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PubMed1997

A dual effect of 1-methyl-4-phenylpyridinium (MPP+)-analogs on the respiratory chain of bovine heart mitochondria.

We examined effects of several compounds, structurally related to 1-methyl-4-phenylpyridinium (MPP+), on the NADH-dependent respiration of bovine heart submitochondrial particles. 1-Methyl-4-(3 '-trimethylammoniophenyl)pyridinium (analog 8) as well as MPP+ completely inhibited O2 consumption, reduction of ubiquinone-10, and reduction of cytochrome b in a dose-dependent manner. The production of superoxide (O2-) induced by MPP+ or analog 8 was to the same extent as that by rotenone, an inhibitor of complex I of the mitochondrial respiratory chain. Rotenone had no additive effect on the maximal production of O2- induced by MPP+ or analog 8, suggesting that the production was mediated by the same way as rotenone. 1-Methyl-4-(4'-nitrophenyl) pyridinium (analog 1) induced about 20-fold more production of O2 than MPP+ and the production was additively increased by rotenone. Analog 1 only partially inhibited rotenone-sensitive O2 consumption. Paraquat induced the production of O2- as much as analog 1. Paraquat, however, did not inhibit rotenone-sensitive O2 consumption or reduction of cytochrome b. These results suggest that MPP+ and its analogs interact with the mitochondrial respiratory chain at two sites, the substrate side of the rotenone-binding site and the rotenone-binding site. The analogs may be reduced to produce O2- at the former site and inhibit the respiratory chain at the latter site.

Animals↗
PubMed1992

Matrix NADH dehydrogenases of plant mitochondria and sites of quinone reduction by complex I.

In order to distinguish the pathways involved in the oxidation of matrix NADH in plant mitochondria, the oxidation of NADH and nicotinamide hypoxanthine dinucleotide (reduced form) was investigated in submitochondrial particles prepared from beetroot (Beta vulgaris L. cv. Derwent Globe) and soybeans (Glycine max L. cv. Bragg). Nicotinamide-hypoxanthine-dinucleotide(reduced form)-oxidase activity was more strongly inhibited by rotenone than the NADH-oxidase activity but both of the rotenone-inhibited activities could be stimulated by adding ubiquinone-1. The corresponding ubiquinone-1-reductase activities were inhibited by rotenone (to 69%) and further inhibited by N,N'-dicyclohexylcarbodiimide (to 79%), whilst the K3Fe(CN)6-reductase activities were not sensitive to either rotenone or N,N'-dicyclohexylcarbodiimide. Immunological analysis of mitochondrial proteins using an antiserum raised against purified beetroot complex I indicated very few differences between soybean and fresh and aged beetroot mitochondria, despite their varying sensitivities to rotenone. We confirm that there are two dehydrogenases capable of oxidising internal NADH and that only one of these, namely complex I, is inhibited by rotenone. Further, we conclude that complex I has two potential sites of quinone reduction, both sensitive to N,N'-dicyclohexycarbodiimide inhibition but only one of which is sensitive to rotenone inhibition.

Benzoquinones↗
PubMed2006

Differential effect of nerve growth factor on dopaminergic neurotoxin-induced apoptosis.

Both rotenone and manganese are possible neurotoxins for a wide variety of cell and neuronal types including dopaminergic neurons and induce apoptosis in various cells. Neurotrophic factors have the potential for therapeutic development when used to prevent Parkinson's disease. In this paper, we focused on the differences between rotenone and manganese as toxins, and characterized the influence of neurotrophic factors on toxin-induced apoptosis in PC12 cells. There were distinct differences in intracellular mechanisms between rotenone- and manganese-induced apoptosis such as the production of reactive oxygen species, the response to antioxidants, and the activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Nerve growth factor (NGF) almost completely prevented rotenone-induced but not manganese-induced caspase activation and DNA fragmentation. The differential effect of NGF was found to be mainly due to the down-regulation of the Trk tyrosine kinase receptor by manganese but not by rotenone. Prevention of rotenone-induced apoptosis by NGF was attenuated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, but not MAPK kinase (MEK) inhibitors, PD98059 or U0126. These results demonstrate that the potential neurotoxins for dopaminergic cells exert their toxic effect by activation of different signaling pathways of apoptosis and that NGF prevents rotenone-induced apoptosis through the activation of the PI 3-kinase pathway not MAPK pathway.

