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 pyridine derivative 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is recognized as a crucial neurotoxin which destroys nigrostriatal dopamine cells, thereby inducing neurological signs relevant to idiopathic Parkinson's disease. In the present study, we have revealed MPTP neurotoxicity to cerebellar Purkinje cells in mice. Systemic MPTP injections to mice resulted in a substantial loss of Purkinje cells in a dose-dependent fashion. The MPTP-induced Purkinje cell loss occurred markedly in the crus I and II ansiform lobules and the paraflocculus. Such a neurotoxic effect was largely prevented by the monoamine oxidase B inhibitors pargyline and deprenyl, and the dopamine uptake inhibitors mazindol and benztropine.
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PMID:MPTP neurotoxicity to cerebellar Purkinje cells in mice. 846 2

Incubation of highly enriched neurons from rat cerebral cortex with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 for 18 h results in fragmentation of DNA at internucleosomal linkers, a feature of apoptosis. We report that neurons respond to exposure to gp120 with an increased release of arachidonic acid via activation of phospholipase A2. This process is not inhibited by antagonists of the N-methyl-D-aspartate (NMDA) receptor channels. To investigate the influence of arachidonic acid on the sensitivity of NMDA receptor towards its against, low concentrations of NMDA were coadministered with arachidonic acid. Under these conditions the NMDA-mediated cytotoxicity was enhanced. We conclude that gp120 causes an activation of phospholipase A2, resulting in an increased release of arachidonic acid which in turn sensitizes the NMDA receptor. Two compounds were found to act cytoprotectively against the deleterious effect caused by gp120 on neurons: Memantine [1-amino-3,5-dimethyladamantane] and Flupirtine [2-amino-3-ethoxycarbonylamino-6-(4-fluoro-benzyl-amino)-pyridine maleate]. Both compounds have been found to display a potent cytoprotective effect on neurons treated with the excitatory amino acid NMDA or with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120. The NMDA antagonist Memantine, a drug currently used in the therapy of spasticity and Parkinson's disease, prevented the effects of gp120 at micromolar concentrations. Flupirtine was previously found to be a centrally acting, nonopiate analgesic agent which additionally possesses anticonvulsant and muscle-relaxant activity at doses similar to those producing analgesia. The cytoprotective effect of Flupirtine in vitro was significant (above 10 microM). Considering the fact that both Memantine and Flupirtine display almost no clinical side effects, these drugs may prove useful both in preventing primary infection of brain cells with the HIV virus, as well as in treating the neurological disorders often associated with the immunodeficiency syndrome such as AIDS-related dementia.
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PMID:Neurotoxicity in rat cortical cells caused by N-methyl-D-aspartate (NMDA) and gp120 of HIV-1: induction and pharmacological intervention. 882 91

In the past few years the focus on central acetylcholine receptors has shifted from compounds with affinity for muscarinic acetylcholine receptors (mAChR) to compounds with affinity for nicotinic acetylcholine receptors (nAChR). The therapeutic potential includes treatment of a variety of diseases, e.g., Alzheimer's disease, Parkinson's disease, and Tourette's syndrome. This work describes the synthesis of six novel series of potent ligands with nanomolar affinity for the alpha4beta2 nAChR subtype. Structure-activity relationship (SAR) was evaluated by the calculation of a 3D-QSAR model. 3D-QSAR analysis of the compounds using the GRID/GOLPE methodology resulted in a model of high quality (R(2) = 0.97, Q(2) = 0.81). The coefficient plots reveal that the steric interactions between the target and our compounds are of major importance for the affinity. Bulky substituents in the 6-position of the pyridine ring will reduce the affinity of the compounds, whereas bulky ring systems including a sp(3)-nitrogen will increase the affinity of the compounds.
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PMID:Novel potent ligands for the central nicotinic acetylcholine receptor: synthesis, receptor binding, and 3D-QSAR analysis. 1084

