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At least 163 records · Page 9Linked to original sources
PubMed1995

Implication of dopamine transporter system on 1-methyl-4-phenylpyridinium and rotenone effect in striatal synaptosomes.

The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) seems to be produced by the inhibition of the respiratory chain by its metabolite 1-methyl-4-phenylpyridinium ion (MPP+). At the same time, its specific selectivity seems to be related especially to the dopamine uptake system. However, it is possible that other specific differences in dopaminergic neurons at the nigrostriatal system, such as constitutive metabolic deficiencies or other differences related to the energy capacity, could determine the greater vulnerability to MPP+. We have addressed this point by studying the effect of MPP+ and different inhibitors of the respiratory chain (rotenone, antimycin A and KCN) on the maximal respiratory rate from both synaptosomes and isolated synaptosomal mitochondria from different brain areas, i.e. cortex, hippocampus and striatum, and in isolated liver mitochondria. The results demonstrate the absence of differences in the effect of the inhibitors in isolated mitochondria. In contrast, a greater inhibition was found in striatal synaptosomes than in cortical or hippocampal synaptosomes when MPP+ and rotenone were used. Moreover, nomifensine or 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride (GBR-12909), inhibitor of the dopamine uptake system, has a protective effect in both cases. Our study indicates the great importance of the dopamine uptake system in the vulnerability of the dopamine striatum system. Moreover, our results show the low selectivity of this dopamine uptake system that is able to transport actively compounds with different chemical structures such as dopamine, MPP+ and rotenone.

1-Methyl-4-phenylpyridinium↗
PubMed2005

The regulation of rotenone-induced inflammatory factor production by ATP-sensitive potassium channel expressed in BV-2 cells.

Our previous studies have demonstrated that activating ATP-sensitive potassium channel (K(ATP) channel), not only improved Parkinsonian behavior and neurochemical symptoms, but also reduced iNOS activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson's disease (PD). In this study, it was first shown that the subunits of K(ATP) channels are expressed in BV-2 cells, and then it was investigated whether K(ATP) channel was involved in regulating inflammatory factor production from BV-2 cells activated by rotenone. It was found that K(ATP) channel was expressed in BV-2 cell and formed by the combination of Kir 6.1 and SUR 2A/2B. K(ATP) channel openers (KCOs) including pinacidil, diazoxide and iptakalim (Ipt) exerted beneficial effects on rotenone-induced morphological alterations of BV-2 cells, decreased tumor necrosis factor alpha (TNF-alpha) production and the expression and activity of inducible isoform of nitric oxide synthase (iNOS). Either glibenclamide or 5-hydroxydecanoate acid (a selective mitochondrial K(ATP) channel blocker) could abolish the effects of KCOs, suggesting that K(ATP) channels, especially mitochondrial ATP-sensitive potassium channels (mitoK(ATP) channels), played a crucial role in preventing the activation of BV-2 cells, and subsequently the production of a variety of proinflammatory factors. Therefore, activation of K(ATP) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders.

ATP-Binding Cassette Transporters↗
PubMed1999

Modulation of oxidative phosphorylation of human kidney 293 cells by transfection with the internal rotenone-insensitive NADH-quinone oxidoreductase (NDI1) gene of Saccharomyces cerevisiae.