Animals↗
PubMedDate not supplied

[Intermembrane electron transport in the dynamics of high-amplitude swelling of rat liver mitochondria].

The rate of rotenone insensitive NADH oxidation depending on the extent of rat liver mitochondria swelling in isotonic sucrose medium has been studied. The rate of exogenous NADH oxidation was determined fluorimetrically in the presence of 4 microM cytochrome c in the medium after the inhibition of high-amplitude swelling at its different stages by means of rotenone +Mg2+ + trifluoromethoxyphenylhydrasonecarbonylcyanide (FCCP) addition. Activation of external pathway of NADH oxidation in phosphate containing medium was conditioned by quick energy and phosphate-dependent mitochondria swelling that leads to the outer membrane disruption. An increase in the rate of NADH oxidation as a result of the outer membrane disruption during high amplitude swelling in isotonic sucrose medium has been shown to be nearly proportional to the extent of the decrease in optical density of mitochondria suspension. Similar decrease in optical density of homogenates incubated 25-30 min in isotonic sucrose medium was also accompanied by a significant increase in Mg(2+)-cytochrome c-dependent rotenone insensitive NADH oxidation. A decrease in optical density of liver homogenates was prevented by EGTA+2+, rotenone+Mg2++FCCP, rotenone or FCCP alone and was nearly completely inhibited at any stages of changes by means of rotenone+Mg2++FCCP addition that usually inhibit mitochondrial swelling. That means that the rate of Mg(2+)-cytochrome-c-dependent rotenone insensitive NADH oxidation in homogenates may be used as the simple method to evaluate the outer mitochondrial membrane disruption with the purpose to analyse the liver bioptate to study the effect of hormonal, xenobiotic and physical factors on mitochondrial macrostructure.

Animals↗
PubMed2004

Correlation between thyroid hormone status and hepatic hyperplasia and hypertrophy caused by the peroxisome proliferator-activated receptor alpha agonist Wy-14,643.

BACKGROUND: The metabolic inhibitor rotenone inhibits hepatocellular proliferation and the incidence of liver cancer resulting from exposure to the PPARalpha agonist Wy-14,643, via unknown mechanisms. Since the absence of thyroid hormones diminishes hepatomegaly, an early biomarker for the hepatocarcinogenicity induced by PPARalpha agonists, this study was undertaken to investigate whether rotenone might interference with the ability of Wy-14,643 to alter the animal thyroid status. METHODS: Male B6C3F1 mice were given Wy-14,643 (100 ppm), rotenone (600 ppm) or a mixture of both, in the feed for 7 days. Bromodeoxyuridine (BrDU), marker of cell replication, was delivered through subcutaneously implanted osmotic mini-pumps. At the end of the experiment, sera were collected and corticosterone and thyroid hormone levels were measured by solid-phase radioimmunoassay kits. In addition, liver tissue samples were stained immunohistochemically for BrDU to determine percentages of labeled cells. Further, cell surface area was determined from images generated by a Zeiss Axioplan microscope equipped with a plan Neofluar x40 0.75 na objective. Tracings of individual hepatocyte perimeters were then analyzed and cell-surface areas were calculated using MicroMeasure FL-4000. RESULTS: Wy-14,643 caused a significant increase in liver weights, hepatocyte BrDU labeling index (LI), and hepatocyte surface area. In animals which received both Wy-14,643 and rotenone simultaneously, all of these effects were significantly less pronounced compared with mice that received Wy-14,643 alone. Rotenone alone decreased liver weights, LI and surface area. The Free Thyroid Index (FTI), which provides an accurate reflection of the animal's thyroid status, was 5.0 +/- 0.3 in control mice. In animals exposed to rotenone, these values decreased to 2.0 +/- 0.9, but in animals which received Wy-14,643, levels increased significantly to 7.7 +/- 0.9. FTI values decreased to 3.4 +/- 0.8 in mice receiving both rotenone and Wy-14,643. CONCLUSION: A strong correlation was observed between the animal thyroid status and both, hepatocyte proliferation (r2 = 0.62), and hepatocyte surface area (r2 = 0.83). These results support the hypothesis that the thyroid status of the animal plays a role in PPARalpha-induced hepatocellular proliferation and liver cell enlargement. Both these events are known to contribute to the expression of liver cancer in response to the activation of PPARalpha.

