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)

In this study reactive oxygen species (ROS) generated in the respiratory chain were measured and the quantitative relationship between inhibition of the respiratory chain complexes and ROS formation was investigated in isolated nerve terminals. We addressed to what extent complex I, III and IV,respectively, should be inhibited to cause ROS generation. For inhibition of complex I, III and IV, rotenone, antimycin and cyanide were used, respectively, and ROS formation was followed by measuring the activity of aconitase enzyme. ROS formation was not detected until complex III was inhibited by up to 71 +/- 4%, above that threshold inhibition, decrease in aconitase activity indicated an enhanced ROS generation. Similarly, threshold inhibition of complex IV caused an accelerated ROS production. By contrast, inactivation of complex I to a small extent (16 +/- 2%) resulted in a significant increase in ROS formation, and no clear threshold inhibition could be determined. However, the magnitude of ROS generated at complex I when it is completely inhibited is smaller than that observed when complex III or complex IV was fully inactivated. Our findings may add a novel aspect to the pathology of Parkinson's disease, showing that a moderate level of complex I inhibition characteristic in Parkinson's disease leads to significant ROS formation. The amount of ROS generated by complex I inhibition is sufficient to inhibit in situ the activity of endogenous aconitase.
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PMID:Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. 1248 7

Several neurological diseases involve focal injury of specific brain structures. Poisons of the electron transport chain complexes (ETCC) can also produce selective injury of brain structures when given systemically and have been implicated in the development of neurological disease. Why ETCC poisons damage particular brain regions is unclear. Calculations of the relative ETCC expression level to glucose utilization rate (GUR) ratio from published observations here reveal that a low ETCC/GUR ratio predisposes a brain structure to injury by a poison of that complex. While GUR can rise with increased neuronal activity, ETCC expression is fixed in the short term. A high ETCC/GUR therefore represents surplus ETCC capacity, allowing for increased ATP generation with short-term increases in demand. A low ETCC/GUR indicates the opposite and will lead to energy failure when the specific ETCC is poisoned. These observations may explain why cyanide, a specific ETCC (IV) inhibitor, can produce selective injury of white matter, which has the lowest ETCC (IV)/GUR found in the brain. They are also consistent with the selective damage of the striatum produced by poisons such as rotenone, a form of injury implicated in Parkinson's disease. The striatum has a low ETCC (I)/GUR ratio, whereas rotenone is a selective ETCC (I) inhibitor.
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PMID:Variations in spare electron transport chain capacity: The answer to an old riddle? 1260

We assessed the antioxidant activity of non-narcotic analgesics, acetaminophen and aspirin in rat brain homogenates and neuroprotective effects in vivo in rats intranigrally treated with 1-methyl-4-phenyl pyridinium (MPP+). Both drugs inhibited cyanide-induced superoxide anion generation, as well as lipid peroxidation in rat brain homogenates, the combination of the agents resulting in a potentiation of this effect. Acetaminophen or aspirin when administered alone or in combination, did not alter dopamine (DA) levels in the forebrain or in the striatum. Intranigral infusion of MPP+ in rats caused severe depletion of striatal DA levels in the ipsilateral striatum in rats by the third day. Systemic post-treatment of acetaminophen afforded partial protection, whereas similar treatment of aspirin resulted in complete blockade of MPP+-induced striatal DA depletion. While these findings suggest usefulness of non-narcotic analgesics in neuroprotective therapy in neurodegenerative diseases, aspirin appears to be a potential candidate in prophylactic as well as in adjuvant therapy in Parkinson's disease.
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PMID:Acetaminophen and aspirin inhibit superoxide anion generation and lipid peroxidation, and protect against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats. 1464 53

Tolcapone and entacapone are catechol-O-methyltransferase (COMT) inhibitors used as adjuncts to levodopa in the treatment of Parkinson's disease (PD). The use of tolcapone has been limited by its hepatotoxicity, the cause of which remains uncertain. Tolcapone compound is an uncoupler of mitochondrial respiration in isolated mitochondria and this action may be relevant to its effect on liver function. We have examined the actions of COMT inhibitors on cultured cells, comparing them with those of the classical uncoupler carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), in order to provide insight into their mechanism of potential toxicity. Tolcapone and FCCP were shown to be toxic to human neuroblastoma SH-SY5Y cells and caused a profound reduction in ATP synthesis. Entacapone was not toxic to SH-SY5Y. Tolcapone and FCCP were shown to be equally toxic to cells depleted of mtDNA and thus devoid of a functional respiratory chain. This study demonstrates that tolcapone markedly inhibits ATP synthesis in cultured cells mirroring the effects of a classical uncoupler. However its toxicity may also involve a mechanism independent of its effects upon oxidative phosphorylation.
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PMID:Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells. 1497 80