In contrast to the mitochondrial proton-translocating NADH-quinone oxidoreductase (complex I), which consists of at least 43 different subunits, the internal rotenone-insensitive NADH-quinone oxidoreductase (Ndi1) of Saccharomyces cerevisiae is a single polypeptide enzyme. The NDI1 gene was stably transfected into the human embryonal kidney 293 (HEK 293) cells. The transfected NDI1 gene was then transcribed and translated in the HEK 293 cells to produce the functional enzyme. The immunochemical and immunofluorescence analyses indicated that the expressed Ndi1 polypeptide was located to the inner mitochondrial membranes. The expression of Ndi1 did not alter the content of existing complex I in the HEK 293 mitochondria, suggesting that the expressed Ndi1 enzyme does not displace the endogenous complex I. The NADH oxidase activity of the NDI1-transfected HEK 293 cells was not affected by rotenone but was inhibited by flavone. The ADP/O ratios coupled to NADH oxidation were lowered from 2.4 to 1.8 by NDI1-transfection while the ADP/O ratios coupled to succinate oxidation (1.6) were not changed. The NDI1-transfected HEK 293 cells were able to grow in media containing a complex I inhibitor such as rotenone and 1-methyl-4-phenylpyridinium ion. The potential usefulness of incorporating the Ndi1 protein into mitochondria of human cells is discussed.

Adenosine Triphosphate↗
PubMed2003

Ca2+-induced oxidative stress in brain mitochondria treated with the respiratory chain inhibitor rotenone.

In this study we show that micromolar Ca(2+) concentrations (>10 microM) strongly stimulate the release of reactive oxygen species (ROS) in rotenone-treated isolated rat forebrain mitochondria. Ca(2+)-stimulated mitochondrial ROS release was associated with membrane lipid peroxidation and was directly correlated with the degree of complex I inhibition by rotenone. On the other hand, Ca(2+) did not increase mitochondrial ROS release in the presence of the complex I inhibitor 1-methyl-4-phenylpyridinium. Cyclosporin A had no effect on Ca(2+)-stimulated mitochondrial ROS release in the presence of rotenone, indicating that mitochondrial permeability transition is not involved in this process. We hypothesized that Ca(2+)-induced mitochondrial oxidative stress associated with partial inhibition of complex I may be an important factor in neuronal cell death observed in the neurodegenerative disorder Parkinson's disease.

Animals↗
PubMed1997

Involvement of cyanide-resistant and rotenone-insensitive pathways of mitochondrial electron transport during oxidation of glycine in higher plants.

Metabolism of glycine in isolated mitochondria and protoplasts was investigated in photosynthetic, etiolated (barley and pea leaves) and fat-storing (maize scutellum) tissues using methods of [1-(14)C]glycine incorporation and counting of 14CO2 evolved, oxymetric measurement of glycine oxidation and rapid fractionation of protoplasts incubated in photorespiratory conditions with consequent determination of ATP/ADP ratios in different cell compartments. The involvement of different paths of electron transport in mitochondria during operation of glycine decarboxylase complex (GDC) was tested in different conditions, using aminoacetonitrile (AAN), the inhibitor of glycine oxidation in mitochondria, rotenone, the inhibitor of Complex I of mitochondrial electron transport, and inhibitors of cytochrome oxidase and alternative oxidase. It was shown that glycine has a preference to other substrates oxidized in mitochondria only in photosynthetic tissue where succinate and malate even stimulated its oxidation. Rotenone had no or small effect on glycine oxidation, whereas the role of cyanide-resistant path increased in the presence of ATP. Glycine oxidation increased ATP/ADP ratio in cytosol of barley protoplasts incubated in the presence of CO2, but not in the CO2-free medium indicating that in conditions of high photorespiratory flux oxidation of NADH formed in the GDC reaction passes via the non-coupled paths. Activity of GDC in fat-storing tissue correlated with the activity of glyoxylate-cycle enzymes, glycine oxidation did not reveal preference to other substrates and the involvement of paths non-connected with proton translocation was not pronounced. It is suggested that the preference of glycine to other substrates oxidized in mitochondria is achieved in photosynthetic tissue by switching to rotenone-insensitive intramitochrondrial NADH oxidation and by increasing of alternative oxidase involvement in the presence of glycine.

Adenosine Diphosphate↗
PubMed1998

Genotoxicity of the insecticide rotenone in cultured human lymphocytes.