Journal Article↗
PubMed2003

Mitochondrial complex inhibitors preferentially damage substantia nigra dopamine neurons in rat brain slices.

Using a rat brain slice preparation, we investigated the role of energy impairment on the selective loss of dopamine neurons in the substantia nigra (SN). Brain slices (400 microm) were incubated at 35 degrees C for 2 h in the presence or absence of mitochondrial complex inhibitors, rotenone, MPP+, 3-nitropropionic acid, and antimycin A. Slices were also incubated in rotenone with excitatory amino acid (EAA) receptor antagonists, MK-801 and CNQX, to determine whether rotenone-induced damage was mediated by EAAs. The slices were then fixed, recut into 30-microm sections, and immunolabeled for tyrosine hydroxylase (TH) to identify catecholamine neurons and to quantify loss of TH-labeled dendrites after treatment. Quantitative comparison was made between SN dopamine neurons, in which rotenone-induced dendrite loss was severe, and hypothalamic A11 dopamine neurons, which were spared. Adjacent sections that were immunolabeled for calbindin or stained with cresyl violet also revealed a striking dendritic degeneration of SN neurons in rotenone-exposed slices, whereas noncatecholamine neurons, such as those in the perifornical nucleus (PeF), were more resistant. Preferential damage to SN dopamine neurons was also evident with other mitochondrial complex inhibitors, MPP+ and antimycin A. EAA receptor antagonists provided partial protection to SN neurons in slices incubated with rotenone (3 microM). The particular vulnerability of SN dopamine neurons in the slice is consistent with the vulnerability of SN in Parkinson's disease. The selective effect of mitochondrial complex inhibition in SN dopamine neurons implies a fundamental deficit in the capacity of these neurons to defend against toxic insult.

1-Methyl-4-phenylpyridinium↗
PubMed2006

Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis.

G93A Cu/Zn superoxide dismutase (SOD1), a human mutant SOD1 associated with familial amyotrophic lateral sclerosis, increased the toxicity of the mitochondrial toxin rotenone in the NSC-34 motoneuronal cell line. G93ASOD1 cells died more than untransfected and wild-type SOD1 cells after 6 and 24h exposure to 12.5 microM rotenone. Biparametric flow cytometry showed that rotenone induced rapid hyperpolarization of mitochondrial membrane potential (deltapsi(m)) in all the cell lines, followed by depolarization, and then by cell death. However, G93ASOD1 mitochondria were significantly more likely to shift from a hyperpolarized to a depolarized condition, and within the still viable cell population there was a higher proportion with depolarized mitochondria, a condition that can be envisaged as a commitment to cell death. ATP, which is needed to prevent loss of deltapsi(m), decreased more rapidly and to a greater extent in rotenone-treated G93ASOD1 cells than in the untransfected and wtSOD1cells. In all the cell lines, 1h after rotenone exposure, mitochondrial hyperpolarization was accompanied by the formation of a comparable amount of reactive oxygen species. However, G93ASOD1 cells reached the highest reactive oxygen species level since their basal level was higher than in untransfected and wild-type SOD1 cells. Our findings indicate that the mutant protein G93ASOD1 enhances the vulnerability of motor neurons to rotenone by mechanism(s) involving oxidative stress and perturbed mitochondrial homeostasis. This suggests that motor neurons from individuals carrying the mutant G93ASOD1 are at greater risk of death after inhibition of the electron transport chain.

Adenosine Triphosphate↗
PubMed2002

The second coenzyme Q1 binding site of bovine heart NADH: coenzyme Q oxidoreductase.

