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)

Lewy bodies are cytoskeletal inclusions associated with neuronal injury and death in idiopathic Parkinson's disease and other neurodegenerative disorders. The chemical composition of the 8-10-nm fibrils of the Lewy body is unknown, although they are related to both normal cytoskeletal elements and paired helical filaments of Alzheimer neurofibrillary tangles. From the Lewy body-rich cerebral cortex of patients with diffuse Lewy body disease we have isolated intact Lewy bodies using a high salt buffer/nonionic detergent gradient centrifugation procedure and extracted the constitutive fibrils with urea and sodium dodecyl sulfate. Urea/detergent-resistant Lewy body fibrils were solubilized with formic acid and found to contain a single protein band of 68 kDa, which was not found in identically prepared normal brain homogenates. The Lewy body derived-polypeptide was recognized on immunoblots by a polyclonal antibody that reacted with both the 68-kDa neurofilament subunit and the microtubule-associated protein tau. The 68-kDa Lewy body protein was not labeled by the monoclonal antibody tau-1 despite prior in vitro enzymatic dephosphorylation. We conclude that the detergent-insoluble component of the cortical Lewy body fibril shares epitopes with neurofilament and tau and may be a posttranslationally modified derivative of either neurofilament or tau with substantially altered biochemical and immunologic properties.
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PMID:Detergent-insoluble cortical Lewy body fibrils share epitopes with neurofilament and tau. 137 81

Choline acetyltransferase (ChAT) activity, the sedimentation and solubility forms of acetylcholinesterase (AChE) as well as total (3H-quinuclidinyl benzilate, QNB) and M1 (3H-pirenzepine, PZ) muscarinic binding were investigated in the temporal cortex (TC) and nucleus caudatus (NC) of both non-demented and demented parkinsonian patients and controls. ChAT activity and low-salt-soluble and detergent-soluble AChE were lower in the TC of demented patients with Parkinson's disease than in controls. ChAT activity and the solubility forms of AChE in the NC did not differ between controls and parkinsonian patients. In the TC, the activity of the intermediate form of AChE was lower in parkinsonian patients, but the activity of the light form of AChE did not differ between controls and parkinsonian patients. In the TC of patients with Parkinson's disease the Bmax of 3H-QNB binding was slightly higher than in controls, but the Bmax of 3H-PZ binding did not differ between controls and parkinsonian patients. In the NC the Bmax of 3H-QNB binding was unchanged compared to that of the controls. The concomitant decrease of ChAT with soluble as well as membrane-bound tetrameric AChE suggests a close relationship between ChAT and tetrameric form of AChE. M1 receptors (3H-PZ binding sites) are not affected in the TC, but are decreased in the NC of demented parkinsonian patients. This decrease may be secondary to the loss of dopaminergic neurons projecting from the substantia nigra to the striatum.
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PMID:Different forms of brain acetylcholinesterase and muscarinic binding in Parkinson's disease. 272 71

1-Methyl-4-phenylpyridinium (MPP+), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which induces Parkinson's disease in man, is a substrate of the monoamine uptake system of chromaffin granules. It is accumulated without chemical modification by bovine chromaffin granule membrane vesicles in the presence of ATP. The transport is saturable and is characterized by a Km value of 0.8 microM at pH 8.0, similar to that of serotonin (5-HT). Transport occurs through the monoamine transporter since it is competitively inhibited by 5-HT and since MPP+ competitively inhibits [3H]5-HT uptake. Moreover, [3H]MPP+ uptake is blocked by the monoamine transporter inhibitors tetrabenazine and reserpine. Finally, MPP+ efficiently displaces [3H]reserpine and [3H]dihydrotetrabenazine from their binding sites on the transporter. In the pH range 6-8, the Km for [3H]MPP+ uptake and the EC50 of MPP+ for the displacement of [3H]dihydrotetrabenazine decrease logarithmically with the pH. MPP+ is the first quaternary ammonium salt shown to be a substrate of the monoamine transporter and it has the same pH-dependency as monoamines.
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PMID:Characteristics of the transport of the quaternary ammonium 1-methyl-4-phenylpyridinium by chromaffin granules. 326 61

