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)

Neuronal death associated with Parkinson's disease is commonly believed to be caused by oxygen- and nitrogen-derived free radical species. Some years ago, however, we showed that peroxidase from the midbrain of dogs is able to kill various cell types, including neuroblastoma cells (M. B. Grisham et al., J. Neurochem. 48: 876-882: 1987). We postulated that a nigral peroxidase may play a significant role in the degeneration of dopaminergic neurons in Parkinson's disease. To further establish proof of principle, we recently performed a series of experiments using horseradish peroxidase and lactoperoxidase. We showed that the cytotoxic activity of lactoperoxidase is fully inhibited by physiological concentrations of dopamine, reduced glutathione, and L-cysteine, as well as by micromolar concentrations of apomorphine, desferal, aspirin, and uric acid. l-Methyl-4-phenyl-1,2-dihydropyridine (MPDP) and l-methyl-4-phenylpyridinium (MPP+) augment the cytotoxic activity, whereas l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, deprenyl, and pargyline had minimal or no effect. We also showed that horseradish peroxidase catalyzes the oxidation of MPDP to MPP+. Thus, contrary to the generally accepted theory that the in vivo oxidation of MPDP occurs spontaneously, this reaction may be catalyzed by a brain peroxidase. These observations lend further support to the suggestion that a brain peroxidase may play an important role in the metabolic events associated with Parkinson's disease.
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PMID:The cytotoxic activity of lactoperoxidase: enhancement and inhibition by neuroactive compounds. 1538 4

Trichloroethylene, a common industrial solvent and a metabolic precursor of chloral hydrate, occurs widely in the environment. Chloral hydrate, which is also used as a hypnotic, has been found to condense spontaneously with tryptamine, in vivo, to give rise to a highly unpolar 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) that has a structural analogy to the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Earlier studies have revealed the relative permeability of the molecule through the blood-brain barrier and its ability to induce Parkinson-like symptoms in rats. In this study, we report that TaClo induces an apoptotic pathway in the human neuroblastoma cell line, SK-N-SH, involving the translocation of mitochondrial cytochrome c to the cytosol and activation of caspase 3. TaClo-induced apoptosis shows considerable differences from that mediated by other Parkinson-inducing agents such as MPTP, rotenone and manganese. Although it is not clear if the clinically administered dosage of chloral hydrate or the relatively high environmental levels of trichloroethylene could lead to an onset of Parkinson's disease, the spontaneous in vivo formation of TaClo and its pro-apoptotic properties, as shown in this report, should be considered.
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PMID:1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline-induced apoptosis in the human neuroblastoma cell line SK-N-SH. 1544 60

In view of the recent focus on the zona incerta (and surrounding regions) as a target for deep brain stimulation in patients with Parkinson Disease, we have explored incertal cyto and chemoarchitecture in normal and MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated macaque monkeys. Brains were processed for routine tyrosine hydroxylase (TH), nitric oxide synthase (NOs), parvalbumin (Pv) and calbindin D 28k (Cal) immunocytochemistry, as well as for Nissl staining. We show four main sectors in the zona incerta, namely rostral, dorsal, ventral and caudal, each with a largely distinct cytoarchitecture. Each of the antibodies screened had signature distribution patterns across the zona incerta; TH+ cells were localised within the rostral sector, NOs+ cells were concentrated in the dorsal sector, Pv+ cells were found mainly in the ventral sector and Cal+ cells were distributed uniformly across all sectors. These patterns match closely those reported in non primates. We found no major differences in the distribution and shape of labelled cells in the zona incerta of MPTP-treated monkeys when compared to control. In conclusion, we report that the primate zona incerta shows considerable cyto and chemoarchitectonic heterogeneity; that it forms a nucleus with distinct sectors presumably associated with diverse functions--from generating arousal to shifting attention, and from controlling visceral activity to influencing posture and locomotion. These functions have been proposed for the zona incerta of non primates. Our results have clinical implications, in that deep brain stimulation of the zona incerta (or parts thereof) could manifest in signs and symptoms other than those associated with the motor system. Such clinical stimulations could well involve other systems, including those of arousal, attention and visceral control.
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PMID:Chemoarchitectonic heterogeneities in the primate zona incerta: clinical and functional implications. 1552 May 28

