski syndrome (SRO) may be difficult. This is reflected by a 20-25% misdiagnosis rate in clinicopathological series of cases labelled as 'Parkinson's disease' in life. The caudate and putamen contain a high density of opioidergic neurons and receptors which have a close anatomical and physiological relationship with the dopaminergic system. We used [11C]diprenorphine with PET to investigate striatal opioid receptor binding in groups of patients with clinically defined Parkinson's disease (n = 8), SND (n = 7) and SRO (n = 6), compared with normal controls (n = 8). There was no significant difference between mean ligand binding in the putamen and caudate of Parkinson's disease cases when compared with normals. Mean putamen, but not caudate, opioid receptor binding was significantly reduced in the SND group, when compared with normals. By contrast, in the SRO group, both mean caudate and putamen opioid receptor binding was significantly reduced when compared with both normal and Parkinson's disease groups. When considering the individual patients, none of the eight Parkinson's disease cases (0%), none of the seven SND cases (0%), but four of the six SRO cases (67%) had caudate opioid receptor binding that was > 2.5 SDs below the normal mean. Corresponding figures for putamen opioid receptor binding were: none of the Parkinson's disease cases (0%); three of the SND cases (43%); and all of the SRO cases (100%). We conclude that there are differences in the pattern of opioid receptor binding in the striatum of Parkinson's disease, SND and SRO patients, as determined by [11C]diprenorphine PET. The different binding patterns may help to differentiate these akinetic-rigid syndromes in life.
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PMID:Striatal opioid receptor binding in Parkinson's disease, striatonigral degeneration and Steele-Richardson-Olszewski syndrome, A [11C]diprenorphine PET study. 765 90

The influence of the kappa-opioid receptor agonist, enadoline, on endogenous glutamate release was investigated in rat and marmoset striatal synaptosomes. Enadoline decreased 4-aminopyridine (2 mM)-stimulated glutamate release (rat: IC50 approximately 8.7 microM, marmoset: IC50 approximately 2.9 microM). The effect of enadoline was reversed by nor-binaltorphimine (5 microM). These data indicate that, in the striatum of the rat and marmoset, kappa-opioid receptor agonists can modulate glutamate release. These findings may have implications for the treatment of Parkinson's disease.
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PMID:Modulation of glutamate release by a kappa-opioid receptor agonist in rodent and primate striatum. 856 6

We molecularly cloned the kappa opioid receptor from a human substantia nigra cDNA library. When expressed in HEK293 cells, the cloned receptor had similar pharmacological characteristics to the rat kappa opioid receptor. Northern blot analysis showed the presence of a single transcript of about 6 kb in size for mRNA prepared from the substantia nigra. Using in situ hybridization histochemistry, we studied the expression of this receptor in postmortem human brains from control and Parkinson's disease subjects. Kappa opioid receptor mRNA was present in melanized (possibly dopaminergic) neurons of the substantia nigra and the nucleus paranigralis. On the other hand, Parkinson's disease brains had markedly fewer melanized neurons, as expected, and correspondingly very low or background levels of mRNA for the kappa opioid receptor. However, in some cases, remaining melanized neurons still expressed the receptor mRNA. From these results we suggest that dopaminergic neurons in the human substantia nigra and the nucleus paranigralis synthesize kappa opioid receptors and express them in their perikarya and their terminal regions. The kappa opioid receptor expressed in the melanized neurons may play a role in the normal function of dopaminergic systems and possibly in the etiology of Parkinson's disease.
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PMID:The expression of mRNA for a kappa opioid receptor in the substantia nigra of Parkinson's disease brain. 903 Jun 93

Levodopa-induced dyskinesias remain a major challenge in the therapeutic management of Parkinson's disease (PD). Their etiology is unknown although dysfunction of striatal opioid transmission has been implicated in experimental models of PD. To determine whether the opioid system is involved in human dyskinetic PD, we measured in vivo opioid receptor binding in PD patients with and without levodopa-induced dyskinesias, using positron emission tomography (PET) and the opioid receptor ligand [11C]diprenorphine. Striatal and thalamic/occipital uptake ratios were calculated using a region of interest (ROI) approach. In addition, we used statistical parametric mapping (SPM) and images reflecting the volume of distribution of [11C]diprenorphine to assess changes in cerebral receptor binding on a voxel-by-voxel basis. By using the ROI approach, we found significantly reduced striatal and thalamic opioid binding in dyskinetic, but not in nondyskinetic, PD patients. The SPM approach confirmed reduced availability in these areas and, in addition, showed decreased cingulate and increased prefrontal opioid receptor binding in the dyskinetic patients. Our findings confirm that altered opioid transmission is part of the pathophysiology of levodopa-induced dyskinesias in PD and support further investigation into the role of opioid agents in the management of these involuntary movements.
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PMID:Alterations in opioid receptor binding in Parkinson's disease patients with levodopa-induced dyskinesias. 939 71