We have investigated the genotoxic activity of rotenone on three genetic endpoints, sister-chromatid exchanges (SCE), chromosome aberrations (CA) and micronuclei (MN) in human lymphocyte cultures in the presence and absence of a metabolic activation system (S9 mix). Our results indicate that rotenone increases the frequency of binucleated micronucleated (BNMN) cells and causes a delay in the cell cycle but does not increase the frequency of CA and SCE at the concentrations used. The presence of S9 mix reduces the genotoxic activity of rotenone.

Animals↗
PubMed2002

Rotenone residues on olives and in olive oil.

The disappearance of rotenone on olives under field conditions was studied. The field data showed that rotenone residues on olives decreased with a half-life (t(1/2)) of 4.0 days. After pre-harvest time (10 days) the residues were higher than the maximum residue level fixed in Italy (0.04 mg/kg). Experiments with model systems showed that the mechanism of disappearance of rotenone is not related to evaporation, thermodegradation, or co-distillation, but only to photodegradation. When the olives were processed for oil, the residues in the oil were higher than the residues on the olives by a factor of 2.4-4.8.

Chromatography, High Pressure Liquid↗
PubMed2000

Determination of whole-body rotenone residues in the brown tree snake (Boiga irregularis).

The brown tree snake (Boiga irregularis) is an introduced pest in Guam, responsible for extensive agricultural damage, the extinction of several bird species, and severe and frequent electrical power outages. Rotenone, a naturally occurring pesticide, has been investigated as a possible chemical control agent. An analytical method was developed to assess whole body rotenone residues ranging in concentration from 0.035 to 250 microg g(-)(1) in snakes. The method employed ethyl acetate extraction of 2 g samples of cryogenically frozen, pulverized snakes, followed by silica and Florisil solid-phase extraction cleanup. Extract analysis was performed using a high-performance liquid chromatography system employing a cyanopropyl analytical column. Tissues fortified to concentrations of 0.035, 4.82, and 250 microg g(-)(1) yielded analyte recoveries of 85.1, 85.6, and 83.5%, respectively. The linear response of rotenone standard solutions was assessed from 0. 025 to 0.25 microg mL(-)(1) (r(2) = 0.9968) and from 0.250 to 125 microg mL(-)(1) (r(2) = 0.9999). The method was simple, rugged, and reliable.

Animals↗
PubMed1977

Spectral and metabolic characteristics of mitochondrial fractions from rotenone-induced tumours.

Mitochondrial fractions isolated from tumours induced with the respiratory inhibitor rotenone lack respiratory control, oxidative phosphorylation, are partially or totally insensitive to cyanide and have a near-normal content of respiratory carriers. These characteristics are more similar to those of mitochondria from atrophic mammary gland than to those of mitochondria from spontaneous mammary adenomas. Thus, the characteristic structural and biochemical mitochondrial alteration of rotenone-induced tumours would represent a lack of mitochondrial differentiation as the tumour develops from the atrophic mammary gland. Slices of rotenone-induced tumours are insensitive to oligomycin and dinitrophenol, thus indicating that glycolysis would be their sole source of metabolic energy.

Adenofibroma↗
PubMed2001

Isolation and characterization of complex I, rotenone-sensitive NADH: ubiquinone oxidoreductase, from the procyclic forms of Trypanosoma brucei.

