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PubMed2006

Neurotrophic factors stabilize microtubules and protect against rotenone toxicity on dopaminergic neurons.

Parkinson disease is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra. Long term epidemiological studies have implicated exposure to agricultural pesticides as a significant risk factor. Systemic administration of rotenone, a widely used pesticide, causes selective degeneration of nigral DA neurons and Parkinson disease-like symptoms in rats. Our previous study has shown that the microtubule depolymerizing activity of rotenone plays a critical role in its selective toxicity on DA neurons. Rotenone toxicity is mimicked by the microtubule-depolymerizing drug colchicine and attenuated by the microtubule-stabilizing agent taxol. Here we show that nerve growth factor (NGF) significantly reduced rotenone toxicity on TH(+) neurons in midbrain neuronal cultures. The protective effect of NGF was completely abolished by inhibiting the microtubule-associated protein kinase kinase (MEK) and partially reversed by blocking phosphatidylinositol 3-kinase. In addition, NGF decreased colchicine toxicity on TH(+) neurons in a manner dependent on MEK but not phosphatidylinositol 3-kinase. The protective effect of NGF against rotenone toxicity was occluded by the microtubule-stabilizing drug taxol. In a MEK-dependent manner, NGF significantly attenuated rotenone- or colchicine-induced microtubule depolymerization and ensuing accumulation of vesicles in the soma and elevation in protein carbonyls. Moreover, other neurotrophic factors such as brain-derived neurotrophic factor and glia cell line-derived neurotrophic factor also reduced rotenone- or colchicine-induced microtubule depolymerization and death of TH(+) through a MEK-dependent mechanism. Thus, our results suggest that neurotrophic factors activate the microtubule-associated protein kinase pathway to stabilize microtubules, and this action significantly attenuates rotenone toxicity on dopaminergic neurons.

Animals↗
PubMed2004

Rotenone-induced apoptosis is mediated by p38 and JNK MAP kinases in human dopaminergic SH-SY5Y cells.

Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson's disease in animal models. Though rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of rotenone-induced neuronal cell death. Our results suggest that rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, rotenone treatment induces phosphorylation of c-Jun, the c-Jun N-terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated rotenone-induced apoptosis. These data suggest that rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases and caspases. These studies provide insights concerning the molecular mechanisms of rotenone-induced apoptosis in neuronal cells.

Apoptosis↗
PubMed1996

The presence of rotenone-sensitive NADH dehydrogenase in the long slender bloodstream and the procyclic forms of Trypanosoma brucei brucei.

The mitochondrial electron-transport chain present in the procyclic and long slender bloodstream forms of Trypanosoma brucei brucei was investigated by means of several experimental approaches. The oxidation of proline, glycerol and glucose in procyclic cells was inhibited 80-90% by antimycin A or cyanide, 15-19% by salicylhydroxamic acid, and 30-35% by rotenone. Cytochrom-c-reductase activity, with proline or glycerol 3-phosphate as substrate, in a mitochondrial fraction isolated from these cells was inhibited by antimycin and rotenone, but not by malonate, while cytochrome-c-reductase activity with succinate as substrate was inhibited by antimycin A and malonate, but not by rotenone. In addition, the reduction of dichloroindophenol by NADH was inhibited by rotenone but not by malonate, which suggests that rotenone-sensitive NADH dehydrogenase (complex I) is present in these mitochondria. The presence of three subunits of NADH dehydrogenase was observed in immunoblots of mitochondrial proteins with specific antibodies raised against peptides corresponding to predicted antigenic regions of these proteins, which provides further evidence for the presence of NADH dehydrogenase. In long slender bloodstream forms, the oxidation of glucose or glycerol was inhibited 100% by salicyhydroxamic acid, unaffected by cyanide or antimycin A, and inhibited 40% or 75%, respectively, by rotenone, which suggests that NADH dehydrogenase is present in these cells. In a mitochondrial fraction isolated from the bloodstream forms, oxygen uptake with glycerol 3-phosphate as substrate was inhibited 65% by rotenone. Low levels of rotenone-sensitive NADH-dependent reduction of dichloroindophenol and the presence of subunits 7 and 8 of NADH dehydrogenase provided additional evidence for the presence of NADH dehydrogenase in bloodstream forms of T. brucei.