Excessive glutamate transmission in the basal ganglia is a major factor in the neural mechanisms underlying parkinsonian akinesia. Activation of kappa opioid receptors causes a presynaptic reduction in glutamate release. Kappa opioid receptors are concentrated in those regions of the basal ganglia associated with increased glutamate transmission in parkinsonism. In this study, we use the alpha-methyl-p-tyrosine and reserpine-treated rat model of parkinsonism to investigate whether systemic administration of the kappa opioid agonists enadoline (CI-977) and U69,593 can alleviate the symptoms of parkinsonism either alone or in conjunction with dopamine replacement therapy. We report that, when administered alone, both enadoline and U69,593 can increase locomotion in monoamine-depleted rats. No increase in locomotor activity was seen after kappa opioid agonist administration in non-parkinsonian rats. The responses to kappa opioid agonists were blocked by co-administration of either the nonspecific opioid receptor antagonist naloxone or the selective kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI). An important finding is that when enadoline and L-dopa are administered together, their anti-akinetic properties are synergistic. Thus, the doses of enadoline and L-dopa required to alleviate akinesia when administered together are lower than either administered alone. These data illustrate the importance of kappa opioid receptors in the neural mechanisms controlling voluntary movement and suggest that kappa opioid agonists may have a role as adjuncts to dopamine replacement in the management of Parkinson's disease.
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PMID:Kappa-opioid receptor agonists increase locomotor activity in the monoamine-depleted rat model of parkinsonism. 953 34

Dyskinesias following long-term dopamine replacement therapy are a major limitation of current treatments for Parkinson's disease. Recently, attention has been focused on the concept of using non-dopaminergic adjuncts to currently available therapies in an attempt to reduce the problem of dyskinesia. Thus, an enhanced understanding of the neural mechanisms underlying dyskinetic symptoms has led to the realization that it might be possible to manipulate non-dopaminergic systems and reduce dyskinesia without compromising the anti-parkinsonian efficacy of drugs such as L-dopa. This article discusses how non-dopaminergic manipulations could reverse the abnormalities in basal ganglia circuitry responsible for generating dyskinesia. It is proposed that potential anti-dyskinetic drugs might include glutamate (NMDA) receptor antagonists, opioid receptor antagonists, cannabinoid receptor agonists or antagonists, alpha2 adrenergic receptor antagonists, and 5-HT-enhancing agents.
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PMID:Adjuncts to dopamine replacement: a pragmatic approach to reducing the problem of dyskinesia in Parkinson's disease. 982 9

This study was carried out in order to examine the effects of acute or chronic L-DOPA treatment on striatally expressed FosB- and JunB-like proteins in a rat model of Parkinson's disease. Rats with a unilateral, near-total 6-hydroxydopamine lesion of the ascending mesostriatal projection received either an acute challenge or a one-week treatment with 10 mg/kg/day methyl L-DOPA (combined with 15 mg/mg benserazide), and were killed at either 3 h or two days post-injection. Both acute and chronic L-DOPA treatment caused a pronounced, persistent increase in the number of FosB-like immunoreactive cells in the dopamine-denervated striata (five- and seven-fold increase, respectively, above the levels found in lesioned but non-drug-treated controls), but the two treatment groups differed markedly with respect to both the average amount of staining per cell, which was two-fold larger in the chronic L-DOPA cases, and the anatomical distribution of the labeled cells. After an acute injection of L-DOPA, FosB-positive cells were distributed rather uniformly across all striatal subregions, whereas chronic L-DOPA treatment induced discrete clusters of strongly FosB-like immunoreactive cells within medial and central striatal subregions, as well as in a large, yet sharply defined portion of the lateral caudate-putamen. Strongly labeled cell clusters that appeared in the medial and central caudate-putamen were preferentially located within calbindin-poor, mu-opioid receptor-rich striosomes, whereas the lateral area displaying FosB activation encompassed both striosomal and matrix domains. In both the medial and the lateral striatum a near-total overlap was found between strongly FosB-like immunoreactive cell groups and areas showing pronounced dynorphin expression. NADPH-diaphorase-positive striatal interneurons did not express FosB-like immunoreactivity after a 6-hydroxydopamine lesion alone, a negligible proportion of them did after an acute L-DOPA challenge, but about 8% of these interneurons were FosB positive following chronic L-DOPA treatment. Like FosB, JunB was induced in the DA-denervated striatum by both acute and chronic L-DOPA treatment, and exhibited similar distribution patterns. However, JunB did not exhibit prolonged expression kinetics, and was somewhat down-regulated in the chronically compared with the acutely L-DOPA-treated rats. The present results show that L-DOPA administration produces a long-lasting increase in the levels of FosB-, but not JunB-like immunoreactivity in the dopamine-denervated striatum. More importantly, these data show that striatal induction of FosB- and JunB-like proteins by chronic L-DOPA treatment exhibits both regional and compartmental specificity.
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PMID:Changes in the regional and compartmental distribution of FosB- and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-dopa treatment. 1057 13