The rotenone sensitivity of bovine heart NADH: coenzyme Q oxidoreductase (Complex I) depends significantly on coenzyme Q1 concentration. The rotenone-insensitive Complex I reaction in Q1 concentration range above 300 microM indicates an ordered sequential mechanism with Q1 and reduced Q1 (Q1H2) as the initial substrate to bind to the enzyme and the last product to be released from the enzyme product complex, respectively. This is the case in the rotenone-sensitive reaction although both Km and Vmax values of the rotenone-insensitive reaction for Q1 are significantly higher than those of the rotenone-sensitive reaction (Nakashima et al., 2002, J. Bioenerg. Biomemb. 34, 11-19). This rigorous control mechanism between the nucleotide and ubiquinone binding sites strongly suggests that the rotenone-insensitive reaction is also physiologically relevant.

Animals↗
PubMed2003

The production of reactive oxygen species in intact isolated nerve terminals is independent of the mitochondrial membrane potential.

Dependence on mitochondrial membrane potential (deltapsim) of hydrogen peroxide formation of in situ mitochondria in response to inhibition of complex I or III was studied in synaptosomes. Blockage of electron flow through complex I by rotenone or that through complex III by antimycin resulted in an increase in the rate of H2O2 generation as measured with the Amplex red assay. Membrane potential of mitochondria was dissipated by either FCCP (250 nM) or DNP (50 microM) and then the rate of H2O2 production was followed. Neither of the uncouplers had a significant effect on the rate of H2O2 production induced by rotenone or antimycin. Inhibition of the F0F1-ATPase by oligomycin, which also eliminates deltapsim in the presence of rotenone and antimycin, respectively, was also without effect on the ROS formation induced by rotenone and only slightly reduced the antimycin-induced H2O2 production. These results indicate that ROS generation of in situ mitochondria in nerve terminals in response to inhibition of complex I or complex III is independent of deltapsim. In addition, we detected a significant antimycin-induced H2O2 production when the flow of electrons through complex I was inhibited by rotenone, indicating that the respiratory chain of in situ mitochondria in synaptosomes has a substantial electron influx distal from the rotenone site, which could contribute to ROS generation when the complex III is inhibited.

Animals↗
PubMed2004

Severe impairment of nucleotide synthesis through inhibition of mitochondrial respiration.

Since de-novo synthesis of pyrimidine nucleotides is coupled to the mitochondrial respiratory chain (RC) via dehydroorotic acid dehydrogenase (DHODH), respiratory chain dysfunction should impair pyrimidine synthesis. To investigate this, we used specific RC inhibitors, Antimycin A and Rotenone, to treat primary human keratinocytes and 143B cells, a human osteosarcoma cell line, in culture. This resulted in severe impairment of de novo pyrimidine nucleotide synthesis. The effects of RC inhibition were not restricted to pyrimidine synthesis, but concerned purine nucleotides, too. While the total amount of purine nucleotides was not diminished, they were significantly broken down from triphosphates to monophosphates, reflecting impaired mitochondrial ATP regeneration. The effect of Rotenone was similar to that of Antimycin A. This was surprising since Rotenone inhibits complex I of the respiratory chain, which is upstream of ubiquinone where DHODH interacts with the RC. In order to avoid unspecific effects of Rotenone, we examined the consequences of a mitochondrial DNA mutation that causes a specific complex I defect. The effect was much less pronounced than with Rotenone, suggesting that complex I inhibiton cannot fully explain the marked effect of Rotenone on pyrimidine nucleotide synthesis.

Adenosine Triphosphate↗
PubMed1969

The effect of respiratory inhibitors on NADH, succinate and malate oxidation in corn mitochondria.

The effect of a series of respiratory inhibitors on the oxidation of NADH in state 4 and state 3 conditions was studied with corn shoot mitochondria. Comparisons were made using malate and succinate as substrates. The inhibitors, rotenone, amytal, antimycin A and cyanide, inhibited oxidation of NADH in state 3 but rotenone and amytal did not inhibit oxidation in state 4. The inhibition by antimycin A was partially overcome by the presence of cytochrome c. The results indicate the presence of alternative pathways available for NADH oxidation depending on the metabolic condition of the mitochondria. Under state 4 conditions, NADH oxidation bypasses the amytal and rotenone sensitive sites but under state 3 conditions a component of the NADH respiration appears to be oxidized by an internal pathway which is sensitive to these inhibitors. Still a third pathway for NADH oxidation is dependent on the addition of cytochrome c and is insensitive to antimycin A. Succinate oxidation was sensitive to cyanide and antimycin A under both state 4 and state 3 conditions as well as amytal and rotenone under state 3 conditions but was not inhibited by amytal and rotenone under state 4 conditions. Malate oxidation was inhibited by cyanide, rotenone and amytal under both state 4 and state 3 conditions. Antimycin A inhibited state 3 but did not appreciably alter state 4 rates of malate oxidation. With all substrates tested inhibition by antimycin A was greatly facilitated by preswelling the mitochondria for 10 min. This was interpreted to indicate that swelling increases the accessibility of antimycin A to the site of inhibition.