One of the prominent pathological features of Parkinson's disease (PD) is the abnormal accumulation of iron in the substantia nigra pars compacta (SNpc), in the reactive microglia, and in association with neuromelanin, within the melanin-containing dopamine (DA) neurons. Lewy body, the morphological hallmark of PD, is composed of lipids, redox-active iron, and aggregated alpha-synuclein, concentrating in its peripheral halo and ubiquitinated, hyperphosphorylated, neurofilament proteins. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times. Recent observations, that iron induces aggregation of inert alpha-synuclein to toxic aggregates, have reinforced the critical role of iron in oxidative stress-induced pathogenesis of DA neuron degeneration and protein degradation via ubiquitination. N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and 6-hydroxydopamine-induced neurodegeneration in rodents and nonhuman primates is associated with increased presence of iron and alpha-synuclein in the SNpc. The accumulation of iron in MPTP-induced neurodegeneration has been linked to nitric oxide-dependent mechanism, resulting in degradation of prominent iron regulatory proteins by ubiquitination. Radical scavengers such as R-apomorphine and green tea catechin polyphenol (-)-epigallocatechin-3-gallate, as well as the recently developed brain-permeable VK-28 series derivative iron chelators, which are neuroprotective against these neurotoxins in mice and rats, prevent the accumulation of iron and alpha-synuclein in SNpc. This study supports the notion that a combination of iron chelation and antioxidant therapy, as emphasized on several occasions, might be a significant approach to neuroprotection in PD and other neurodegenerative diseases.
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PMID:Iron and alpha-synuclein in the substantia nigra of MPTP-treated mice: effect of neuroprotective drugs R-apomorphine and green tea polyphenol (-)-epigallocatechin-3-gallate. 1565 62

Parkinson's disease (PD) is a major cause of morbidity and mortality among older individuals. Although the causes of Parkinson's disease are multifactorial, considerable evidence indicates that elevated labile iron in the substantia nigra pars compacta plays an important role in producing oxyradicals which subsequently damage nigro-striatal neurons. Based on this several researchers have suggested that blood-brain barrier crossing iron chelators might have clinical efficacy in treating PD. Work demonstrating that iron chelators protect nigro-striatal neurons in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine-induced rodent PD models supports this hypothesis. Recently, we found that the ATM gene product (mutated in ataxia-telangiectasia, A-T), is required for cell survival and genomic stability maintenance following exposure to low labile iron concentrations. Iron chelators (desferal, quercetin, and apoferritin) also increase A-T cell genomic stability and viability, and activate ATM-dependent cellular events in normal cells. Additionally Atm-deficient mice exhibit a selective loss of dopaminergic nigro-striatal neurons. Based on this, we propose that iron chelators protect the substantia nigra pars compacta not only by chelating labile iron and reducing oxyradical formation, but also by inducing ATM activity, leading to increased oxidative stress resistance and DNA repair. Support for this hypothesis comes from the recent observation that the iron chelating flavonoid quercetin both directly activates ATM and protects neuronal cells from the toxic effects of the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Therefore since; (1) ATM is required for iron toxicity resistance, (2) iron chelators such as quercetin, desferal, and apoferritin induce ATM activity and/or ATM-dependent events, and (3), Atm-deficient mice preferentially lose dopaminergic nigro-striatal neurons, we propose that ATM activity has an important function in PD. Furthermore, pharmacological manipulation of ATM activity via iron chelation might have clinical efficacy in PD treatment.
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PMID:Pharmacological manipulation of ataxia-telangiectasia kinase activity as a treatment for Parkinson's disease. 1569 90

Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK-28, possessing the monoamine oxidase (MAO) and neuroprotective N-propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitochondrial MAO-A and -B inhibitor in vitro (IC50, MAO-A, 0.037 +/- 0.02; MAO-B, 0.057 +/- 0.01). Acute (1-5 mg/kg) and chronic [5-10 mg/kg intraperitoneally (i.p.) or orally (p.o.) once daily for 14 days]in vivo studies have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO-A and -B inhibitor. It has little effects on the enzyme activities of the liver and small intestine. Its N-desmethylated derivative, M30A is significantly less active. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin(5-HT), noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5-HIAA (5-hydroxyindole acetic acid) as determined in striatum and hypothalamus. In the mouse MPTP (N-methy-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD) it attenuates the DA depleting action of the neurotoxin and increases striatal levels of DA, 5-HT and NA, while decreasing their metabolites. As DA is equally well metabolized by MAO-A and -B, it is expected that M30 would have a greater DA neurotransmission potentiation in PD than selective MAO-B inhibitors, for which it is being developed, as MAO-B inhibitors do not alter brain dopamine.
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PMID:Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. 1618 14