1. The treatment of Parkinson's disease relies predominantly upon dopamine replacement therapy, usually with l-dihydroxyphenylalanine (L-DOPA). However, side-effects of long-term treatment, such as L-DOPA-induced dyskinesias can be more debilitating than the disease itself. Non-dopaminergic treatment strategies might therefore be advantageous. 2. The aim of this study was to investigate the potential anti-parkinsonian efficacy of the kappa-opioid receptor agonist, enadoline, and the alpha-adrenoreceptor agonist, clonidine, both alone or in combination, in the reserpine-treated rat model of Parkinson's disease. 3. Rats were treated with reserpine (3 mg kg-1), and experiments carried out 18 h later, at which time they exhibited profound akinesia (normal animals 1251+/-228 mobile counts h-1, reserpine-treated animals 9+/-2 mobile counts h-1). Both enadoline and clonidine increased locomotion in reserpine-treated rats in a dose-dependent manner. The maximum locomotor-stimulating effect of enadoline alone was seen at a dose of 0.2 mg kg-1 (208+/-63 mobile counts h-1). The maximum effect of clonidine was seen at a dose of 2 mg kg-1 (536+/-184 mobile counts h-1). 4. Co-administration of enadoline (0.1 mg kg-1) and clonidine (0.01 - 0.1 mg kg-1) at sub-threshold doses, synergistically increased locomotion. 5. The synergistic stimulation of locomotion in the reserpine-treated rat involved activation of kappa-opioid receptors and a combination of both alpha1 and alpha2-adrenoreceptors. 6. The results presented suggest a need for further studies on the potential of stimulating kappa-opioid and/or alpha-adrenoreceptors as a therapy for Parkinson's disease. Furthermore, the studies may offer potential mechanistic explanations of the ability of alpha2-adrenergic receptor antagonist to reduce L-DOPA-induced dyskinesia in Parkinson's disease.
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PMID:The adrenergic receptor agonist, clonidine, potentiates the anti-parkinsonian action of the selective kappa-opioid receptor agonist, enadoline, in the monoamine-depleted rat. 1060 39

Degeneration of dopaminergicrgic neurons in the substantia nigra of the brain is a hallmark of Parkinson's disease and inflammation and oxidative stress are closely associated with the pathogenesis of degenerative neurological disorders. Treatment of rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS)-activated microglia, resident immune cells of the brain, to release proinflammatory and neurotoxic factors tumor necrosis factor-alpha, interleukin-1beta, nitric oxide, and superoxide and subsequently caused damage to midbrain neurons, including dopaminergic neurons. The LPS-induced degeneration of the midbrain neurons was significantly reduced by cotreatment with naloxone, an opioid receptor antagonist. This study focused on understanding the mechanism of action for the protective effect of naloxone on dopaminergic neurons because of relevance to Parkinson's disease. Both naloxone and its opioid receptor inactive stereoisomer (+)-naloxone protected the dopaminergic neurons with equal potency. Naloxone inhibited LPS-induced activation of microglia and release of proinflammatory factors, and inhibition of microglia generation of superoxide free radical best correlated with the neuroprotective effect of naloxone isomers. To further delineate the site of action, naloxone was found to partially inhibit the binding of [(3)H]LPS to cell membranes, whereas it failed to prevent damage to dopaminergic neurons by peroxynitrite, a product of nitric oxide and superoxide. These results suggest that naloxone at least in part interferes with the binding of LPS to cell membranes to inhibit microglia activation and protect dopaminergic neurons as well as other neurons in the midbrain cultures from inflammatory damage.
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PMID:Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. 1077 35


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