The neurotoxic effects of the dopamine-selective neurotoxin MPTP (15 mg/kg, s.c.), in mice, were totally prevented by systemic administration of salicylate (ED50 = 40 mg/kg, i.p.), aspirin (ED50 = 60 mg/kg, i.p.), or the soluble lysine salt of aspirin, Aspegic (ED50 = 80 mg/kg, i.p.). The protective effects of aspirin are unlikely to be related to cyclooxygenase inhibition as paracetamol (100 mg/kg, i.p.), diclofenac (100 mg/kg, i.p.), ibuprofen (20 mg/kg, i.p.) and indomethacin (100 mg/kg, i.p.) were ineffective. Dexamethasone (3-30 mg/kg, i.p.), which, like aspirin and salicylate, has been reported to inhibit the transcription factor NF-kappaB, was also ineffective. Aspirin or salicylate (100 microM) had no effect on dopamine uptake into striatal synaptosomes or on monoamine oxidase B activity. The neuroprotective effects of salicylate derivatives could perhaps be related to hydroxyl radical scavenging. This was suggested by the fact that hydroxylated metabolites of salicylate (2,3- and 2,5-dihydrobenzoic acid) were recovered in brain tissue following the combined administration of MPTP and aspirin to a greater extent than following aspirin alone. The surprising neuroprotective effects of aspirin in an animal model of Parkinson's disease warrant further clinical investigation.
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PMID:Aspirin and salicylate protect against MPTP-induced dopamine depletion in mice. 975 Nov 97

Pramipexole, a novel non-ergoline dopamine (DA) agonist, has been applied successfully for treatment of Parkinson's disease (PD). We report here that pramipexole can protect dopaminergic cell line Mes23.5 against dopamine- and levodopa-induced cytotoxicity possibly through a mechanism related to antioxidant activity. In the MES 23.5 cultures, DA and L-DOPA induce a dose- and time-dependent cytotoxicity, as determined by tetrazolium salt and trypan blue assays. Furthermore, an in situ terminal deoxynucleotidyl transferase assay demonstrates that DA-induced cell death is apoptotic. Pretreatment with pramipexole in a concentration range (4-100 microM) significantly attenuates DA- or L-DOPA-induced cytotoxicity and apoptosis, an action which is not blocked by D3 antagonist U-99194 A or D2 antagonist raclopride. Pramipexole also protects MES 23.5 cells from hydrogen peroxide-induced cytotoxicity in a dose-dependent manner. In cell-free system, pramipexole can effectively inhibit the formation of melanin, an end product resulting from DA or L-DOPA oxidation. These results indicate that pramipexole exerts its neuroprotective effect possibly through a mechanism, which is independent of DA receptors but related to antioxidation or scavenging of free radicals (e.g. hydrogen peroxide). As a direct DA agonist and potentially neuroprotective agent, pramipexole remains attractive in the treatment of PD.
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PMID:Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity. 1022 83

Chronic dopaminomimetic administration to parkinsonian animal models or Parkinson's disease patients leads to characteristic alteration in motor response. Previous studies suggested that the nonphysiologic stimulation of dopaminergic receptors on striatal medium spiny neurons enhances the synaptic efficacy of juxtaposed glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. Resultant NMDA receptor sensitization due to differential changes in subunit phosphorylation appears to favor alterations in striatal output in ways that influence motor function. To detail the involvement of NMDA receptors further as well as to determine whether similar functional changes might develop in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, the effects of selective antagonist of AMPA receptors (6-nitro-7-sulfamoyl-benzo[f]-quinoxaline-2,3 (1H,4H)-dione sodium salt, NBQX, 10 mg/kg) on levodopa-induced response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats were compared with drugs which act competitively (3-(+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonicacid, CPP, 6.25 mg/kg) or noncompetitively (dextromethorphan, 40 mg/kg) to block NMDA receptors, or a nonselective inhibitor of glutamatergic transmission (2-amino-6-trifluoromethoxy benzothiazole, riluzole, 5 mg/kg). We found that the shortened duration of the motor response to levodopa, which underlies human wearing-off fluctuations, was reversed to a similar degree by the acute coadministration of CPP, NBQX, or riluzole (n = 4-6) but dextromethorphan did not. These observations strengthen the possibility that a reduction in levodopa-associated changes in motor response by inhibitors of glutamatergic transmission acting generally or selectively at the glutamate binding-sites may relate to their ability to attenuate pathologic gain in striatal glutamatergic function. The capacity of NBQX to reverse these altered responses suggests that an enhanced synaptic efficacy of striatal AMPA receptors may also participate in the generation of these motor response changes in levodopa-treated parkinsonian rats.
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PMID:Non-NMDA receptor-mediated mechanisms are involved in levodopa-induced motor response alterations in Parkinsonian rats. 1081 4

