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)

Male albino rats received a stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the right substantia nigra. Animals demonstrating contralateral rotations 2 weeks postoperatively with apomorphine (0.5 mg/kg i.p.) were treated with L-Dopa (55 mg/kg i.p.), bromocriptine (2 mg/kg i.p.), or polyethylene glycol (vehicle) every 12 h for 30 days. Striatal dopamine (DA) receptors were analyzed by Scatchard plot using 3H-spiroperidol (3H-SP) as ligand. 3,4-Dihydroxyphenylacetic acid (DOPAC) and DA were measured by use of high pressure liquid chromatography. 6-OHDA lesions produced a supersensitivity in striatal DA receptors. Chronic L-Dopa or bromocriptine treatment reversed this supersensitivity. Neither lesion nor drug treatment alone or together produced a significant change in affinity (KD) for 3H-SP. Drug treatment alone also had no effect on Bmax. DA and DOPAC levels were reduced by greater than 98% in lesioned striata. Neither drug treatment affected DA or DOPAC levels as compared with controls. These results indicate that chronic administration of either bromocriptine or L-Dopa will reverse the DA receptor denervation supersensitivity in striatum seen following 6-OHDA lesion. This reversal may play a role in the clinical changes seen in Parkinson's disease patients following chronic use of these drugs.
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PMID:Dopamine receptors: effects of chronic L-dopa and bromocriptine treatment in an animal model of Parkinson's disease. 643 70

A reliable and economical silver staining method is recommended for demonstration of Lewy bodies (LB) and Lewy neurites (LN) in Parkinson's disease (PD) and of argyrophilic oligodendrocytes in multiple system atrophy (MSA). The technique can be applied to routinely formalin-fixed autopsy material and does not require particular skills. It permits processing of frozen sections and sections from polyethylene glycol or paraffin embedded material. It takes advantage of the physical development of nucleation sites and thereby permits tight control of the entire staining procedure.
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PMID:Silver staining method for demonstrating Lewy bodies in Parkinson's disease and argyrophilic oligodendrocytes in multiple system atrophy. 1006

Five studies compared polyethylene glycol (PEG), an osmotic laxative, with placebo. In two studies the comparison was lactulose and in one study two different doses of PEG 3350 and PEG 4000, respectively were evaluated. PEG is associated with an increase in bowel movement frequency when compared with placebo. There was inadequate evidence to establish whether PEG was superior to lactulose. Data from elderly patients are lacking and data from patients with constipation due to Parkinson's disease, multiple sclerosis or opioid therapy was only evaluated in two very small studies. Severe side-effects with PEG are rare. There are no convincing data regarding the superiority with PEG in flatulence. On the whole there is a real lack of research into treatment of the chronic constipation in adults as well as in the elderly.
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PMID:[The effect of polyethylene glycol in chronic constipation is not sufficiently evaluated. A systematic literature review]. 1544 95

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of G GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D2-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D2-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D2DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D2DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D2DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D2DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease.
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PMID:D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways. 1572 56

Parkinson disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the presence of intracytoplasmatic inclusions known as Lewy bodies. Chronic administration of rotenone (RT) produces Parkinson's-like symptoms in rats. Because PD patients have disrupted sleep patterns, we determined if chronic RT administration produces similar changes in rat sleep. RT was administered for 28 days to rats. Basal and vehicle (VH) rats received saline or dimethyl sulfoxide and polyethylene glycol (1:1), respectively. VH infusion induced a progressive decrease in non-rapid eye movement sleep (NREMS) during the 4-week period of VH infusion and REMS was reduced in the third and fourth week of VH infusion. VH infusion did not induce dopaminergic cell degeneration. Rats receiving RT infusion also showed decreased NREMS during the treatment. REMS was dramatically reduced on day 7 although subsequently on days 13 and 20 REMS was similar to basal values. After 4 weeks of RT infusion, time in REMS was decreased again. In RT-treated rats, progressive dopaminergic cell degeneration occurred in the SNc. After 4 weeks of daily injections of L-dopa in RT-infused rats, NREMS values remained similar to those values obtained after RT alone. L-dopa therapy did, however, induce a recovery of REMS in weeks 3 and 4 of RT infusion. Dopaminergic cell damage persisted in the L-dopa-RT-infused rats. We conclude that the RT-PD rat model is associated with large long-term sleep disruption, however, the vehicle, DMSO/PEG had as large an effect as RT on sleep, thus changes in sleep cannot be ascribed to loss of dopaminergic cells. Such results question the validity of the RT-PD rat model.
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PMID:Sleep disturbances in the rotenone animal model of Parkinson disease. 1585 87

Inhibitors of the enzyme catechol-O-methyltransferase (COMT) are used as co-adjuvants in the therapy of Parkinson's disease. A recombinant form of the soluble cytosolic COMT from rat has been co-crystallized with a new potent inhibitor, BIA 8-176 [(3,4-dihydroxy-2-nitrophenyl)phenylmethanone], by the vapour-diffusion method using PEG 6K as precipitant. Crystals diffract to 1.6 A resolution on a synchrotron-radiation source and belong to the monoclinic space group P2(1), with unit-cell parameters a = 52.77, b = 79.63, c = 61.54 A, beta = 91.14 degrees.
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PMID:Crystallization and preliminary X-ray diffraction studies of a catechol-O-methyltransferase/inhibitor complex. 1650 9