Animals↗
PubMed2005

Intracellular dopamine oxidation mediates rotenone-induced apoptosis in PC12 cells.

AIM: To study the role of dopamine (DA) in rotenone-induced neurotoxicity in PC12 cells. METHODS: Cell viability was assessed by detecting the leakage of lactate dehydrogenase (LDH) into the medium. Apoptosis rate was measured by flow cytometry. Caspase-3-like activity was measured by fluorescence assay using the probe Ac-DEVD-AMC. The level of intracellular hydrogen peroxide and other peroxides in PC12 cells were quantified by loading cells with 2'-7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) in fluorescence assay. Lactic acid was measured spectrophotometrically. The DA levels in PC12 cells were determined by HPLC-ECD. RESULTS: A 48-h incubation of PC12 cells with rotenone caused an apoptotic cell death and elevated intracellular reactive oxygen species (ROS) and lactic acid accumulation. Intracellular DA depletion with reserpine significantly attenuated rotenone-induced ROS accumulation and apoptotic cell death. No change was found in rotenone-induced ROS accumulation when cells were co-treated with deprenyl. Brief treatment with reserpine at the end of rotenone treatment had no effect on rotenone-induced neurotoxicity. However, when cells were first incubated with deprenyl, a monoamine oxidase-B inhibitor for 30 min then co-incubated with rotenone plus deprenyl, a brief treatment with reserpine enhanced cell injury. CONCLUSION: Rotenone-induced apoptosis in PC12 cells was mediated by intracellular dopamine oxidation.

Animals↗
PubMed2006

Controversies on new animal models of Parkinson's disease pro and con: the rotenone model of Parkinson's disease (PD).

A general complex I deficit has been hypothesized to contribute to neurodegeneration in Parkinson's disease (PD) and all toxins used to destroy dopaminergic neurons are complex I inhibitors. With MPTP or 6-OHdopamine, this hypothesis can not be tested since these toxins selectively accumulate in the dopaminergic neurons. However with rotenone, which penetrates all cells, the hypothesis can be tested. Thus, the proof of the hypothesis is whether or not rotenone-induced neurodegeneration mimics the degenerative processes underlying PD. Low doses of rotenone (1.5 or 2.5 mg/kg in oil i.p.) were administered to Sprague Dawley rats on a daily basis. After about 20 days of treatment, signs of parkinsonism occurred and the concentrations of NO and peroxidase products rose in the brain, especially in the striatum. After 60 days of treatment, rotenone had destroyed dopaminergic neurons. Behaviourally, catalepsy was evident, a hunchback posture and reduced locomotion. Other transmitter systems were not, or much less affected. L-DOPA-methylester (10 mg/kg plus decarboxylase inhibition) potently reversed the parkinsonism in rats. Also when infused directly into the dopaminergic neurons, rotenone produced parkinsonism which was antagonized by L-DOPA. Some peripheral symptoms of PD are mimiced by rotenone too, for example a low testosterone concentration in the serum and a loss of dopaminergic amacrine cells in the retina. These results support the hypothesis of an involvement of complex I in PD and render the rotenone model as a suitable experimental model. The slow onset of degeneration make it suitable also to study neuroprotective strategies. Evidence that rotenone-induced neurodegeneration spreads beyond the dopaminergic system is not contradictory given that, according to the new staging studies, also degeneration in PD is not confined to dopamine neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Systematic administration of iptakalim, an ATP-sensitive potassium channel opener, prevents rotenone-induced motor and neurochemical alterations in rats.