Amobarbital↗
PubMed1996

Limitation of glycolysis by hexokinase in rat brain synaptosomes during intense ion pumping.

Incubation of rat brain synaptosomes under conditions of either increased energy utilization (addition of Na+ channel opener, veratridine, or ionophores, monensin and nigericin) or inhibition of oxidative phosphorylation (addition of rotenone), or a combination thereof, decreased [ATP], increased [ADP] and stimulated glycolysis. The rates of lactate generation were linear over a 15-min interval in the presence of rotenone alone but decreased in the other two conditions. During the first 5 min, the amount of lactate formed with veratridine, monensin or nigericin was as high or higher than with rotenone, but it was lower in the last 10 min. With a combination of one of the stimulators of ion movements and rotenone the rate of glycolysis was always markedly lower than with each compound added singly. The stimulated rates of lactate formation correlated positively with the synaptosomal content of [ATP]. After 15 min, [ATP] was 0.9-1.0 nmol/mg with rotenone, 0.5-0.9 nmol/mg with veratridine (or ionophores), and <0.3 nmol/mg with a combination of the two. Under the conditions used, calcium did not affect glycolytic activity directly. The Lineweaver-Burk plot of the rate of lactate formation against [ATP] yielded a straight line with a Km for ATP of about 0.1 mM, which is very similar to the Km for this nucleotide of brain hexokinase bound to mitochondria. In C6 cells glycolytic rate measured with a combination of an ionophore and rotenone was higher than with each of these compounds added singly while [ATP] never declined below about 9 nmol/mg prot. It is concluded that in synaptosomes, the high rate of energy utilization required for intense ion movement decreases [ATP] to a level that limits hexokinase activity kinetically. This may contribute to a reduction in the rate of glycolysis and hence energy production in brain hypoxia and ischemia.

Adenosine Diphosphate↗
PubMed2003

[Sublethal effects of insecticides on fecundity of multicolored Asian ladybird Harmonia axyridis].

The effects of sublethal doses of 6 insecticides (imidacloprid, rotenone, fenvalerate, abamectin, pirimicarb and azadirachtin) on the fecundity of multicolored Asian ladybird Harmonia axyridis were determined respectively. The results showed that in all treatments, the daily average number of eggs per female ladybird was about 40-55. Ladybirds pretreated with imidacloprid by contact and feeding methods, and with rotenone by feeding method produced significantly fewer eggs, compared with control. But the accumulative oviposition of ladybirds pretreated with 6 insecticides at sublethal level was no significant differences, compared with untreated ladybirds. The hatching rates of the eggs laid by ladybirds pretreated with 6 insecticides by two methods were all lower than that of control. The accumulative survivals from egg to pupal stage of all treatments decreased significantly. The developmental duration from egg to pupa of those treated with imidacloprid by two methods and with fenvalerate by contact method prolonged significantly, while that of those treated with rotenone by two methods and with fenvalerate, abamectin, pirimicarb, and azadirachtin by feeding method shortened obviously, but that of those treated with rotenone and abamectin by contact method had no differences with control. After the eggs were immersed with sublethal concentrations of imidacloprid, rotenone, fenvalerate and abamectin, the successful hatching rates were all lower than that of control, and the development periods prolonged clearly. The 1st instar larval survival rates of those treated with fenvalerate decreased significantly, and the survivals from 2nd instar larval to pupal stage also reduced to some extent. The total developmental duration of those treated with rotenone and fenvalerate prolonged significantly. These findings suggested that the effects of insecticides at low doses on the fecundity of ladybird were very complicated. The class, action mode, toxicity and exposure route of insecticides could affect the results of experiments.

