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PubMed1990

The measurement of the rotenone-sensitive NADH cytochrome c reductase activity in mitochondria isolated from minute amount of human skeletal muscle.

Mitochondria isolated from minute amounts (100-500 mg) of human skeletal muscle displayed a very high rotenone-resistant NADH cytochrome c reductase activity. Moreover, compared to succinate cytochrome c reductase activity, a low rate of rotenone-sensitive NADH cytochrome c reductase activity was measured when using standard procedures to disrupt mitochondrial membranes. Only a drastic osmotic shock in distillated water as a mean to disrupt mitochondrial membrane was found to strongly increase the actual rate of the rotenone-sensitive activity. This was accompanied by a decrease in the rotenone-insensitive activity. Using such a simple procedure, the NADH cytochrome c reductase was found 70-80% inhibited by rotenone and roughly equivalent to 70-85% of the activity of the succinate cytochrome c reductase.

Cell Fractionation↗
PubMed2002

Possible involvement of both mitochondria- and endoplasmic reticulum-dependent caspase pathways in rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells.

Recently, it has been shown that rotenone, a specific inhibitor of mitochondrial complex I, is a useful tool in animal models of Parkinson's disease, but the mechanism of rotenone-induced neuronal death is not fully understood. In human neuroblastoma SH-SY5Y cells, rotenone induced the degradation of procaspases-12, -9 and -3, followed by cleavage of poly (adenosine diphosphate-ribose) polymerase, DNA fragmentation and cell death. Pretreatment with phorbol-12-myristate-13-acetate inhibited the rotenone-induced decrease in procaspases-9 and -3, but not that in procaspase-12. In contrast, benzyloxycarbonyl-Val-Ala-Asp(OCH(3))-CH(2)F inhibited the decrease in procaspase-12, but not those in procaspases-9 and -3 in this study. These results suggest that rotenone may induce activation of both mitochondria- and endoplasmic reticulum-dependent caspases in human SH-SY5Y cells.

Apoptosis↗
PubMed2003

Rotenone and oxalic acid as alternative acaricidal treatments for Varroa destructor in honeybee colonies.

This experiment assessed the efficacy of rotenone and oxalic acid (OA) in an aqueous sugar solution in controlling the honeybee mite Varroa destructor. Colonies were populated with mite-infested brood combs and worker bees. Three rotenone or OA treatments administered during the period with capped brood on 31 July, 14 and 18 August resulted in an average efficacy of 24.10%. In untreated colonies mite mortality averaged 5.40%. No significant differences (P>0.05) were found between the rotenone and OA treatments. Three OA treatments administered on 9, 12 and 18 September resulted in a 77.93% mite mortality. An increase in mite drop (P<0.05) was observed at 2 and 4 days after each treatment. OA applications in broodless colonies resulted in significantly (P<0.001) higher mite mortality rates (98.65% average) than the three treatments of rotenone or OA in colonies with capped brood. The dynamics of mite mortality after each rotenone or OA treatment are discussed in this study.

Acari↗
PubMedDate not supplied

Oxidation of rotenone by Polyporus anceps laccase.

The extracellular laccase produced by Polyporus anceps transforms rotenone to a single, more polar product. This transformation occurs in incubation mixtures containing chlorpromazine, laccase, and rotenone where rotenone serves as a pseudosubstrate for the enzyme. Chlorpromazine, the true substrate, serves as a cycling redox component of the system forming a radical-cation species that abstracts an electron from rotenone in the oxidation process. Physicochemical properties of the product were determined on an analytically pure sample obtained by preparative hplc. High resolution ms, high-field pmr and cmr, uv, and optical rotation analyses indicated that rotenone had been transformed to 6a beta, 12a beta-rotenolone by P. anceps laccase.

Basidiomycota↗
PubMed1982

Regulation of malate oxidation in plant mitochondria. Response to rotenone and exogenous NAD+.

