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)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP(+)) by B-form monoamine oxidase (MAO) in the brain, which is one of the most potent dopamine (DA)-releasing agents. MPP(+) perfusion into the striatum increases extracellular DA levels and this increase may concomitantly induce the formation of reactive free oxygen radicals, such as hydroxyl radical (.OH). These elevations seem to induce lipid peroxidation of striatum membranes, as detected by increases non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels. Sustained increase in striatal DA efflux by MAO inhibition produce.OH generation by products of monoamine. Therefore, reserpine-induced DA depletion clearly decreased MPP(+)-induced.OH formation. Neuromelanine synthesis from DA produce highly reactive free radicals. Nitric oxide (NO) contributes to produce MPP(+)-induced.OH generation via NO synthase (NOS) activation by depolarization. The antioxidation effect of angiotensin converting enzyme (ACE) inhibitor protects against MPP(+)-induced.OH generation due to the suppression of the Ca(2+)-dependent release of DA. These findings may be useful in elucidating the actual mechanism of free radical formation in the pathogenesis of neurodegenerative brain disorders, including Parkinson's disease and traumatic brain injuries. This review describes the free radicals mechanisms involved in MPTP toxicity and their possible involvement in the the pathogenesis of Parkinson's disease.
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PMID:Dopamine efflux by MPTP and hydroxyl radical generation. 1220 43

Tea is one of the most frequently consumed beverages in the world. It is rich in polyphenols, a group of compounds that exhibit numerous biochemical activities. Green tea is not fermented and contains more catechins than black tea or oolong tea. Although clinical evidence is still limited, the circumstantial data from several recent studies suggest that green tea polyphenols may promote health and reduce disease occurrence, and possibly protect against Parkinson's disease and other neurodegenerative diseases. Green tea polyphenols have demonstrated neuroprotectant activity in cell cultures and animal models, such as the prevention of neurotoxin-induced cell injury. The biological properties of green tea polyphenols reported in the literature include antioxidant actions, free radical scavenging, iron-chelating properties, (3)H-dopamine and (3)H-methyl-4-phenylpyridine uptake inhibition, catechol-O-methyltransferase activity reduction, protein kinase C or extracellular signal-regulated kinases signal pathway activation, and cell survival/cell cycle gene modulation. All of these biological effects may benefit patients with Parkinson's disease. Despite numerous studies in recent years, the understanding of the biological activities and health benefits of green tea polyphenols is still very limited. Further in-depth studies are needed to investigate the safety and efficacy of green tea in humans and to determine the different mechanisms of green tea in neuroprotection.
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PMID:Potential therapeutic properties of green tea polyphenols in Parkinson's disease. 1287 8

Xenobiotic enzymes normally protect against toxins but on occasion can convert protoxins into toxins. N-methylated pyridines (such as the N-methyl-4 phenylpyridinium ion (MPP+)) are well-established dopaminergic toxins. The enzyme nicotinamide N-methyltransferase (NNMT) can covert otherwise harmless pyridines such as 4-phenylpyridine into MPP+ like compounds. This enzyme has recently been shown to be present in the human brain, which is a necessity for neurotoxicity, as charged compounds such as MPP+ cannot cross the blood brain barrier. Moreover, it is present in increased concentration in the brain of patients with Parkinson's disease (PD). This would increase MPP+ like compounds at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, thus creating a "multiple hit", as additionally complex 1 of the mitochondrial complex would also be poisoned and starved of its major substrate, nicotinamide adenine dinucleotide (NAD). Thus, PD may be a disease of autointoxication. Xenobiotic enzyme inhibitors of NNMT, with or without dietary modification, would be a novel way to attempt primary prevention of PD.
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PMID:Autotoxicity, methylation and a road to the prevention of Parkinson's disease. 1563 3

Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.
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PMID:Parkinson's disease: the first common neurological disease due to auto-intoxication? 1572 3