Chronic exposure to the pesticide rotenone induces a selective degeneration of nigrostriatal dopaminergic neurons and reproduces the features of Parkinson's disease in experimental animals. This action is thought to be relevant to its inhibition of the mitochondrial complex I, but the precise mechanism of this suppression in selective neuronal death is still elusive. Here we investigate the mechanism of dopaminergic neuronal death mediated by rotenone in primary rat mesencephalic neurons. Low concentrations of rotenone (5-10 nM) induce the selective death of dopaminergic neurons without significant toxic effects on other mesencephalic cells. This cell death was coincident with apoptotic events including capsase-3 activation, DNA fragmentation, and mitochondrial membrane depolarization. Pretreatment with coenzyme Q10, the electron transporter in the mitochondrial respiratory chain, remarkably reduced apoptosis as well as the mitochondrial depolarization induced by rotenone, but other free radical scavengers such as N-acetylcysteine, glutathione, and vitamin C did not. Furthermore, the selective neurotoxicity of rotenone was mimicked by the mitochondrial protonophore carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a cyanide analog that effectively collapses a mitochondrial membrane potential. These data suggest that mitochondrial depolarization may play a crucial role in rotenone-induced selective apoptosis in rat primary dopaminergic neurons.
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PMID:Mitochondrial membrane depolarization and the selective death of dopaminergic neurons by rotenone: protective effect of coenzyme Q10. 1593 40

Complex I inhibition has been implicated in the neurotoxicity of MPTP and rotenone, which reproduce a neurochemical and neuropathological feature of Parkinson's disease in experimental animals. Previous studies performed in rat striatal slices have shown that dopaminergic neurotoxins, MPTP and manganese, inhibit tyrosine hydroxylation, a rate-limiting step of dopamine biosynthesis. In this study, we examined the effect of mitochondrial toxins such as rotenone and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on tyrosine hydroxylation in rat striatal slices. Rotenone and CCCP inhibited DOPA formation with an accompanying decrease in ATP and increase in lactate of rat striatal slices during 1h incubation. Furthermore, rotenone reduced dopamine (DA), dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) levels in PC12 cells after 20 h incubation. These results suggest that tyrosine hydroxylation is inhibited in dopaminergic neurons soon after exposure to sub-micromolar concentrations of rotenone and CCCP, leading to dopamine depletion.
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PMID:Rotenone and CCCP inhibit tyrosine hydroxylation in rat striatal tissue slices. 1611 19

Mutations in the ubiquitin ligase-encoding Parkin gene have been implicated in the pathogenesis of autosomal recessive Parkinson disease. Outside of the central nervous system, Parkin is prominently expressed in skeletal muscle. We have found accumulations of Parkin protein in skeletal muscle biopsies taken from patients with inclusion body myositis, a degenerative disorder in which intramyofiber accumulations of the beta-amyloid peptide are pathognomonic. In comparing primary cultures of skeletal muscle derived from parkin knock-out and wild-type mice, we have found the absence of parkin to result in greater sensitivity to mitochondrial stressors rotenone and carbonyl cyanide 3-chlorophenylhydrazone, without any alteration in sensitivity to calcium ionophore or hydrogen peroxide. Utilizing viral expression constructs coding for the Alzheimer disease and inclusion body myositis-linked beta-amyloid precursor protein and for its metabolic byproducts A beta42 and C100, we found that parkin knock-out muscle cells are also more sensitive to the toxic effects of intracellular A beta. We also constructed a lentiviral system to overexpress wild-type Parkin and have shown that boosting the levels of parkin expression in normal skeletal muscle cultures provides substantial protection against both mitochondrial toxins and overexpressed beta-amyloid. Correspondingly, exogenous Parkin significantly lowered A beta levels. These data support the hypothesis that in myocytes parkin has dual properties in the maintenance of skeletal muscle mitochondrial homeostasis and in the regulation of A beta levels.
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PMID:Parkin protects against mitochondrial toxins and beta-amyloid accumulation in skeletal muscle cells. 1651 3