Animals↗
PubMed1976

An alternate respiratory pathway in Candida albicans.

Usual concentrations of antimycin A, rotenone and EDTA, individually or in combination, reduced aerobic growth rate and cell yield of Candida albicans to about half its normal level and to about the levels of previously-described acetate-negative, cytochrome-complete and aa3-deficient variants which were little affected by the inhibitors. Anaerobic conditions (not affected by antimycin A) reduced growth rate and cell yield of all cultures-including that of a nonrespiring aa3, b-deficient mutant-to low, equal levels. Antimycin A but not rotenone prevented growth of the normal strain on ethanol medium. Cyanide and antimycin A blocked most of the respiration of the normal strain and cytochrome-complete variant, but did not affect that of the cytochrome aa3-deficient mutant. Rotenone and EDTA did not affect respiration of any of the cultures. SHAM blocked cyanide-and antimycin A-insensitive respiration and prolonged the lag phases of the three respiring cultures, especially in the presence of antimycin A, but alone increased oxygen-uptake rate of the cytochrome-complete cultures while curtailing that of the cytochrome aa3-deficient mutant. Resting cells, especially wild-type, grown in medium containing antimycin A exhibited lowered oxygen-uptake rate, which was increased upon the addition of cyanide or antimycin A. Antimycin A stimulated, but cyanide inhibited, respiration of cytochrome-complete cultures grown in the presence of rotenone but did not affect that of the cytochrome aa3-deficient mutant. SHAM inhibited respiration of all antimycin A- or rotenone-grown cultures. The high rate of respiration of C. albicans in the presence of inhibitors for three sites of electron transport in the conventional oxidative pathway, the inhibition of this respiration by SHAM and its loss by the absence of cytochrome b, indicate an alternate oxidative pathway in this organism which crosses the conventional one at cytochrome b.

Aerobiosis↗
PubMed1985

The influence of cellular ATP levels on receptor-mediated endocytosis and degradation of asialo-glycoproteins in suspended hepatocytes.

Receptor-mediated endocytosis in suspended hepatocytes was studied in conjunction with ATP levels of the cells, which were decreased by the use of metabolic inhibitors. The receptor system studied was the asialo-glycoprotein receptor, and multiple aspects of the endocytic pathway were examined: binding of ligand, internalization, intracellular transport and proteolysis. Moderate concentrations of the inhibitors (e.g. 30 microM rotenone or 200 microM iodoacetamide) produced only a transient decline in the ATP levels of the cells. Two to four times higher concentrations reduced the ATP levels to about 1/10 of control cells. At low levels of ATP (less than 30% of controls) the uptake ceased completely after 10-20 min. Moderate reductions brought about by rotenone reduced the uptake roughly in proportion to the ATP levels; iodoacetamide and sodium fluoride had little influence on the energy production by the cells, but the rate of asialo-glycoprotein uptake was reduced to a small fraction of controls. The effect of rotenone on the rate of uptake was mainly due to a lower rate of internalization of occupied receptors; the half-time for internalization of surface-bound ligand was increased from 2.9 to 6.2 min in the presence of 42 microM rotenone. The binding capacity of the cell surface was also somewhat lower. There was no degradation of the asialo-glycoproteins which were taken up by cells treated with high concentrations of rotenone or iodoacetamide. This was shown to be due to a low rate of transport of the endocytosed protein into those endosomes (at density 1.15 g/ml in a sucrose gradient) which were delivering their contents to the lysosomes; coincidentally, there was an accumulation of ligand in light endosomes (density 1.11 g/ml), in which the ligand appears immediately after endocytosis.

Adenosine Triphosphate↗
PubMed1995

Complex I inhibitor effect on the nigral and striatal release of dopamine in the presence and absence of nomifensine.