Exogenous NAD+ stimulated the rotenone-resistant oxidation of all the NAD+-linked tricarboxylic acid-cycle substrates in mitochondria from Jerusalem artichoke (Helianthus tuberosus L.) tubers. The stimulation was not removed by the addition of EGTA, which is known to inhibit the oxidation of exogenous NADH. It is therefore concluded that added NAD+ gains access to the matrix space and stimulates oxidation by the rotenone-resistant NADH dehydrogenase located on the matrix surface of the inner membrane. Added NAD+ stimulated the activity of malic enzyme and displaced the equilibrium of malate dehydrogenase; both observations are consistent with entry of NAD+ into the matrix space. Analysis of products of malate oxidation showed that rotenone-resistant oxygen uptake only occurred when the concentration of oxaloacetate was low and that of NADH was high. Thus it is proposed that the concentration of NADH regulates the activity of the two internal NADH dehydrogenases. Evidence is presented to suggest that the rotenone-resistant NADH dehydrogenase is engaged under conditions of high phosphorylation potential, which restricts electron flux through the rotenone-sensitive dehydrogenase (coupled to ATP synthesis).

Adenosine Diphosphate↗
PubMed2002

Prostaglandin A1 inhibits rotenone-induced apoptosis in SH-SY5Y cells.

The degeneration of nigral dopamine neurons in Parkinson's disease (PD) reportedly involves a defect in brain mitochondrial complex I in association with the activation of nuclear factor-kappaB (NF-kappaB) and caspase-3. To elucidate molecular mechanisms possibly linking these events, as well as to evaluate the neuroprotective potential of the cyclopentenone prostaglandin A1 (PGA1), an inducer of heat shock proteins (HSPs), we exposed human dopaminergic SH-SY5Y cells to the complex I inhibitor rotenone. Dose-dependent apoptosis was preceded by the nuclear translocation of NF-kappaB and then the activation of caspase-3 over the ensuing 24 h. PGA1 increased the expression of HSP70 and HSP27 and protected against rotenone-induced apoptosis, without increasing necrotic death. PGA1 blocked the rotenone-induced nuclear translocation of NF-kappaB and attenuated, but did not abolish, the caspase-3 elevation. Unexpectedly, the caspase-3 inhibitor, Ac-DEVD.CHO (DEVD), at a concentration that completely prevented the caspase-3 elevation produced by rotenone, failed to protect against apoptosis. These results suggest that complex I deficiency in dopamine cells can induce apoptosis by a process involving early NF-kappaB nuclear translocation and caspase-3 activation. PGA1 appears to protect against rotenone-induced cell death by inducing HSPs and blocking nuclear translocation of NF-kappaB in a process that attenuates caspase-3 activation, but is not mediated by its inhibition.

Active Transport, Cell Nucleus↗
PubMed2003

Role of nitric oxide in rotenone-induced nigro-striatal injury.

Rotenone, a widely used pesticide, causes a syndrome in rats that mimics, both behaviorally and pathologically, the symptoms of Parkinson's disease. The present study evaluated the role of nitric oxide in rotenone-induced nigro-striatal injury. After administration of rotenone in rats for 40 days, there was a moderate but significant injury of the nigro-striatal pathway indicated by a 47% decrease in striatal dopamine levels and a 28% loss of substantia nigra tyrosine hydroxylase-immunopositive neurons. Furthermore, a significant (37%) increase in the number of cells positive for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in the striatum was observed, accompanied by a 83% increase in nitric oxide synthase (NOS) activity and a significant increase in the production of 3-nitrotyrosine (3-NT). There was a significant increase (45%) in the optical density of NADPH-d staining and an increase (72%) in NOS activity in the substantia nigra. Moreover, administration of the neuronal NOS inhibitor 7-nitroindazole significantly attenuated the increased NOS activity and 3-NT production, and provided significant protection against rotenone-induced nigro-striatal injury. Our data suggest that chronic rotenone administration can lead to significant injury to the nigro-striatal system, mediated by increased generation of nitric oxide.

Animals↗
PubMed2003

Rotenone selectively occludes sensitivity to hypoxia in rat carotid body glomus cells.