Our previous studies revealed that iptakalim, a novel ATP-sensitive potassium channel opener, has a significant neuroprotective function against ischemia in vivo or rotenone-induced neurotoxicity in vitro. To investigate the potential pharmaceutical benefit of ATP-sensitive potassium channel openers on neurodegenerative diseases, we studied the effects of iptakalim and diazoxide, a selective mitochondrial ATP-sensitive potassium channel opener, on the rotenone-induced nigrostriatal degeneration in rats. Iptakalim (1.5 mg/kg/day, orally) or diazoxide (1.5 mg/kg/day, orally) alone was administered to rats for 3 days, and then for 4 weeks was used daily with an injection of rotenone (2.5 mg/kg/day, subcutaneously) 1 hr later each time. The results showed that rotenone-infused rats exhibited parkinsonian symptoms and had dopamine depletion in the striatum and substantia nigra. Pretreatment with iptakalim or diazoxide prevented rotenone-induced catalepsy and the reduction of striatum dopamine contents. Moreover, iptakalim and diazoxide reduced the enzymatic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. These neuroprotective effects of iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium channel blocker. In conclusion, our data suggested that mitochondrial ATP-sensitive potassium channels might play a key role in preventing both parkinsonian symptoms and neurochemistry alterations induced by rotenone in rats. The selective activation of mitochondrial ATP-sensitive potassium channels may provide a new therapeutic strategy for prevention and treatment of neurodegenerative disorders such as Parkinson's disease.

ATP-Binding Cassette Transporters↗
PubMed2003

Rotenone increases glutamate-induced dopamine release but does not affect hydroxyl-free radical formation in rat striatum.

Impairment of the mitochondrial complex I has been found in Parkinson's disease and recently long-term treatment with the complex I inhibitor rotenone led to neurodegeneration and Lewy body-like inclusions in rats. To investigate the relationship of free radical formation, complex I inhibition, and dopamine release, rotenone (15 mg/kg s.c.) was injected in male Sprague Dawley rats. Complex I inhibition was measured in the striatum and substantia nigra using the lactate accumulation assay. Dopamine release and free radical formation was determined using striatal microdialysis in combination with the salicylate hydroxylation assay. In a second experiment, glutamate (10 mM) stimulation via the microdialysis probe was used to provoke hydroxyl radical formation and dopamine release 60 min after rotenone or vehicle pretreatment. Rotenone significantly increased striatal and nigral lactate levels. However, rotenone did not produce a significant increase in hydroxyl radical formation and dopamine release, but led to a pronounced hypokinesia. In contrast, rotenone in comparison to vehicle pretreatment produced a significant augmentation of glutamate-induced dopamine release (67-fold and 31-fold increase, respectively) and did not affect the glutamate-induced hydroxyl free radical formation (23-fold and 21-fold increase, respectively). The present study demonstrates that a single systemic rotenone administration does not lead to neurotoxicity, but rather to enhanced glutamate-induced dopamine release with no further increase of hydroxyl free radical formation. Thus, acute complex I inhibition in the presence or absence of high extracellular dopamine and glutamate levels is not critically involved in the formation of hydroxyl free radicals.

Amphetamine↗
PubMed1982

Further characterization of the growth inhibitory effect of rotenone on in vitro cultured Ehrlich ascites tumour cells.

As an approach for a better understanding of the mode of action of rotenone on mammalian cells we have studied the proliferation properties, metabolism and basic cell composition of Ehrlich ascites tumour cells cultured in vitro in the presence of 2.5 microM rotenone and after removal of the inhibitor. Experiments on asynchronous cells showed a rapid cessation of cell division accompanied by increased glycolytic rate, reduced oxygen consumption, moderate increase in DNA content and a fair increase in protein and RNA content of the cultures. DNA histograms obtained by flow-cytometry revealed an accumulation of cells in the G2 and M phase of the cell cycle. Electron micrographs taken after a 24 h treatment of cells illustrated the formation of giant mitochondria and fragmented nuclei. In order to elucidate the dual effect of rotenone- inhibition of mitochondrial energy metabolism and of mitotic processes- the influence on cells of rotenone at different stages of the cell cycle was tested using Ehrlich ascites tumour cells enriched in G1, S and G2 by centrifugal elutriation. DNA histograms and [3H]thymidine labelling index curves of cells from the different fractions cultured in the presence of 2,5 microM rotenone indicated that in addition to the observed accumulation in G2 and mitotic arrest of cells, the cell cycle progression is delayed in G1 phase. This may be explained by an effect of the inhibitor on the respiratory chain. S phase cells seemed to continue the cycle for several hours at a rate comparable to that of controls. Recultivation experiments on rotenone-treated asynchronous cells in inhibitor-free medium confirmed that some cells reinitiate DNA synthesis without preceeding cell division. Thus it must be concluded that cells at all stages of the cycle are affected by rotenone, but the impairment of cellular metabolism becomes manifest and lethal as soon as the acute block at mitosis is abolished and cells reenter the cycle.