The effect of inhibitors of complex I respiratory chain--1-methyl-4-phenylpyridinium ion (MPP+, 10 microM) and rotenone (100 microM)--on the release and metabolism of dopamine was studied by in vivo microdialysis in the striatum and substantia nigra. Both compounds produced a marked increase in the release of dopamine in the striatum and substantia nigra, which was diminished when nomifensine (20 microM) was included in the perfusion fluid. The 3,4-dihydroxyphenylacetic acid (DOPAC) extracellular output was decreased under MPP+ (10 microM) perfusion in the striatum and substantia nigra, in the presence and in the absence of nomifensine (20 microM). However, perfusion of rotenone (100 microM) increased or had no effect on DOPAC outflow. Homovanillic acid levels were affected in the same way as DOPAC levels, but the changes were always much less pronounced. These results suggest that the neurotoxic action of MPP+ or rotenone is similar in the striatum and substantia nigra, indicating the importance of the dopamine uptake system in this neurotoxic action of MPP+ or rotenone, also suggesting that the dopamine uptake system could have low selectivity and also transports other substances such as rotenone.

1-Methyl-4-phenylpyridinium↗
PubMed1988

Ca2+-dependent and Ca2+-independent glutamate release, energy status and cytosolic free Ca2+ concentration in isolated nerve terminals following metabolic inhibition: possible relevance to hypoglycaemia and anoxia.

Hypoglycaemia and anoxia both cause massive release of glutamate from the brain in vivo, and the nature of this release was investigated using guinea-pig cerebral-cortical synaptosomes and iodoacetate and rotenone to simulate the energetic consequences of these conditions. Glutamate release (by continuous fluorimetry), cytoplasmic free Ca2+ (by fura-2), membrane potentials, ATP, ADP and creatine phosphate were determined in parallel, following the addition of iodoacetate or rotenone, alone or in combination. Ca2+-dependent glutamate release had a high energy requirement which could only be satisfied by aerobic glycolysis. Respiration using endogenous substrates, or anaerobic glycolysis following rotenone, caused a progressive inhibition of Ca2+-dependent release, correlating with a decline in the total ATP/ADP ratio and creatine phosphate. With rotenone, an increase in Ca2+-independent glutamate release was observed, correlating with a decline in plasma membrane potential. Only a slight increase in free Ca2+ was seen. Rotenone plus iodoacetate caused an almost immediate collapse of ATP/ADP ratio and a parallel loss of Ca2+-dependent glutamate release before free Ca2+ had risen to a level sufficient for exocytosis. In contrast, Ca2+-independent glutamate release increased. The Ca2+-dependent release of L-glutamate had the characteristics of an exocytotic transmitter release mechanism, being energy-dependent and triggered by elevated cytoplasmic free Ca2+ concentration. A distinct Ca2+-independent release of cytoplasmic glutamate occurred by reversal of the Na+-coupled uptake carrier, which was accelerated by a decline in the Na+ gradient. It is concluded that the Ca2+-independent release of cytoplasmic glutamate may make the major contribution to the excitotoxic release of glutamate in hypoglycaemic and anoxic conditions.

Adenosine Diphosphate↗
PubMed1984

Timbós: ichthyotoxic plants used by Brazilian Indians.

The pharmacology of serjanosides, active principles isolated from the fish-poison plant Serjania lethalis St. Hil, a Sapindaceae, was investigated by comparing their actions in fishes and mammals with those of rotenone and certain saponins. The ichthyocid activity of the serjanosides was 2.5 times greater than that of the crude plant extract, approximately 10 times lower than the activity of rotenone, but from 10 to 50 times greater than the activity of the other saponins. When injected in mammals, the serjanosides induced deep prostration, dyspnea, cyanosis, ectopic heart beats, cardiovascular failure and respiratory arrest. These effects, leading to death that was not prevented by artificial respiration, indicated several mechanisms for the toxic action of the serjanosides. In vitro studies with these substances have shown that membrane depolarization and muscle contracture were probably due to unspecific surface actions. Rotenone, under the same experimental conditions induced hypotension, bradycardia and respiratory arrest. Death was prevented by artificial respiration. Ectopic foci, membrane depolarization, contractures and neuromuscular block were not observed after rotenone. Apparently, death from rotenone poisoning was a consequence of respiratory failure of central origin. The serjanosides are rather potent fish poison saponins. Mammals, however, are apparently insensitive to the same specific action since other toxic effects induced by those substances in rats and mice were also observed by employing saponins devoid of fish-killing activity.

Animals↗