The propargylamine derivative CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine) has previously been found to exhibit neurorescuing and antiapoptotic properties in several in vitro and in vivo paradigms. After showing that this compound does not inhibit monoamine oxidase B and only marginally inhibits monoamine oxidase A at concentrations or doses far above those relevant for its reported neuroprotective effects, we investigated it in models considered relevant for Parkinson's disease. CGP 3466 or its hydrogen maleate salt, CGP 3466B, at concentrations between 10(-11) M and 10(-7) M, protected rat embryonic mesencephalic dopaminergic neurons in free-floating or dispersed cell culture from death inflicted by treatment with 1-methyl-4-phenyl pyridinium ion (MPP+) as measured by different readouts such as dopamine uptake, tyrosine hydroxylase activity, and counts of tyrosine hydroxylase-positive cells. Treatment of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2x30 mg/kg s.c. at a 72-h interval) with CGP 3466 (0.1 mg/kg s.c.) or CGP 3466B (0.014 mg/kg and 0.14 mg/kg p.o.) b.i.d. for 18 days partially prevented the loss of tyrosine hydroxylase-positive cells in the substantia nigra; a lower dose of CGP 3466B (0.0014 mg/kg p.o.) showed a marginal effect, whereas a high dose, i.e. 1.4 mg/kg p.o., was ineffective, suggesting a bell-shaped dose-response relationship which has also been observed in other paradigms. The effect of CGP 3466 on motor function was evaluated in rats that received intrastriatal injections of 6-OHDA unilaterally, according to a four-site injection protocol, and that were subsequently treated b.i.d. with 0.014 mg/kg i.p. CGP 3466B for 3 weeks. After another 3 weeks without treatment, skilled paw use was assessed by means of the staircase test. The results indicated a significant improvement of skilled motor performance as measured by means of the number of eaten pellets. Since due to the long wash-out period a symptomatic effect of CGP 3466B can be ruled out, it is likely that this improvement was related to interference with the course of the degeneration of the dopaminergic neurons. In conclusion, our results indicate that CGP 3466 is able to prevent death of dopaminergic cells in in vitro and in vivo models of Parkinson's disease. In addition, treatment with CGP 3466 resulted in improved skilled motor performance in 6-OHDA-lesioned rats.
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PMID:CGP 3466 protects dopaminergic neurons in lesion models of Parkinson's disease. 1113 45

Alpha-synuclein is the major component of Lewy bodies in patients with Parkinson's disease, and mutations in the alpha-synuclein gene are responsible for some familial forms of the disease. alpha-Synuclein is enriched in the presynapse, but its synaptic targets are unknown. Synphilin-1 associates in vivo with alpha-synuclein promoting the formation of intracellular inclusions. Additionally synphilin-1 has been found to be an intrinsic component of Lewy bodies in patients with Parkinson's disease. To understand the role of synphilin-1 in Parkinson's disease, we sought to define its localization and function in the brain. We now report that, like alpha-synuclein, synphilin-1 was enriched in neurons. In young rats, synphilin-1 was prominent in neuronal cell bodies but gradually migrated to neuropil during development. Immunoelectron microscopy of adult rat cerebral cortex demonstrated that synphilin-1 was highly enriched in presynaptic nerve terminals. Synphilin-1 co-immunoprecipitated with synaptic vesicles, indicating a strong association with these structures. In vitro binding experiments demonstrated that the N terminus of synphilin-1 robustly associated with synaptic vesicles and that this association was resistant to high salt washing but was abolished by inclusion of alpha-synuclein in the incubation medium. Our data indicated that synphilin-1 is a synaptic partner of alpha-synuclein, and it may mediate synaptic roles attributed to alpha-synuclein.
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PMID:Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by alpha-synuclein. 1195 99