Additional characterization of complex I, rotenone-sensitive NADH:ubiquinone oxidoreductase, in the mitochondria of Trypanosoma brucei brucei has been obtained. Both proline:cytochrome c reductase and NADH:ubiquinone oxidoreductase of procyclic T. brucei were inhibited by the specific inhibitors of complex I rotenone, piericidin A, and capsaicin. These inhibitors had no effect on succinate: cytochrome c reductase activity. Antimycin A, a specific inhibitor of the cytochrome bc1 complex (ubiquinol:cytochrome c oxidoreductase), blocked almost completely cytochrome c reductase activity with either proline or succinate as electron donor, but had no inhibitory effect on NADH:ubiquinone oxidoreductase activity. The rotenone-sensitive NADH:ubiquinone oxidoreductase of procyclic T. brucei was partially purified by sucrose density centrifugation of mitochondria solubilized with dodecyl-beta-D-maltoside, with an approximately eightfold increase in specific activity compared to that of the mitochondrial membranes. Four polypeptides of the partially purified enzyme were identified as the homologous subunits of complex I (51 kDa, PSST, TYKY, and ND4) by immunoblotting with antibodies raised against subunits of Paracoccus denitrificans and against synthetic peptides predicted from putative complex I subunit genes encoded by mitochondrial and nuclear T. brucei DNA. Blue Native polyacrylamide gel electrophoresis of T. brucei mitochondrial membrane proteins followed by immunoblotting revealed the presence of a putative complex I with a molecular mass of 600 kDa, which contains a minimum of 11 polypeptides determined by second-dimensional Tricine-SDS/PAGE including the 51 kDa, PSST and TYKY subunits.

Animals↗
PubMed1998

Interaction of alpha-phenyl-N-tert-butyl nitrone and alternative electron acceptors with complex I indicates a substrate reduction site upstream from the rotenone binding site.

Mitochondrial complexes I, II, and III were studied in isolated brain mitochondrial preparations with the goal of determining their relative abilities to reduce O2 to hydrogen peroxide (H2O2) or to reduce the alternative electron acceptors nitroblue tetrazolium (NBT) and diphenyliodonium (DPI). Complex I and II stimulation caused H2O2 formation and reduced NBT and DPI as indicated by dichlorodihydrofluorescein oxidation, nitroformazan precipitation, and DPI-mediated enzyme inactivation. The O2 consumption rate was more rapid under complex II (succinate) stimulation than under complex I (NADH) stimulation. In contrast, H2O2 generation and NBT and DPI reduction kinetics were favored by NADH addition but were virtually unobservable during succinate-linked respiration. NADH oxidation was strongly suppressed by rotenone, but NADH-coupled H2O2 flux was accelerated by rotenone. Alpha-phenyl-N-tert-butyl nitrone (PBN), a compound documented to inhibit oxidative stress in models of stroke, sepsis, and parkinsonism, partially inhibited complex I-stimulated H2O2 flux and NBT reduction and also protected complex I from DPI-mediated inactivation while trapping the phenyl radical product of DPI reduction. The results suggest that complex I may be the principal source of brain mitochondrial H2O2 synthesis, possessing an "electron leak" site upstream from the rotenone binding site (i.e., on the NADH side of the enzyme). The inhibition of H2O2 production by PBN suggests a novel explanation for the broad-spectrum antioxidant and antiinflammatory activity of this nitrone spin trap.

Animals↗
PubMed2003

Activation of mitochondrial ATP-sensitive potassium channels increases cell viability against rotenone-induced cell death.

We recently showed that activation of ATP-sensitive potassium (KATP) channels in PC12 cells induces protection against the neurotoxic effect of rotenone, a mitochondrial complex I inhibitor. In this study, we sought to determine the locus of the KATP channels that mediate this protection in PC12 cells. We found that pretreatment of PC12 cells with diazoxide, a mitochondrial KATP channel selective opener, dose-dependently increases cell viability against rotenone-induced cell death as indicated in trypan blue exclusion assays. The protective effect of this preconditioning is attenuated by 5-hydroxydecanoic acid (5-HD), a selective mitochondrial KATP channel antagonist but not in the presence of HMR-1098, a selective plasma membrane KATP potassium channel antagonist. In contrast, P-1075, a selective plasma membrane KATP channel opener, does not induce protection. Using specific antibodies against SUR1 and Kir6.1, we detected immunoreactive proteins of apparent molecular masses 155 and 50 kDa, corresponding to those previously reported for SUR1 and Kir6.1, respectively, in the mitochondria-enriched fraction of PC12 cells. In addition, whole cell patch-clamp studies revealed that inward currents in PC12 cells are insensitive to P-1075, HMR-1098, glibenclamide and diazoxide, indicating that functional plasma membrane KATP channels are negligible. Taken together, our results demonstrate for the first time that activation of mitochondrial KATP channels elicits protection against rotenone-induced cell death.