Previous studies have demonstrated a deficiency in mitochondrial function in Parkinson's disease. We measured the ability of mitochondrial inhibitors of complexes I (rotenone, MPP(+), and HPP(+)), II (amdro), IV (Na cyanide), and an uncoupler (dinoseb) to release preloaded dopamine from murine striatal synaptosomes. These compounds were potent dopamine releasers, and the effect was calcium-dependent. The striatum also contains a significant density of K(ATP)(+) channels, which play a protective role during ATP decline. Blockage of these channels with glibenclamide only potentiated the dopamine release by complex I inhibitors, and a selective potentiating effect of glibenclamide on the toxicity of MPTP was also observed, in vivo, using C57BL/6 mice. Western blots of striatal dopamine transporter (DAT) and tyrosine hydroxylase (TH) proteins demonstrated that 30 mg/kg of glibenclamide alone did not affect the expression of DAT and TH after two weeks of daily treatments, but it significantly enhanced the reduction of DAT and TH by a single dose of 20 mg/kg of MPTP. Amdro or dinoseb alone, or in conjunction with glibenclamide did not alter the expression of DAT and TH. The possible mechanisms underlying dopamine release and the selectivity of glibenclamide were further evaluated, in vitro. (86)Rb efflux assay showed that glibenclamide inhibited rotenone-induced K(+) efflux, but not dinoseb-induced K(+) efflux. Analysis of ATP titers in treated synaptosomes did not support a correlation between mitochondrial inhibition and K(ATP)(+) channel activation. However, assay of reactive oxygen species (ROS) showed that greater amounts of ROS generated by complex I inhibitors was a contributory factor to K(ATP)(+) channel activation and glibenclamide potentiation. Overall, these findings suggest that co-exposure to mitochondrial complex I inhibitors and glibenclamide or a genetic defect in K(ATP)(+) channel function, may increase neurotoxicity in the striatal dopaminergic system.
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PMID:Potentiating effect of the ATP-sensitive potassium channel blocker glibenclamide on complex I inhibitor neurotoxicity in vitro and in vivo. 1672 3

Partial inhibition of mitochondrial respiratory complex I by rotenone reproduces aspects of Parkinson's disease in rodents. The hypothesis that rotenone enhancement of neuronal cell death is attributable to oxidative stress was tested in an acute glutamate excitotoxicity model using primary cultures of rat cerebellar granule neurons. As little as 5 nM rotenone increased mitochondrial superoxide (O2*-) levels and potentiated glutamate-induced cytoplasmic Ca2+ deregulation, the first irreversible stage of necrotic cell death. However, the potent cell-permeant O2*- trap manganese tetrakis (N-ethylpyridinium-2yl) porphyrin failed to prevent the effects of the inhibitor. The bioenergetic consequences of rotenone addition were quantified by monitoring cell respiration. Glutamate activation of NMDA receptors used the full respiratory capacity of the in situ mitochondria, and >80% of the glutamate-stimulated respiration was attributable to increased cellular ATP demand. Rotenone at 20 nM inhibited basal and carbonyl cyanide p-trifluoromethoxyphenylhydrazone-stimulated cell respiration and caused respiratory failure in the presence of glutamate. ATP synthase inhibition by oligomycin was also toxic in the presence of glutamate. We conclude that the cell vulnerability in the rotenone model of partial complex I deficiency under these specific conditions is primarily determined by spare respiratory capacity rather than oxidative stress.
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PMID:Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone. 1761 Dec 83

Parkinson's disease is a common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mitochondrial dysfunction has been strongly implicated in the pathogenesis of Parkinson's disease. Thus, therapeutic approaches that improve mitochondrial function may prove to be beneficial. Previously, we have documented that near-infrared light via light-emitting diode (LED) treatment was therapeutic to neurons functionally inactivated by tetrodotoxin, potassium cyanide (KCN), or methanol intoxication, and LED pretreatment rescued neurons from KCN-induced apoptotic cell death. The current study tested our hypothesis that LED treatment can protect neurons from both rotenone- and MPP(+)-induced neurotoxicity. Primary cultures of postnatal rat striatal and cortical neurons served as models, and the optimal frequency of LED treatment per day was also determined. Results indicated that LED treatments twice a day significantly increased cellular adenosine triphosphate content, decreased the number of neurons undergoing cell death, and significantly reduced the expressions of reactive oxygen species and reactive nitrogen species in rotenone- or MPP(+)-exposed neurons as compared with untreated ones. These results strongly suggest that LED treatment may be therapeutic to neurons damaged by neurotoxins linked to Parkinson's disease by energizing the cells and increasing their viability.
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PMID:Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and 1-methyl-4-phenylpyridinium ion-induced neurotoxicity. 1844 Jul 9


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