Carotid body glomus cells release transmitters in response to hypoxia due to the increase of excitability resulting from inhibition of O2 -regulated K+ channels. However, the mechanisms involved in the detection of changes of O2 tension are unknown. We have studied the interaction between glomus cell O2 sensitivity and inhibition of the mitochondrial electron transport chain (ETC) in a carotid body thin slice preparation in which catecholamine release from intact single glomus cells can be monitored by amperometry. Inhibition of the mitochondrial ETC at proximal and distal complexes induces external Ca2+-dependent catecholamine secretion. At saturating concentration of the ETC inhibitors, the cellular response to hypoxia is maintained. However, rotenone, a complex I blocker, selectively occludes the responsiveness to hypoxia of glomus cells in a dose-dependent manner. The effect of rotenone is mimicked by 1-methyl-4-phenylpyridinium ion (MPP+), an agent that binds to the same site as rotenone, but not by complex I inhibitors acting on different sites. In addition, the effect of rotenone is not prevented by incubation of the cells with succinate, a substrate of complex II. These data strongly suggest that sensitivity to hypoxia of carotid body glomus cells is not linked in a simple way to mitochondrial electron flow and that a rotenone (and MPP+)-sensitive molecule critically participates in acute oxygen sensing in the carotid body.

Animals↗
PubMed1976

Action of rotenone and related respiratory inhibitors on mammalian cell division. 1 Cell kinetics and biochemical aspects.

Inhibitors of mitochondrial respiration, phosphorylation inhibitors, and uncoupling agents have been reported to delay or inhibit mitosis in cultured mammalian cells. Although the molecular mechanism by which mitosis is delayed in the presence of most respiratory inhibitors presumably involves lowered ATP production for mitotic requirements, one respiratory inhibitor, rotenone, was determined to arrest mitosis by an unrelated mechanism. Cell cycle kinetics studies, oxygen consumption measurements, and viscosity assays indicate that rotenone arrests cultured mammalian cells in mitosis by inhibiting spindle microtubule assembly by a mechanism analogous with colchicine, Colecemid and related antimitotic drugs. Amytal, which blocks electron transport at the same site as does rotenone, failed to arrest cell progression at mitosis. Rotenone delayed cell progression in all phases of the cell cycle, apparently as a direct result of respiration inhibition. Thus, rotenone appears to exert a dual function on events of the cell cycle.

Amobarbital↗
PubMed2005

Genotoxic effects of rotenone on cultured lymphocytes.

Rotenone is a heterocyclic compound widely used as an insecticide, acaricide and piscicide. Its toxicity is mainly caused by the inhibition of mitochondrial respiratory processes and ATP production, resulting in the generation of reactive oxygen species. Reactive oxygen species can interact with DNA, RNA and proteins, leading to cell damage, followed by death. We used the Comet assay, and we analyzed chromosome aberrations, in order to evaluate the genotoxic and clastogenic effects of rotenone on the different phases of the cell cycle. Cultured human lymphocytes were treated with 1.0, 1.5 and 2.0 microg/mL rotenone during the G1, G1/S, S (pulses of 1 and 6 h), and G2 phases of the cell cycle. Rotenone induced DNA damage and was clastogenic, but the clastogenicity was detected only with treatments conducted during the G1/S and S phases of the cell cycle. Rotenone also induced endoreduplication and polyploidy in treatments made during G1, while it significantly reduced the mitotic index in all phases of the cell cycle.

Adult↗
PubMedDate not supplied

[Effect of ischemia and rotenone on lipid and adenine nucleotide levels and functional activity of heart mitochondria].

Myocardial mitochondria (MCh), isolated with rotenone (MCh + RO) and in absence of rotenone (MCh - RO), were studied in rabbits with ischemia (0.5 hr autolysis) and in controls. Content of acyl-CoA was increased by 50%, linoleic acid - by 49% and lysophosphatidyl choline - by 37% in MCh + RO of control animals as compared with the MCh - RO preparation. In the MCh + RO preparation from rabbits with ischemia content of acyl-CoA was increased by 62%, while concentration of free fatty acids (FFA) and phospholipids was similar to those of the MCh - RO preparation. After isolation of mitochondria with rotenone composition of adenine nucleotides was distinctly altered. Content of ATP was decreased by 27% in mitochondria of both ischemic and control animals, although total amount of adenine nucleotides was decreased only slightly. As shown by estimation of succinate oxidation and membrane potential rotenone did not affect the mitochondrial respiration. In mitochondria of ischemic rabbits concentrations of FFA and lysophosphatidyl choline were increased, whereas content of ATP, total amount of adenine nucleotides, the rate of succinate oxidation and membrane potential were decreased. The method developed, isolation of mitochondria with rotenone, may be used in studies of the role of acyl-CoA in energy metabolism of cells.