ATP-Binding Cassette Transporters↗
PubMed1970

Reaction sites of rotenone, piericidin A, and amytal in relation to the nonheme iron components of NADH dehydrogenase.

The locus of inhibition of nicotinamide adenine dinucleotide, reduced form (NADH) oxidation in mitochondria by rotenone, piercidin A, and barbiturates is considered in the light of available information. Most lines of evidence indicate that the point of inhibition is on the O(2) side of NADH dehydrogenase. Kinetic experiments on the substrate-induced appearance of the electron paramagnetic resonance signal at g = 1.94 in membrane preparations (ETP) reveal that these inhibitors do not interfere with the reduction of the electron paramagnetic resonance detectable iron by NADH. Our spectrophotometric studies on complex I give no evidence for absorbance differences between untreated and rotenone or piericidin inhibited preparations, which can be attributed to nonheme iron. Whatever changes were observed appear to be due to cytochromes. These experiments, therefore, do not support the idea that in inhibited preparations electron transport is interrupted between the flavin and nonheme iron components of NADH dehydrogenase. The specific binding of rotenone and piericidin seems to involve both lipid and protein. The possibility that NADH dehydrogenase participates in the binding is suggested by the apparent stoichiometric relation between specific binding site titer and NADH dehydrogenase content and the profound effect of mersalyl inhibition of the enzyme on piericidin binding capacity.ETP, electron transport particle.

Amobarbital↗
PubMed2003

Circadian rhythms of oxidative phosphorylation: effects of rotenone and melatonin on isolated rat brain mitochondria.

Mitochondrial experiments are of increasing interest in different fields of research. Inhibition of mitochondrian activities seems to play a role in Parkinson's disease and in this regard several animal models have used inhibitors of mitochondrial respiration such as rotenone or MPTP. Most of these experiments were done during the daytime. However, there is no reason for mitochondrial respiration to be constant during the 24 h. This study investigated the circadian variation of oxidative phosphorylation in isolated rat brain mitochondria and the administration-time-dependent effect of rotenone and melatonin. The respiratory control ratio, state 3 and state 4, displayed a circadian fluctuation. The highest respiratory control ratio value (3.01) occurred at 04:00 h, and the lowest value (2.63) at 08:00 h. The highest value of state 3 and state 4 oxidative respiration occurred at 12:00 h and the lowest one at 20:00 h. The 24 h mean decrease in the respiratory control ratio following incubation with melatonin and rotenone was 7 and 32%, respectively; however, the exact amount of the inhibition exerted by these agents varied according to the time of the mitochondria isolation. Our results show the time of mitochondrial isolation could lead to interindividual variability. When studies require mitochondrial isolation from several animals, the time between animal experiments has to be minimized. In oxidative phosphorylation studies, the time of mitochondria isolation must be taken into account, or at least specified in the methods section.

Animals↗
PubMed2006

Divergent mechanisms of paraquat, MPP+, and rotenone toxicity: oxidation of thioredoxin and caspase-3 activation.

Paraquat, N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, and rotenone have been shown to reproduce several features of Parkinson's disease in animal and cell culture models. Although these chemicals are known to perturb dopamine homeostasis and induce dopaminergic cell death, their molecular mechanisms of action are not well defined. We have previously shown that paraquat does not require functional dopamine transporter and does not inhibit mitochondrial complex I in order to mediate its toxic action (Richardson et al., 2005). In this study, we show that paraquat specifically oxidized the cytosolic form of thioredoxin and activated Jun N-terminal kinase (JNK), followed by caspase-3 activation. Conversely, 1-methyl-4-phenylpyridinium (MPP(+)) and rotenone oxidized the mitochondrial form of thioredoxin but did not activate JNK-mitogen-activated protein kinase and caspase-3. Loading cells with exogenous dopamine did not exacerbate the toxicity of any of these compounds. These data suggest that oxidative modification of cytosolic proteins is critical to paraquat toxicity, while oxidation of mitochondrial proteins is important for MPP(+) and rotenone toxicity. In addition, intracellular dopamine does not seem to exacerbate the toxicity of these dopaminergic neurotoxicants in this model.