In the present study, we evaluated the effect of the prototypical metabotropic glutamate receptor 5 (mGlu(5)) antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on motor behaviour in rats using the accelerating rotarod, spontaneous locomotor activity and the 6-hydroxy-dopamine (6-OHDA) lesion model to assess its treatment potential for Parkinson's disease. The data indicate that MPEP at doses between 7.5 and 300 mg/kg, p.o. did not disrupt endurance performance on the accelerating rotarod (4-40 rpm in 300 s) which indicates that MPEP has a relatively high safety margin. However, while ineffective at doses of 3.75, 7.5 and 15 mg/kg (p.o.) MPEP inhibited spontaneous locomotor activity at doses of 30 and 100 mg/kg (p.o.). In the 6-OHDA rat rotation model, at doses of 7.5, 15 and 30 mg/kg (p.o.), MPEP induced a dose-dependent ipsilateral rotational response that reached statistical significance at the highest dose tested. This effect was relatively small but consistent. In combination with direct or indirect dopamine agonists, i.e. apomorphine (0.25 mg/kg, s.c.) and D-amphetamine (2.5 mg/kg, i.p.), MPEP (7.5, 15 or 30 mg/kg, p.o.) was found to significantly inhibit these dopamine receptor mediated rotational responses. MPEP injected at a dose of 30 mg/kg also inhibited the rotational response induced by L-DOPA (25 mg/kg, i.p.). (+)MK-801 was used in these rotation experiments as the reference compound. In view of these findings, it could be concluded that MPEP and potentially other mGlu(5) receptor antagonists are probably not appropriate drug candidates for the symptomatic treatment of Parkinson's disease.
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PMID:Effects of the prototypical mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. 1104 Mar 47

The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is may be initiated or precipitated by endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. The higher cerebrospinal fluid levels of N-methylated azaheterocyclic amines, such as beta-carboline and tetrahydroisoquinoline, have been found in parkinsonian patients compared with age-matched controls. To estimate the N-methylation ability for azaheterocyclic amines in parkinsonian patient, nicotinamide was dosed with 100 mg to 26 parkinsonians and 20 controls consisted of 16 other neurogenic disease patients and 4 healthy volunteers. The urine was collected for 4 h, and then analyzed urinary its metabolites by an improved HPLC method. Nicotinamide has a pyridine ring in its structure and may be metabolized through the pathways similar to those for the endogenous neurotoxins. The urinary excretions of nicotinamide metabolites were significantly affected by aging. The excretion of N1-methylnicotinamide decreased along with aging both in PD patients and controls. In younger (65 years old or younger) PD patients, the excretion amount of N1-methylnicotinamide was significantly higher than that in younger controls. The decline rate of N1-methylnicotinamide excretion in parkinsonians was significantly greater than that in controls; the rate is more than 2-fold higher in parkinsonian patients. The age-associated decrease in 1-methyl-2-pyridone-5-carboxyamide excretion was observed only in parkinsonian patients, but not in controls. The total excreted amount of N-methylated metabolites (N1-methylnicotinamide plus 1-methyl-2-pyridone-5-carboxyamide) was also observed the age-related decline in both groups. The urinary excretions of nicotinamide and nicotinamide-N-oxide were not influenced by aging. These results would indicate that the excess N-methylation ability for azaheterocyclic amines before the onset had been implicated in PD. On the other hand, the present results suggested that the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.
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PMID:N-methylation ability for azaheterocyclic amines is higher in Parkinson's disease: nicotinamide loading test. 1104 Dec 77

Marrow stromal cells, which have many characteristics of stem cells, populate various non-hematopoietic tissues including the brain. In the present study, the cDNA for the dopaminergic neurotrophic factor Glial Cell Line-Derived Neurotrophic Factor (GDNF) was delivered using marrow cells in the mouse 1-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) model of Parkinson's disease. Following cross-sex intravenous bone marrow transplantation with male donor cells that had been transduced with GDNF (GDNF-BMT) or with non-manipulated marrow (Control-BMT), female recipient mice were subjected to systemic MPTP injections. Eight weeks after neurotoxin exposure, more tyrosine hydroxylase immunoreactive nigral neurons and striatal terminal density were observed in the GDNF-BMT mice compared with the Control-BMT group. In addition, following the expected initial behavioral hyperactivity in both groups, a significant difference in motor activity was detected between the two groups. GDNF immunoreactive male donor marrow derived cells were detected in the brains of GDNF-BMT mice but not in controls. These data indicate that marrow derived cells that seed the brain can express biologically active gene products and, therefore, can function as effective vehicles for therapeutic gene transfer to the brain.
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PMID:Protection of nigral neurons by GDNF-engineered marrow cell transplantation. 1146 77