Ethylene glycol and methanol are toxic alcohols commonly found in a variety of commercial products. We report two cases, one associated with ethylene glycol and one with methanol poisoning, which both led to acute hemorrhagic necrosis of the basal ganglia and resulted in acute Parkinson's syndrome. It is unlikely that oxalate crystal deposition is the only mechanism for such basal ganglia necrosis, because similar findings were seen following methanol intoxication. We discuss other possible mechanisms that may contribute towards this unusual neurotoxicity. Both of our patients survived their toxic ingestions, but then developed acute Parkinson's syndrome within 10 days of the ingestion. However, the patient who ingested methanol developed respiratory muscle stiffness/weakness, which responded poorly to anti-Parkinsonian drug therapy. Treatment with carbidopa/levodopa improved cogwheel rigidity and bradykinesia in both patients. We conclude that acute Parkinsonism is one of the lesser-recognized devastating complications of both ethylene glycol and methanol poisoning.
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PMID:Two cases of rapid onset Parkinson's syndrome following toxic ingestion of ethylene glycol and methanol. 1718 9

Clinical signs frequently recognized in early phases of sporadic Parkinson's disease (PD) may include autonomic dysfunctions and the experience of pain. Early disease-related lesions that may account for these symptoms are presently unknown or incompletely known. In this study, immunocytochemistry for alpha-synuclein was used to investigate the first relay stations of the pain system as well as parasympathetic and sympathetic pre- and postganglionic nerve cells in the lower brainstem, spinal cord, and coeliac ganglion in 100 microm polyethylene glycol embedded sections from six autopsy individuals, whose brains were staged for PD-associated synucleinopathy. Immunoreactive inclusions were found for the first time in spinal cord lamina I neurons. Lower portions of the spinal cord downwards of the fourth thoracic segment appeared to be predominantly affected, whereas the spinal trigeminal nucleus was virtually intact. Additional involvement was seen in parasympathetic preganglionic projection neurons of the vagal nerve, in sympathetic preganglionic neurons of the spinal cord, and in postganglionic neurons of the coeliac ganglion. The known interconnectivities between all of these components offer a possible explanation for their particular vulnerability. Lamina I neurons (pain system) directly project upon sympathetic relay centers, and these, in turn, exert influence on the parasympathetic regulation of the enteric nervous system. This constellation indicates that physical contacts between vulnerable regions play a key role in the pathogenesis of PD.
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PMID:Parkinson's disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. 1729 2

Selective delivery of antioxidants to the substantia nigra pars compacta (SNpc) during Parkinson's disease (PD) can potentially attenuate oxidative stress and as such increase survival of dopaminergic neurons. To this end, we developed a bone-marrow-derived macrophage (BMM) system to deliver catalase to PD-affected brain regions in an animal model of human disease. To preclude BMM-mediated enzyme degradation, catalase was packaged into a block ionomer complex with a cationic block copolymer, polyethyleneimine-poly(ethylene glycol) (PEI-PEG). The self-assembled catalase/PEI-PEG complexes, "nanozymes", were ca. 60 to 100 nm in size, stable in pH and ionic strength, and retained antioxidant activities. Cytotoxicity was negligible over a range of physiologic nanozyme concentrations. Nanozyme particles were rapidly, 40-60 min, taken up by BMM, retained catalytic activity, and released in active form for greater than 24 h. In contrast, "naked" catalase was rapidly degraded. The released enzyme decomposed microglial hydrogen peroxide following nitrated alpha-synuclein or tumor necrosis factor alpha activation. Following adoptive transfer of nanozyme-loaded BMM to 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-intoxicated mice, ca. 0.6% of the injected dose were found in brain. We conclude that cell-mediated delivery of nanozymes can reduce oxidative stress in laboratory and animal models of PD.
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PMID:A macrophage-nanozyme delivery system for Parkinson's disease. 1776 Apr 17

An oral push-pull system that can deliver pramipexole for extended period of time has been developed and characterized. A bilayer osmotic drug delivery system was developed using a basic design consisting of an oral controlled porosity osmotic pump. Unlike other osmotic systems, which require a preformed orifice for drug release, controlled porosity membranes contain water-soluble pore-formers in the coating membrane. When such systems come in contact with water, the additives dissolve resulting in an in-situ formation of a microporous membrane. The push layer swells releasing the drug at a controlled rate. In advanced Parkinson's disease the usual dose of pramipexole is 1.5 mg three to four times a day. Hence, an attempt was made to develop a once-a-day controlled release system. This may offer significant patient benefits by providing enhanced efficacy and reduced side effects and may also reduce the number of daily doses compared to conventional therapies. This developed push-pull system was compared with other types of osmotic delivery systems, such as an asymmetric membrane coating and a dense coat with mechanical drilling. An optimized system was selected to study the effect of the concentration of a pore-forming agent such as PEG 400 and dibutyl phthalate, the pH of dissolution media, the effect of agitation and osmotic agents on drug release. The osmotic pressure generated was determined using a 3D3 freezing point osmometer. The drug release was found to follow zero order kinetics. Drug release increased with an increase in osmotic pressure. The developed push-pull osmotic system showed the desired once-a-day release kinetics.
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PMID:Development and evaluation of push-pull based osmotic delivery system for pramipexole. 1840 65


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