We explore the patterns of cell loss in the pedunculopontine tegmental nucleus (PpT), a major locomotor and muscle tone suppression centre of the brainstem, in two animal models of Parkinson disease, namely MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated monkeys and 6-hydroxydopamine(6OHDA)-lesioned rats. Although there have been many studies documenting the loss of dopaminergic cells from the substantia nigra in these animal models, there has been little, if any, documentation of a loss of cells in the PpT. Results were obtained from macaque monkeys (Macaca fascicularis) and Sprague-Dawley rats. For the monkey series, animals were injected intramuscularly with MPTP (0.2 mg/kg) for 8 days consecutively and then allowed to survive for 21 days thereafter. Each monkey underwent behavioural assessment for parkinsonian symptoms. For the rat series, 6OHDA was injected into the midbrain using stereotactic coordinates. Rats were then allowed to survive for either 7, 14, 28, or 84 days thereafter. Monkey and rat brains were aldehyde-fixed and processed for routine tyrosine hydroxylase (TH; to label nigral dopaminergic cells) and nitric oxide synthase (NOs; to label PpT cholinergic cells) immunocytochemistry. In monkeys, the morphology, distribution and number of NOs(+) cells in the controls and MPTP-treated cases were very similar. In fact, in terms of number, there was only a 1% difference in the mean cell number between the controls and MPTP-treated cases. A comparable pattern was evident in 6OHDA-lesioned rats; there was no substantial difference in morphology, distribution and number of NOs(+) cells on the 6OHDA-lesioned cases when compared to the controls at each of the survival periods post-surgery. In summary, we show no loss of the large cholinergic/NOs(+) cells in the PpT in two animal models of Parkinson disease. This is in contrast to the heavy loss of these cells reported by previous findings in idiopathic Parkinson disease in patients.
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PMID:Cell survival patterns in the pedunculopontine tegmental nucleus of methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys and 6OHDA-lesioned rats: evidence for differences to idiopathic Parkinson disease patients? 1623 36

Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse has been widely used as a rodent model of Parkinson's disease. In this study, alpha-tocopherol (alphaT) transfer protein knockout (heteromutant type, alpha-TTP((+/-))) mice were used to evaluate the protective effects of alphaT and gamma-tocopherol (gammaT) against MPTP-induced neurotoxicity. The intraperitoneal administration of MPTP to mice induced a decrease in the striatal levels of dopamine (DA) 3 days after the administration in both alpha-TTP((+/-)) and wild-type mice; these mice were fed an alphaT-deficient diet for 3 weeks before the MPTP administration. The DA levels in the alpha-TTP((+/-)) mice, which had been fed a gammaT-fortified diet (0.10 wt.%) for 3 weeks and were administered with MPTP, were recovered to those of the control, whereas there was no significant protective effect of alphaT despite the considerably higher striatal concentration of alphaT than gammaT. The immunohistochemical study also revealed that gammaT exerted a protective effect against neurodegenerative toxicity of MPTP. Collectively, this is the first report showing that the protective effect of gammaT is stronger than that of alphaT against the MPTP-induced damage of dopaminergic neurons in the mouse.
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PMID:gamma-Tocopherol attenuates MPTP-induced dopamine loss more efficiently than alpha-tocopherol in mouse brain. 1671 12

In MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-hydroxydopamine induced dopaminergic neurotoxicity and Parkinson's disease iron accumulates in substantia nigra pars compacta which has been suggested to participate in oxidative stress induced neurodegeneration. Pretreatment with iron chelators desferal, clioquinol, VK-28 and M30 are neuroprotective in both models. To determine the specificity of chelation neuroprotective activity we have examined the effect of D-penicillamine, a relatively specific copper chelator, in the mice model of MPTP-induced dopamine depletion. Our studies show that D-penicillamine, employed for removal of copper in Wilson disease is relatively weak in preventing dopaminergic neurotoxicity induced by MPTP, as compared to iron chelators previously studied. The results indicate that for prevention of MPTP-induced dopamine depletion and dopamine neurodegeneration, iron rather than copper chelation may be more effective and specific.
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PMID:The copper chelator, D-penicillamine, does not attenuate MPTP induced dopamine depletion in mice. 1673 32

A number of previous studies have demonstrated a positive effect of exogenously administered monosialoganglioside GM1 on striatal dopamine (DA) levels and DA neuron survival in animal models of parkinsonism. However, due to low bioavailability of peripherally administered GM1, the present study investigated the neuroprotective/neurorestorative potential of enhancing endogenous GM1 biosynthesis by administration of the synthetic ceramide analog L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP) in two mouse models of Parkinsonism produced by acute or subacute 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. L-PDMP treatment caused an increase in brain GM1 levels in both Parkinson models and resulted in a partial sparing of striatal DA levels in the subacute MPTP model but not in the acute MPTP model. L-PDMP treatment had no effect on DA neuron survival in either model. These data suggest that the administration of L-PDMP as a means to enhance endogenous brain GM1 levels may hold limited promise as a potential neuroprotective or neurorestorative therapeutic strategy for Parkinson's disease.
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PMID:The synthetic ceramide analog L-PDMP partially protects striatal dopamine levels but does not promote dopamine neuron survival in murine models of parkinsonism. 1676 37


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