Neuroinflammation mediated by microglial activation appears to play an essential role in the pathogenesis of Parkinson disease; however, the mechanisms by which microglia are activated are not fully understood. Thus, we first evaluated the effects of two parkinsonian toxicants, manganese ethylene bisdithiocarbamate (Mn-EBDC) and 1-methyl-4-phenylpyridine (MPP+), on microglial activation as well as associated dopaminergic (DAergic) neurotoxicity in primary cell culture systems. The results demonstrated that, when rat primary mesencephalic neuron-enriched or neuron-microglia mixed cultures were treated with Mn-EBDC at 2-8 microm or MPP+ at 0.25-5 microm, respectively, for 7 days, both toxicants were capable of inducing DAergic neurodegeneration as well as activating microglia via a mechanism secondary to DAergic neurodegeneration. Furthermore activated microglia subsequently enhanced DAergic neurotoxicity induced by Mn-EBDC or MPP+. Detailed scrutiny of neuron-microglia interactions identified a fraction of the conditioned media derived from a DAergic cell line treated with Mn-EBDC or MPP+ that potently activated microglia. To further define potential mediators leading to microglial activation secondary to neurodegeneration, we utilized a quantitative proteomic technique termed SILAC (for stable isotope labeling by amino acids in cell culture) to compare the protein profiles of MPP+-treated cellular fraction that mediated microglial activation as compared with controls. The search revealed numerous novel proteins that are potentially important in neurodegeneration-mediated microglial activation, a process believed to be critical in Parkinson disease progression.
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PMID:Microglial activation induced by neurodegeneration: a proteomic analysis. 1597 14

Although nicotine has been associated with a decreased risk of developing Parkinson disease, the underlying mechanisms are still unclear. By using isolated brain mitochondria, we found that nicotine inhibited N-methyl-4-phenylpyridine (MPP(+)) and calcium-induced mitochondria high amplitude swelling and cytochrome c release from intact mitochondria. Intra-mitochondria redox state was also maintained by nicotine, which could be attributed to an attenuation of mitochondria permeability transition. Further investigation revealed that nicotine did not prevent MPP(+)- or calcium-induced mitochondria membrane potential loss, but instead decreased the electron leak at the site of respiratory chain complex I. In the presence of mecamylamine hydrochloride, a nonselective nicotinic acetylcholine receptor inhibitor, nicotine significantly postponed mitochondria swelling and cytochrome c release induced by a mixture of neurotoxins (MPP(+) and 6-hydroxydopamine) in SH-SY5Y cells, suggesting that there is a receptor-independent nicotine-mediated neuroprotective effect of nicotine. These results show that interaction of nicotine with mitochondria respiratory chain together with its antioxidant effects should be considered in the neuroprotective effects of nicotine.
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PMID:Investigating the receptor-independent neuroprotective mechanisms of nicotine in mitochondria. 1598 39

PTEN-induced putative kinase 1 (Pink1) is a recently identified gene linked to a recessive form of familial Parkinson's disease (PD). The kinase contains a mitochondrial localization sequence and is reported to reside, at least in part, in mitochondria. However, neither the manner by which the loss of Pink1 contributes to dopamine neuron loss nor its impact on mitochondrial function and relevance to death is clear. Here, we report that depletion of Pink1 by RNAi increased neuronal toxicity induced by MPP(+). Moreover, wild-type Pink1, but not the G309D mutant linked to familial PD or an engineered kinase-dead mutant K219M, protects neurons against MPTP both in vitro and in vivo. Intriguingly, a mutant that contains a deletion of the putative mitochondrial-targeting motif was targeted to the cytoplasm but still provided protection against 1-methyl-4-phenylpyridine (MPP(+))/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. In addition, we also show that endogenous Pink1 is localized to cytosolic as well as mitochondrial fractions. Thus, our findings indicate that Pink1 plays a functional role in the survival of neurons and that cytoplasmic targets, in addition to its other actions in the mitochondria, may be important for this protective effect.
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PMID:Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. 1821 82