Animals↗
PubMed2006

Rotenone produces opposite effects upon mouse striatal dopamine function as a result of environmental temperature.

Rotenone is a commonly used pesticide that can function as an environmental neurotoxin. Rotenone is a known mitochondrial complex I inhibitor which can lead to oxidative stress and results in dopaminergic cell death. Another environmental factor known to exacerbate oxidative stress and result in striatal dopaminergic cell death is elevated environmental temperature. In this study we evaluated the effects of a single injection of various doses of rotenone (0.65, 1.3 and 2.6 mg/kg) on striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations in CD-1 mice and compared this with a single injection of two doses of methamphetamine (MA - 10 or 20 mg/kg), a known striatal DA depleting agent, as administered to mice maintained at 21 degrees C (Experiment 1). These results were then compared to striatal DA and DOPAC concentrations of mice treated with rotenone (1.3 or 2.6 mg/kg) or MA (10 or 20 mg/kg) administered to mice maintained at 28 degrees C (Experiment 2). A single injection of rotenone to mice maintained at 21 degrees C resulted in a significant increase in DA and decrease in DOPAC concentrations for all doses tested compared to controls, whereas a single injection of MA at the same temperature resulted in a significant decrease in DA and no change in DOPAC concentrations. At a temperature of 28 degrees C, a single injection of rotenone resulted in a significant decrease in both DA and DOPAC concentrations similar to that seen with the MA-treated mice. Collectively, these results indicate that rotenone interacts with environmental temperature to produce opposite effects upon striatal DA concentrations -- significantly increasing striatal DA when administered at 21 degrees C and significantly decreasing striatal DA when administered at 28 degrees C, while producing similar decreases in striatal DOPAC under both temperatures.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Carcinogenesis with the insecticide rotenone.

Rotenone is an insecticide which has been used extensively for a long time, and is now widely used in the U.S.A. and other industrialized countries. Rotenone is used mainly as an agricultural insecticide, household garden insecticide and water plant pesticide. Through these uses, rotenone may now be reaching the human male and female in these countries in substantial amounts, carried by fresh or cooked vegetables, consumed fish and drinking water. A review of the existing published reports and unpublished official documents dealing with the capacity of rotenone to induce neoplastic, paraneoplastic and preneoplastic lesions in the rat is presented here. It is strongly suggested that rotenone is carcinogenic to the rat (at doses from 2 to 25 parts per million continuously in food, or from 0.8 to 2.5 mg/kg weight for 1 to 4 months by oral administration), above all, when the rats receive deficient diets, especially those poor in riboflavin. Rotenone carcinogenesis, among other things, seems to exhibit a peculiar dose response pattern, which could be explained by its possible hormonal mechanism of action. Further studies to assess definitively the role of rotenone as a possible environmental carcinogen are proposed as being highly necessary.

Animals↗
PubMed2004

L-DOPA reverses the hypokinetic behaviour and rigidity in rotenone-treated rats.

Peripherally and locally administered rotenone (an inhibitor of mitochondrial complex I) has been proposed as a model of Parkinson's disease (PD) as it induces nigrostriatal degeneration associated with alpha-synuclein inclusions. If rotenone-induced symptoms represent a model of PD, than they should be counteracted by L-DOPA. To answer this question, rats were treated with rotenone 2.5 mg/kg over 48 days. Behavioural data showed a strong increase in catalepsy, a decrease in locomotor activity and biochemical data showed a significant depletion of dopamine levels in the striatum (Cpu) and substantia nigra in rotenone treated animals compared to vehicle. To examine the effectiveness of L-DOPA in reversing the motor deficit in rats, a dose of L-DOPA (10 mg/kg) in combination with the peripheral amino acid decarboxylase inhibitor benserazide were daily administrated intraperitonially for a period of 10 days in the rotenone-treated rats. This treatment counteracted catalepsy and increased locomotor activity and number of rearings but decreased inactive sitting. In this animal model (rotenone model), catalepsy tests and motor activities showed that the clinically used anti-parkinsonian drug L-DOPA substitutes rotenone-induced dopamine (DA) deficiency.