Acetyl Coenzyme A↗
PubMed1978

High pressure liquid chromatographic determination of rotenone and degradation products in animal chow and tissues.

An analytical procedure is described for determining residues of rotenone, rotenolone, dehydrotenone, and rotenone in admixture in animal chow and tissues. The methanol or ethyl ether extracts from samples of chow and tissues, respectively, are subjected to a liquid-liquid partitioning cleanup with hexane-acetonitrile, further cleanup on a column of silica gel, and subsequent analysis by high pressure liquid chromatography using an ultraviolet absorption detector set at 295 nm. Animal chow, mouse fetuses, and gastrointestinal tracts spiked with 0.5 ppm of each compound in admixture yielded average recoveries of 92, 51, and 79%, respectively; minimum quantities of the 4 compounds detectable in the 3 substrates averaged 0.12, 0.04, ajd 0.14 ppm, respectively. Stability studies indicate that rotenone reacts with animal chow with a half-life of 7--8 days and is photodegraded in incandescent light with a half-life of 0.65 day. No transplacental transfer of rotenone or its products was observed in fetuses from mice receiving 7 consecutive daily doses of rotenone at levels up to 25 mg/kg.

Animal Feed↗
PubMed2005

Dopamine-derived dopaminochrome promotes H(2)O(2) release at mitochondrial complex I: stimulation by rotenone, control by Ca(2+), and relevance to Parkinson disease.

Inhibitors of Complex I of the mitochondrial respiratory chain, such as rotenone, promote Parkinson disease-like symptoms and signs of oxidative stress. Dopamine (DA) oxidation products may be implicated in such a process. We show here that the o-quinone dopaminochrome (DACHR), a relatively stable DA oxidation product, promotes concentration (0.1-0.2 mum)- and respiration-dependent generation of H(2)O(2) at Complex I in brain mitochondria, with further stimulation by low concentrations of rotenone (5-30 nm). The rotenone effect required that contaminating Ca(2+) (8-10 mum) was not removed. DACHR apparently extracts an electron from the constitutively autoxidizable site in Complex I, producing a semiquinone, which then transfers an electron to O(2), generating O(2)(.) and then H(2)O(2). Mitochondrial removal of H(2)O(2) monoamine, formed by either oxidase activity or DACHR, was performed largely by glutathione peroxidase and glutathione reductase, which were negatively regulated by low intramitochondrial Ca(2+) levels. Thus, the H(2)O(2) formed accumulated in the medium if contaminating Ca(2+) was present; in the absence of Ca(2+), H(2)O(2) was completely removed if it originated from monoamine oxidase, but was less completely removed if it originated from DACHR. We propose that the primary action of rotenone is to promote extracellular O(2)(.) release via activation of NADPH oxidase in the microglia. In turn, O(2)(.) oxidizes DA to DACHR extracellularly. (The reaction is favored by the lack of GSH, which would otherwise preferably produce GSH adducts of dopaminoquinone.) Once formed, DACHR (which is resistant to GSH) enters neurons to activate the rotenone-stimulated redox cycle described.

Animals↗
PubMed2006

The rotenone model of parkinsonism--the five years inspection.

Treatment of rats with rotenone has been proposed in the year 2000 to provide an animal model of idiopathic Parkinson's disease. We review here the experience that has been gained meanwhile with this model. The published data suggest that the model does not ideally reproduce the pathophysiology of Parkinson's disease, that Rotenone treatment does not cause a purely neurodegenerative concondition, that the Rotenone model does not ideally recapitulate the motor symptoms of Parkinson's disease, that degeneration of the dopaminergic neurons is highly variable, that striatal neurons appear to degenerate more consistently than neurons in the substantia nigra, and that cytoplasmic accumulation of the tau protein is more abundant than alpha-synuclein aggregation in severely lesioned animals. In summary, these data suggest that Rotenone-treated rats model atypical Parkinsonism rather than idiopathic Parkinson's disease.

Animals↗
PubMed1992

Sensitive period for the induction of endoreduplication by rotenone in cultured Chinese hamster cells.