Nicotinic acetylcholine receptors (nAChRs) in the basal ganglia are a potential target for new therapeutics for Parkinson's disease. As an approach to detect expression of nAChRs in monkeys, we used 125I-epibatidine, an agonist at nAChRs containing alpha2 to alpha6 subunits. 125I-Epibatidine binding sites are expressed throughout the control monkey brain, including the basal ganglia. The alpha3/alpha6-selective antagonist alpha-conotoxin MII maximally inhibited 50% of binding in the caudate-putamen and had no effect on 125I-epibatidine binding in the frontal cortex or thalamus. In contrast, inhibition experiments with nicotine, cytisine, and 3-(2(S)-azetidinylmethoxy)pyridine-2HCl (A85380) showed a complete block of 125I-epibatidine binding in all regions investigated and did not discriminate between the alpha-conotoxin MII-sensitive and -insensitive populations in the striatum. To assess the effects of nigrostriatal damage, monkeys were rendered parkinsonian with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals with moderate striatal damage (dopamine transporter levels approximately 30% of control) had a 40 to 50% decrease in 125I-epibatidine binding. Inhibition studies showed that the decrease in epibatidine binding was due to loss of alpha-conotoxin MII-sensitive nAChRs. Monkeys with severe nigrostriatal damage (dopamine transporter levels < or = 5% of control) exhibited a 55 to 60% decrease in 125I-epibatidine binding, which seemed to be due to a complete loss of alpha-conotoxin MII nAChRs and a partial loss of other nAChR subtypes. These results show that nAChRs expressed in the primate striatum have similar affinities for nicotine, cytisine, and A85380, that alpha-conotoxin MII discriminates between nAChR populations in the caudate and putamen, and that alpha-conotoxin MII-sensitive nAChRs are selectively decreased after MPTP-induced nigrostriatal damage.
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PMID:Loss of nicotinic receptors in monkey striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment is due to a decline in alpha-conotoxin MII sites. 1175 25

Metabotropic glutamate receptors (mGluRs) have recently been considered as potential pharmacological targets in the treatment of neurodegenerative disorders and particularly in parkinsonism. Within the basal ganglia, receptors of group I (mGluR1 and mGluR5) are widely expressed; the present study was thus aimed at blocking these receptors in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease in the rat. Considering the prominent expression of mGluR5, we have used the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) to target these receptors. In rats trained to quickly depress a lever after a visual cue, bilateral lesions of the dopaminergic nerve terminals in the striatum produced severe akinetic deficits, which were expressed by increases in delayed responses and reaction times. Acute MPEP injection (1.5, 3, and 6 mg/kg, i.p.) had no effect, whereas chronic administration, ineffective in a control group, significantly reversed the akinetic deficits. Alleviation of these deficits was seen after 1 week of treatment, and the preoperative performance was fully recovered after a 3 week treatment of MPEP at all doses. Chronic MPEP also induced ipsilateral rotation in the unilateral 6-OHDA circling model. However, no effect was seen of MPEP (1.5, 3, or 6 mg/kg, i.p.) on haloperidol-induced catalepsy (1 mg/kg, i.p.). Altogether, these results suggest a specific role of mGluRs in the regulation of extrapyramidal motor functions and a potential therapeutic value for mGluR5 antagonists in the treatment of Parkinson's disease.
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PMID:Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism. 1209 18

The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is maybe initiated or precipitated by environmental or endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. Endogenous analogs of MPTP, such as beta-carbolines (betaCs) and tetrahydroisoquinolines, have been proposed as possible causative candidates causing PD and are bioactivated into potential neurotoxins by N-methylation enzyme(s). These N-methylated betaCs and tetrahydroisoquinoline have been higher cerebrospinal levels in parkinsonian patients than age-matched controls. Thus, there is a hypotheses to influence the pathogenesis of PD, that is, the excess enzyme activity to activate neurotoxins, such as N-methyltransferase, might be higher in PDs. Indeed, simple betaCs, via N-methylation steps, induced bradykinesia with the decreased dopamine contents in the striatum and midbrain in C57/BL mice. In younger (65 years old) PD patients, the excretion amount of N(1)-methyl-nicotinamaide was significantly higher than that in younger controls. The protein amount of nicotinamide N-methyltransferase (NNMT) was also significantly higher in younger PD patients than that in younger controls. These findings described here would indicate that the excess N-methylation ability for azaheterocyclic amines, such as betaCs, before the onset had been implicated in PD pathogenesis. On the other hand, the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.
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PMID:N-methylation underlying Parkinson's disease. 1220 Jan 90

An 89-year-old male patient, hospitalized with Parkinson's syndrome, suddenly died shortly after an intravenous drug injection. The conditions indicated that an overdose of nicardipine (1.3 mg/(mlkg)) may be given to the patient. At the autopsy, no pathological changes were noted. With a capillary gas chromatograph with mass spectrometer (GC-MS), nicardipine (4.97 microg/ml) and its pyridine metabolite (M-5, 5.0 microg/ml) were detected in the heart blood of the deceased. This result indicated that an overdose of intravenous nicardipine caused a sudden death of a patient in a poor condition.
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PMID:Detection of the calcium antagonist nicardipine and its metabolites by gas chromatography-mass spectrometry. 1242 46


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