1-Methyl-4-phenylpyridinium↗
PubMed2004

Rotenone induces non-specific central nervous system and systemic toxicity.

We investigated the dopaminergic (DA) neuronal degeneration in animals subjected to systemic treatment of rotenone via subcutaneous delivery. Behavioral observations revealed a hypokinetic period in rats sacrificed at 3 and 5 days, and dystonic episodes in animals sacrificed at 8 days. Less than 20% of the total number of animals given rotenone depicted brain lesions after 8 days of treatment, as demonstrated by a significant loss of DA fibers in the striatum, but not of DA nigral neurons. Tyrosine hydroxylase-negative striatal territories were characterized by post-synaptic toxicity as demonstrated by a decreased number of interneurons labeled for choline acetyltransferase, NADPH-diaphorase, parvalbumin, and projection neurons labeled for calbindin and nerve growth factor inducible-B (NGFI-B). Post-synaptic neurodegeneration was demonstrated further by abundant striatal staining for Fluoro-Jade. Decrease in the nuclear orphan receptor Nurr1 expression was the only significant change observed at the level of the substantia nigra. Autopsy reports confirmed that animals suffered from severe digestion problems. These data suggest that hypokinesia observed between 3 and 5 days is the result of general health problems rather than a specific motor deficit associated to Parkinson's disease (PD) symptoms. Overall, the effects of rotenone toxicity are widespread, and subcutaneous administration of this toxin does not provide the neuropathological and behavioral basis for a relevant and reliable PD model.

Animals↗
PubMed2003

Dopamine is involved in selectivity of dopaminergic neuronal death by rotenone.

Mitochondrial complex I activity is partially suppressed in patients with Parkinson's disease, which is characterized by dopaminergic neuronal death. However, the precise relationship between neuronal death and mitochondrial complex I suppression has been unresolved. We investigated the involvement of superoxide and endogenous dopamine in neurotoxicity by rotenone, a complex I inhibitor. A short exposure to rotenone at high concentrations reduced the viability of both dopaminergic and non-dopaminergic neurons. The toxicity was significantly prevented by a membrane-permeable superoxide dismutase mimetic and alpha-methyl-p-tyrosine (alpha-MT), a tyrosine hydroxylase inhibitor. Chronic treatment with low-concentration rotenone caused selective toxicity to dopaminergic neurons, and this toxicity was attenuated by alpha-MT. These data suggest that superoxide and endogenous dopamine play an important role in dopaminergic neuronal loss.

Animals↗
PubMed2004

Menadione reduces rotenone-induced cell death in cerebellar granule neurons.

Oxidative stress has been implicated in neuronal death caused by cerebral ischemia or some neurologic disorders. Chemical hypoxia (term defining the simulation by using respiratory inhibitors) chosen as in vitro ischemic model, was induced in primary cultures of rat cerebellar granule neurons by inhibitors of mitochondrial electron transport such as rotenone or paraquat (complex I), 3-nitropropionic acid (3-NPA, complex II), antimycin A (complex III), or sodium azide (complex IV). All compounds caused neuronal death determined by trypan blue staining and MTT-test. On the other hand, neurotoxicity of rotenone and paraquat but not of 3-NPA, antimycin or azide was significantly abolished by menadione (vitamin K3, 2-methyl-1,4-naphthoquinone). This neuroprotective effect of menadione was associated with a decrease of rotenone-induced free radical production.

Animals↗