Rotenone-induced endoreduplication was investigated in Chinese hamster CHL cells. Cell cycle analyses, using 5-bromo-2'-deoxyuridine (BrdU) labeling, revealed that endoreduplication was induced between the G2-phase and mitotic metaphase. Morphological studies indicated that the chromosomes of cells in metaphase at the time of rotenone exposure immediately aggregated. Within 1 h, however, the aggregated chromosomes began to decondense forming telophase nuclei. Cells with aggregated chromosomes were collected by mitotic selection using the mitotic arrestant TN-16 and then cultured for 30 h following rotenone administration. This population of cells demonstrated an extremely high frequency of endoreduplicated metaphases. Further analysis by BrdU labeling indicated that the aggregated metaphases underwent only one round of DNA replication before endoreduplicated metaphases were formed. The most sensitive period for the induction of endoreduplication by rotenone occurs during mitotic metaphase.

Animals↗
PubMed1978

The role of lipid-protein interactions in NADH-cytochrome c reductase (rotenone-insensitive) of rat liver mitochondria.

The phospholipid depletion of rat liver mitochondria, induced by acetoneextraction or by digestion with phospholipase A2 or phospholipase C, greatly inhibited the activity of NADH-cytochrome c reductase (rotenone-insensitive). A great decrease of the reductase activity also occurred in isolated outer mitochondrial membranes after incubation with phospholipase A2. The enzyme activity was almost completely restored by the addition of a mixture of mitochondrial phospholipids to either lipid-deficient mitochondria, or lipid-deficient outer membranes. The individual phospholipids present in the outer mitochondrial membrane induced little or no stimulation of the reductase activity. Egg phosphatidylcholine was the most active phospholipid, but dipalmitoyl phosphatidylcholine was almost ineffective. The lipid depletion of mitochondria resulted in the disappearance of the non-linear Arrhenius plot which characterized the native reductase activity. A non-linear plot almost identical to that of the native enzyme was shown by the enzyme reconstituted with mitochondrial phospholipids. Triton X-100, Tween 80 or sodium deoxycholate induced only a small activation of NADH-cytochrome c reductase (rotenone-insensitive) in lipid-deficient mitochondria. The addition of cholesterol to extracted mitochondrial phospholipids at a 1 : 1 molar ratio inhibited the reactivation of NADH-cytochrome c reductase (rotenone-insensitive) but not the binding of phospholipids to lipid-deficient mitochondria or lipid-deficient outer membranes. These results show that NADH-cytochrome c reductase (rotenone-insensitive) of the outer mitochondrial membrane requires phospholipids for its activity. A mixture of phospholipids accomplishes this requirement better than individual phospholipids or detergents. It also seems that the membrane fluidity may influence the reductase activity.

Animals↗
PubMed1992

The effect of delta mu H+ on the interaction of rotenone with complex I of submitochondrial particles.

The inhibition by rotenone of the forward (NADH-oxidase) and reverse (delta mu H(+)-dependent succinate-NAD+ reductase activities of submitochondrial vesicles was measured. The inhibition of NADH-oxidase, measured in the presence of uncoupler, followed a monophasic inhibition curve with Ki < or = 2 nM. The reverse electron flow was only partially (40%) inhibited at these rotenone concentrations. The rest of the activity was less sensitive to the inhibitor (Ki approximately 30 nM). The lower affinity for the inhibitor of the reverse electron flow is a consequence of enhanced rate of rotenone dissociation caused by the high delta mu H+ value required for this reaction. The analysis of the results indicates that the AS-SMP preparation consists of two subpopulations: one with a relatively low degree of coupling, which exhibits high sensitivity to rotenone and the other which is highly coupled with lower affinity to the inhibitor.

Mitochondria↗
PubMed1990

Evidence that the blockade of mitochondrial respiration by the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) involves binding at the same site as the respiratory inhibitor, rotenone.

It has been postulated that 1-methyl-4-phenylpyridinium (MPP+) blocks mitochondrial respiration by combining at the same site as rotenone, a potent inhibitor of NADH oxidation in mitochondria, known to act at the junction of NADH dehydrogenase and coenzyme Q (CoQ). The present experiments show that MPP+ and two of its analogs indeed act in a concentration dependent manner to prevent the binding of [14C]-rotenone to submitochondrial particles (ETP) and significantly decrease the inhibition of electron transport caused by rotenone. It therefore appears that MPP+ binds at the same site as rotenone or an adjacent site, supporting the hypothesis that its neurotoxic action is due to the inhibition of mitochondrial respiration.

1-Methyl-4-phenylpyridinium↗