Animals↗
PubMed2005

Acute intranigral infusion of rotenone in rats causes progressive biochemical lesions in the striatum similar to Parkinson's disease.

We examined in Sprague-Dawley rats whether intranigral administration of complex-I inhibitor, rotenone, produces biochemical lesions in the striatum similar to those observed in Parkinson's disease (PD). Unilateral stereotaxic infusion of rotenone (2-12 mug in 1 mul) into substantia nigra (SN) pars compacta caused significant inhibition of complex-I activity and increased production of hydroxyl radicals in vivo as measured employing spectrophotometric and HPLC-electrochemical procedures, respectively. It also caused a significant time- and dose-dependent reduction of dopamine level, but not serotonin, in the ipsilateral striatum when assayed using an HPLC electrochemical method. This effect was found to be progressive for 90 days. A dose-dependent decrease in nigral glutathione level, as measured fluorimetrically, was also observed to be progressive till 90th day. A significant decrease in tyrosine hydroxylase immunoreactivity in the striatum (73 +/- 8.4% as assessed by densitometric studies) or in SN ipsilateral to the side of infusion suggested nigrostriatal neuronal degeneration. A dose of rotenone (6 microg in 1 microl) that caused 55% striatal dopamine depletion when infused into the SN failed to affect serotonin levels in the terminal regions when infused into the nucleus raphe dorsalis, indicating rotenone's specificity of action towards dopaminergic neurons. Our findings suggest that unilateral infusion of rotenone reproduces neurochemical and neuropathological features of hemiparkinsonism in rats and indicate an active involvement of oxidative stress in rotenone-induced nigrostriatal neurodegeneration. The present study also demonstrates more sensitivity of dopaminergic neurons towards rotenone and establishes mitochondrial complex-I damage as one of the major contributory components of neurodegeneration in PD. The progressive nature of pathology in this model closely mimics idiopathic PD, and absence of mortality warrants the use of this model in drug discovery programs.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Behavioral differences in a rotenone-induced hemiparkinsonian rat model developed following intranigral or median forebrain bundle infusion.

A mitochondrial complex-I inhibitor, rotenone was unilaterally infused into the substantia nigra pars compacta (SNpc) or median forebrain bundle (MFB) to create hemiparkinsonian animal models and investigated spontaneous and drug-induced stereotypic rotations, as well as certain postural behaviors in Sprague-Dawley rats. Animals infused intranigrally, but not intra-MFB, with rotenone exhibited spontaneous contralateral rotations immediately after recovery from anesthesia. Head position bias and elevated body swing test showed insignificant contralateral bias in animals with nigral damage but a significant ipsilateral bias in MFB-lesioned rats. General motor activity of the animals was reduced in both the groups as indicated by reduced performance on a Plus-Maze. Intranigrally, rotenone-infused animals exhibited progressive ipsilateral rotations when challenged with d-amphetamine on the 7th, 14th, 21st, and 28th days or with apomorphine on 9th, 16th, 23rd, and 30th days. However, animals that received rotenone in MFB exhibited ipsilateral or contralateral rotations when challenged respectively with d-amphetamine or apomorphine only in the 5th week (28th and 30th days). Stereotaxic administration of rotenone into SNpc or MFB caused a significant loss of dopamine in the ipsilateral striatum (>80% in SNpc; >95% in MFB), when assayed employing an HPLC equipped with electrochemical detector on the 32nd day. Neuronal loss in SNpc was confirmed in coronal sections stained with cresyl violet and revealed extension of lesion towards SN pars reticulata, in SNpc-infused animals. Our results demonstrate that rotenone-induced neurodegeneration is a slow, yet progressive process similar to that in idiopathic Parkinson's disease and unlike that observed in other classical neurotoxin-mediated lesions which are abrupt and developed in few hours to days. Thus, intranigral or intra-MFB infusion of rotenone could be used for producing hemiparkinsonian animal models in rats. These findings further suggest that, while both d-amphetamine and apomorphine-induced stereotypic rotations could be used as a valuable behavioral assay procedure to test novel drugs against Parkinson's disease, yet apomorpine-induced contralateral bias in turning is a reliable indicator of specific destruction in nigrostriatal pathway and development of postsynaptic dopamine receptor supersensitivity.