Parkinson's disease (PD) is a movement disorder resulting from nigrostriatal dopaminergic neurodegeneration. The impairment of mitochondrial function and dopamine synaptic transmission are involved in the pathogenesis of PD. Two mitochondrial inhibitors, 1-methyl-4-phenylpyridine (MPP(+)) and rotenone, have been used to induce dopaminergic neuronal death both in in vitro and in vivo models of PD. Because the uptake of MPP(+) is mediated by the dopamine transporter (DAT), we used a cell-permeable rotenone-induced PD model to investigate the role of DAT and dopamine D2 receptor (D2R) on dopaminergic neuronal loss. Rotenone subcutaneously infused for 14 days induced PD symptoms in rats, as indicated by reduced spontaneous locomotor activity (hypokinesis), loss of tyrosine hydroxylase (TH, a marker enzyme for dopamine neurons) immunoreactivity in the substantia nigra and striatum, obvious alpha-synuclein accumulation, downregulated DAT protein expression, and upregulated D2R expression. Interestingly, rotenone also caused significant noradrenergic neuronal loss in the locus coeruleus. Melatonin, an antioxidant, prevented nigrostriatal neurodegeneration and alpha-synuclein aggregation without affecting the rotenone-induced weight loss and hypokinesis. However, rotenone-induced hypokinesis was markedly reversed by the DAT antagonist nomifensine and body weight loss was attenuated by the D2R antagonist sulpiride. In addition, both antagonists significantly prevented the reduction of striatal TH or DAT immunoreactivity but not the loss of nigral TH- and DAT-immunopositive neurons. These results suggested that oxidative stress and DAT downregulation are involved in the rotenone-induced pathogenesis of nigrostriatal dopaminergic neurodegeneration, whereas D2R upregulation may simply represent a compensatory response.
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PMID:Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats. 1828 73

Neoechinulin A, an alkaloid from Eurotium rubrum, can protect neuronal PC12 cells against cytotoxicity of a potent oxidant, peroxynitrite. Because involvement of peroxynitrite has been suggested in the pathogenesis of Parkinson's disease, we assessed whether this alkaloid could also protect PC12 cells from the cytocidal action of 1-methyl-4-phenylpyridine (MPP+), a neurotoxin capable of provoking acute Parkinson's-like neurodegeneration in humans. Neoechinulin A could protect PC12 cells from MPP+ cytotoxicity without protecting against mitochondrial complex I dysfunction, suggesting the alkaloid can ameliorate downstream events of mitochondrial failure. Thus, neoechinulin A has the potential to intervene in this progressive neurodegeneration.
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PMID:Neoechinulin A protects PC12 cells against MPP+-induced cytotoxicity. 1865 1

In 1983, it was reported that certain drug users with a history of exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a contaminant of an illicitly produced meperidine analogue, developed an irreversible syndrome resembling idiopathic Parkinson disease (PD). Soon thereafter, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine's active metabolite, 1-methyl-4-phenylpyridine, was shown to be a complex I inhibitor. Activity of complex I (the point of entry for most electrons that traverse the mitochondrial electron transport chain) has been found to be impaired in the substantia nigra pars compacta and also in other brain tissues in PD patients. In 2006, high temporal and spatial resolution phosphorous functional magnetic resonance spectroscopy was used to demonstrate that, in 20 PD patients, mitochondrial dysfunction extended to the visual cortex. Epidemiologic studies have implicated a number of apparently disparate exogenous factors in the causation of PD. For example, exposure to certain pesticides and herbicides (many known to inhibit electron transport chain activity) increases PD risk. Parkinson disease risk can be doubled, tripled, or more in individuals with repeated head injuries. Over time, PD risk is almost doubled in men and women with prior type 2 diabetes mellitus. Nevertheless, despite evidence that certain exogenous and/or developmental factors play a role in causation of PD, their potential effect on PD incidence is greatly overshadowed by that of advancing age. In 1 prospective study, PD incidence rate in subjects at least 85 years old was about 14 times that observed in subjects aged 56 to 65 years. The dramatic effect of aging on PD risk may be explained in part by the fact that mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra pars compacta neurons. High levels of these mutations are associated with electron transport chain deficiency, a situation that favors increased oxidative damage, Lewy body formation, and apoptotic cell death. Systematic study of the effects of putative risk factors in animal models of parkinsonism may be expected to improve our understanding of PD's complex pathogenesis.
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PMID:Parkinson disease: primacy of age as a risk factor for mitochondrial dysfunction. 1880 67


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