Alpha-synuclein is the major component of Lewy bodies and Lewy neurites, which are granular and filamentous protein inclusions that are the defining pathological features of several neurodegenerative conditions such as Parkinson's disease. Fibrillar aggregates formed from alpha-synuclein in vitro resemble brain-derived material, but the role of such aggregates in the etiology of Parkinson's disease and their relation to the toxic molecular species remain unclear. In this study, we investigated the effects of pH and salt concentration on the in vitro assembly of human wild-type alpha-synuclein, particularly with regard to aggregation rate and aggregate morphology. Aggregates formed at pH 7.0 and pH 6.0 in the absence of NaCl and MgCl(2) were fibrillar; the pH 6.0 fibrils displayed a helical twist, as clearly evident by scanning force and electron microscopy. Incubations at pH 7.0 remained transparent during the process of aggregation and exhibited strong thioflavin-T and weak 8-anilino-1-naphthalenesulfonate (ANS) binding; furthermore, they were efficient in seeding fibrillization of fresh solutions. In contrast, incubating alpha-synuclein at low pH (pH 4.0 or pH 5.0) resulted in the rapid formation of turbid suspensions characterized by strong ANS binding, reduced thioflavin-T binding and reduced seeding efficiency. At pH 4.0, fibril formation was abrogated; instead, very large aggregates (dimensions approximately 100 microm) of amorphous appearance were visible by light microscopy. As with acidic conditions, addition of 0.2M NaCl or 10mM MgCl(2) to pH 7.0 incubations led to a shorter aggregation lag time and formation of large, amorphous aggregates. These results demonstrate that the morphology of alpha-synuclein aggregates is highly sensitive to solution conditions, implying that the fibrillar state does not necessarily represent the predominant or most functionally significant aggregated state under physiological conditions.
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PMID:Dependence of alpha-synuclein aggregate morphology on solution conditions. 1221 98

The term dysautonomia refers to a change in autonomic nervous system function that adversely affects health. The changes range from transient, occasional episodes of neurally mediated hypotension to progressive neurodegenerative diseases; from disorders in which altered autonomic function plays a primary pathophysiologic role to disorders in which it worsens an independent pathologic state; and from mechanistically straightforward to mysterious and controversial entities. In chronic autonomic failure (pure autonomic failure, multiple system atrophy, or autonomic failure in Parkinson disease), orthostatic hypotension reflects sympathetic neurocirculatory failure from sympathetic denervation or deranged reflexive regulation of sympathetic outflows. Chronic orthostatic intolerance associated with postural tachycardia can arise from cardiac sympathetic activation after "patchy" autonomic impairment or blood volume depletion or, as highlighted in this discussion, from a primary abnormality that augments delivery of the sympathetic neurotransmitter norepinephrine to its receptors in the heart. Increased sympathetic nerve traffic to the heart and kidneys seems to occur as essential hypertension develops. Acute panic can evoke coronary spasm that is associated with sympathoneural and adrenomedullary excitation. In congestive heart failure, compensatory cardiac sympathetic activation may chronically worsen myocardial function, which rationalizes treatment with beta-adrenoceptor blockers. A high frequency of positive results on tilt-table testing has confirmed an association between the chronic fatigue syndrome and orthostatic intolerance; however, treatment with the salt-retaining steroid fludrocortisone, which is usually beneficial in primary chronic autonomic failure, does not seem to be beneficial in the chronic fatigue syndrome. Dysautonomias are an important subject in clinical neurocardiology.
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PMID:Dysautonomias: clinical disorders of the autonomic nervous system. 1241 49


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