Adrenergic Agents↗
PubMed2006

L-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats.

The present study investigated oxidative damage and neuroprotective effect of the antiparkinsonian drug, L-deprenyl in neuronal death produced by intranigral infusion of a potent mitochondrial complex-I inhibitor, rotenone in rats. Unilateral stereotaxic intranigral infusion of rotenone caused significant decrease of striatal dopamine levels as measured employing HPLC-electrochemistry, and loss of tyrosine hydroxylase immunoreactivity in the perikarya of ipsilateral substantia nigra (SN) neurons and their terminals in the striatum. Rotenone-induced increases in the salicylate hydroxylation products, 2,3- and 2,5-dihydroxybenzoic acid indicators of hydroxyl radials in mitochondrial P2 fraction were dose-dependently attenuated by L-deprenyl. L-deprenyl (0.1-10mg/kg; i.p.) treatment dose-dependently attenuated rotenone-induced reductions in complex-I activity and glutathione (GSH) levels in the SN, tyrosine hydroxylase immunoreactivity in the striatum or SN as well as striatal dopamine. Amphetamine-induced stereotypic rotations in these rats were also significantly inhibited by deprenyl administration. The rotenone-induced elevated activities of cytosolic antioxidant enzymes superoxide dismutase and catalase showed further significant increase following L-deprenyl. Our findings suggest that unilateral intranigral infusion of rotenone reproduces neurochemical, neuropathological and behavioral features of PD in rats and L-deprenyl can rescue the dopaminergic neurons from rotenone-mediated neurodegeneration in them. These results not only establish oxidative stress as one of the major causative factors underlying dopaminergic neurodegeneration as observed in Parkinson's disease, but also support the view that deprenyl is a potent free radical scavenger and an antioxidant.

Amphetamine↗
PubMed2004

The effect of rotenone on the urinary ethanol cycle in rats fed ethanol intragastrically.

Chronic ethanol ingestion alters mitochondrial function in the liver including inhibition of complex I of the electron transport chain. This leads to a shift in the NAD/NADH ratio to the reduced state when blood ethanol levels are high. Rotenone also inhibits complex I and induces a reduced state. The combination of ethanol feeding and rotenone toxicity should amplify the reduced state and block the cyclic increase and decrease in the rate of metabolism in the liver. The change in the redox state occurs during the urinary ethanol cycle in the intragastric tube feeding rat model of alcoholic liver disease. To test this hypothesis, rats were fed ethanol with rotenone and the 24-h urinary ethanol levels were measured daily. When ethanol was fed alone, the urinary ethanol cycle occurred. However, when ethanol was fed with rotenone the cycle was prevented and the urinary ethanol levels remained at the 200-mg% range. The rats fed ethanol or fed ethanol plus rotenone had the same increase in the pathology score and ALT elevations in the blood. Rotenone fed alone had the same normal values as the dextrose pair fed control rats. The results indicate that the UAL cycle is driven by fluctuation in the NAD/NADH ratio. When this fluctuation is blocked by rotenone, the cycle does not occur. It is concluded that the urinary ethanol cycle is dependent on cyclic fluctuation of the NAD/NADH ratio, which regulates the rate of ethanol elimination.

Administration, Oral↗
PubMed2005

Activation of mitochondrial ATP-sensitive potassium channels improves rotenone-related motor and neurochemical alterations in rats.

