Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.
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PMID:Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease. 1135 Nov 30

The neuropathology associated with Parkinson's disease (PD) is thought to involve excessive production of free radicals, dopamine autoxidation, defects in glutathione peroxidase expression, attenuated levels of reduced glutathione, altered calcium homeostasis, excitotoxicity and genetic defects in mitochondrial complex I activity. While the neurotoxic mechanisms are vastly different for excitotoxins and 1-methyl-4-phenylpyridinium ion (MPP(+)), both are thought to involve free radical production, compromised mitochondrial activity and excessive lipid peroxidation. We show here that the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) increased significantly after treatment of cultured cerebellar granule cells (CGCs) with 50 microM MPP(+). Co-treatment with antioxidants such as ascorbate (ASC), catalase, alpha-tocopherol (alpha-TOH), coenzyme Q(10) (CoQ(10)) or superoxide dismutase (SOD) rescued the cells from MPP(+)-induced death. MPP(+)-induced cell death was also abolished by co-treatment with nitric oxide synthase (NOS) inhibitors such as 7-nitroindazole (7-NI), 2-ethyl-2-thiopseudourea hydrobromide (EPTU) or S-methylisothiourea sulphate (MPTU). We also tested the protective effects of an iron chelator (deferoxamine mesylate, DFx) and a peroxynitrite scavenger (FeTTPS) and the results lend further support to the view that the free radical cytotoxicity plays an essential role in MPP(+)-induced death in primary cultures of CGC.
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PMID:Protection against MPP+ neurotoxicity in cerebellar granule cells by antioxidants. 1519 80

The effects of exogenous toxins (MPP(+), rotenone) and potentially neurotoxic properties of levodopa (L-DOPA) on the survival rate of dopaminergic neurons in dissociated primary culture are presented. Dopamine agonists show a capacity to counteract MPP(+)-toxicity. Moreover, a preserving potential of the antioxidant and bioenergetic coenzyme Q(10) (CoQ(10)) on the activities of tyrosine hydroxylase (TH), complexes I and II of the respiratory chain, and hexokinase activity in striatal slice cultures against MPP(+) is demonstrated.
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PMID:Oxidative stress to dopaminergic neurons as models of Parkinson's disease. 1524 Apr 12

Coenzyme Q10, an endogenous lipophilic antioxidant, plays an indispensable role in ATP synthesis. The therapeutic value of coenzyme Q10 in Parkinson's disease and other neurodegenerative disorders is still being tested and the preliminary results are promising. The 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP)-treated mouse is a valid and accepted animal model for Parkinson's disease. 1-methyl-4-phenylpyridinium (MPP(+)) is an active toxic metabolite of MPTP. MPP(+) and MPTP are known to induce oxidative stress and mitochondrial dysfunction. However, the effect of MPP(+) and MPTP on coenzyme Q is not clearly understood. The present study investigated the in vitro and in vivo effect of MPP(+) and MPTP on coenzyme Q content. Coenzyme Q content was measured using HPLC-UV detection methods. In the in vitro studies, MPP(+) (0-50 microM) was incubated with SH-SY5Y human neuroblastoma cells and NG-108-15 (mouse/rat, neuroblastomaxglioma hybrid) cells. MPP(+) concentration dependently increased coenzyme Q10 content in SH-SY5Y cells. In NG-108-15 cells, MPP(+) concentration dependently increased both coenzyme Q9 and Q10 content. In the in vivo study, mice were administered with MPTP (30 mg/kg, twice 16 h apart) and sacrificed one week after the last administration. Administration of MPTP to mice significantly increased coenzyme Q9 and coenzyme Q10 levels in the nigrostriatal tract. However, MPTP did not affect the coenzyme Q content in the cerebellum, cortex and pons. This study demonstrated that MPP(+)/MPTP significantly affected the coenzyme Q content in the SH-SY5Y and NG-108 cells and in the mouse nigrostriatal tract.
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PMID:Effect of dopaminergic neurotoxin MPTP/MPP+ on coenzyme Q content. 1856 46

Coenzyme Q(10) (CoQ(10)) exerts neuroprotective effects in several in vivo and in vitro models of neurodegenerative disorders. However, the mechanisms of action are not fully understood. The aim in this study was to investigate whether oral administration of CoQ(10) could inhibit cytochrome c (cyt c) release from mitochondria induced by 1-methyl-4-phenylpyridinium ion (MPP(+)), which causes dopaminergic cell death by selective inhibition of complex I of the electron transport chain, in mouse brain synaptosomes. An increase of cyt c was detected in the cytosolic fraction from mouse brain synaptosomes treated with MPP(+). Oral administration of CoQ(10) prevented the mitochondrial cyt c release in the MPP(+)-treated synaptosomes. In addition, CoQ(10) did not affect the MPP(+)-induced decrease in mitochondrial oxidation-reduction activity and membrane potential in brain synaptosomes. Our findings demonstrate that MPP(+)-induced mitochondrial cyt c release in brain synaptosomes is prevented by oral administration of CoQ(10) independently of mitochondrial dysfunction prior to the cyt c release.
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PMID:Oral administration of coenzyme Q(10) prevents cytochrome c release from mitochondria induced by 1-methyl-4-phenylpyridinium ion in mouse brain synaptosomes. 1963