Our previous studies revealed that activation of mitochondrial ATP-sensitive potassium channels exerted protective effects on rotenone-treated rats and cultured cells. The aim of the present study is to examine the potential therapeutic effects of iptakalim, an ATP-sensitive potassium-channel opener, and diazoxide, a selective mitochondrial ATP-sensitive potassium-channel opener, on Parkinsonian symptoms in rats induced by rotenone. Rats were treated with rotenone (2.5 mg/kg s.c.) daily for 4 wk. This treatment caused a depletion of dopamine in the striatum and substantia nigra. Behaviourally, rotenone-infused rats exhibit Parkinsonian symptoms. Catalepsy was estimated by a 9-cm bar test. Treatment with L-dopa (10 mg/kg.d p.o.), iptakalim (0.75, 1.5, 3.0 mg/kg.d p.o.) and diazoxide (3.0 mg/kg.d p.o.) for 2 wk improved behavioural dysfunction and elevated dopamine contents in the striatum and substantia nigra of rotenone-treated rats. Studies also found that iptakalim and diazoxide could reduce the enzymic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. All neurorestorative effects by both iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium-channel blocker. Collectively, the data suggested that mitochondrial ATP-sensitive potassium channels play a key role in improving both Parkinsonian symptoms and neurochemistry alterations of rotenone model rats, and selective activation of mitochondrial ATP-sensitive potassium channels may provide a new therapeutic strategy for treatment of early Parkinson's disease.

Animals↗
PubMed1999

Diminished energy metabolism and enhanced apoptosis in livers of B6C3F1 mice treated with the antihepatocarcinogen rotenone.

Rotenone decreases the incidence of hepatocellular carcinoma and lowers rates of hepatocellular proliferation. In an effort to delineate mechanisms involved, the in vivo effect of rotenone on liver mitochondrial metabolism, apoptotic machinery as well as elements of the hepatic signal transduction pathways were investigated. Mitochondria from livers of male B6C3F1 mice fed a standard diet containing 600 ppm rotenone for 7 days were uncoupled or inhibited when succinate or glutamate plus malate were used as the substrate, respectively. These livers also showed a significant increase in apoptosis compared with control livers. Furthermore, rotenone increased the expression of c-myc mRNA to 5-fold of control values within 3 days, an effect which was still observed (3-fold) after 7 days. Levels of p53 mRNA were also increased 3-fold after 1 day, but declined to control levels by 7 days. Rotenone also caused a transient, yet marked increase in liver particulate glyceraldehyde phosphate dehydrogenase (GAPDH) protein expression, while it did not alter the expression of the cytosolic form of the enzyme. Conversely, mRNA of the proto-oncogene H-ras showed a decline of 35% after 3 days of rotenone treatment, and remained diminished for the duration of the experiment. These data suggest that rotenone may act as an anticancer agent by diminishing mitochondrial bioenergetics which prevents basal hepatocyte proliferation and lowers the threshold for liver cells with DNA damage to undergo apoptosis.

Animals↗
PubMed2006

Metallothionein isoform 2A expression is inducible and protects against ROS-mediated cell death in rotenone-treated HeLa cells.

The role of MT (metallothionein) gene expression was investigated in rotenone-treated HeLa cells to induce a deficiency of NADH:ubiquinone oxidoreductase (complex I). Complex I deficiency leads to a diversity of cellular consequences, including production of ROS (reactive oxygen species) and apoptosis. HeLa cells were titrated with rotenone, resulting in dose-dependent decrease in complex I activity and elevated ROS production at activities lower than 33%. Expression of MT2A (MT isoform 2A), but not MT1A or MT1B RNA, was significantly inducible by rotenone (up to 7-fold), t-BHP (t-butyl hydroperoxide; 5-fold) and CdCl2 (50-fold), but not ZnCl2. Myxothiazol treatment did not elevate either ROS or MT2A levels, which supports a ROS-related mechanism for rotenone-induced MT2A expression. To evaluate the role of MT2A expression, MT2A and MT1B were overexpressed in HeLa cells and treated with rotenone. Compared with control and MT1B-overexpressing cells, ROS production was significantly lower and cell viability higher in MT2A-overexpressing HeLa cells when ROS production was enhanced by treatment with t-BHP. Mitochondrial membrane potential was noticeably less reduced in both MT-overexpressing cell lines. MT2A overexpression in rotenone-treated cells also significantly reduced or delayed apoptosis induction, as measured by caspase 3/7 activity and cytosolic nucleosome enrichment. We conclude that MT2A offers significant protection against the main death-causing consequences of rotenone-induced complex I deficiency in HeLa cells. Our results are in support of the protective role against oxidative stress ascribed to MTs and provide evidence that MT2A expression may be a beneficial downstream adaptive response in complex I-deficient cells.

Adenosine Triphosphate↗