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PubMed1998

Bioenergetics of rat prostate cancer cell migration.

BACKGROUND: Increased cell motility and increased glycolysis are two well-known hallmarks of cancer. We undertook these studies to determine whether increased glycolysis is required for prostate cancer cell locomotion. METHODS: We studied the highly metastatic MatLu cell line, which is a variant of the Dunning R-3327 rat prostate adenocarcinoma model. Using videomicroscopy and computer image analysis, we compared the speed of migration of cells grown in serum-free medium in either the presence or absence of glucose. RESULTS: We found that cells grown in glucose-free, conditioned medium maintained speeds of migration and intracellular ATP levels for 24 hr which were equivalent to those of cells grown in conditioned medium containing glucose. In contrast, migration was significantly inhibited by growth in glucose-free, unconditioned medium. We also tested the effect of antimycin A and rotenone, two inhibitors of mitochondrial electron transport, on cell migration and ATP levels. Antimycin A had no significant effect on either feature, while rotenone slightly inhibited cell migration without affecting ATP levels. CONCLUSIONS: 1) Glycolysis is not necessary for rat prostate cancer cell locomotion in the presence of conditioned medium. 2) MatLu cells grown in the absence of both serum and conditioned medium require glucose to maintain cellular ATP levels and cell migration. 3) MatLu cells in conditioned medium adapt to inhibition of glycolysis or mitochondrial respiration by increasing the activity of the uninhibited pathway.

Adenocarcinoma↗
PubMed1998

Differentiation of HL-60 promyelocytic leukemia cells is accompanied by a modification of magnesium homeostasis.

Magnesium homeostasis in HL-60 promyelocytic leukemia cells was compared to that in neutrophyl-like HL-60 cells obtained by 1.3% DMSO treatment. Magnesium homeostasis was studied by the characterization of magnesium efflux, the identification of intracellular magnesium pools, and the regulation of intracellular ionized Mg2+. In both undifferentiated and neutrophyl-like HL-60 cells, magnesium efflux occurred via the Na-Mg antiporter which was inhibited by imipramine and stimulated by db cAMP and forskolin. Receptor-mediated signals such as ATP, IFN-alpha, or PGE1, which can trigger cAMP-dependent magnesium efflux, were ineffective in undifferentiated HL-60 cells but induced 60-70% increase of magnesium efflux in neutrophyl-like HL-60 cells. Selective membrane permeabilization by the cation ionophore A23187 induced a large magnesium release when cells were treated with rotenone. In both cell populations, the addition of glucose to rotenone-treated cells restored magnesium release to the control level. Permeabilization by 0.005% digitonin provoked the release of 90% cell total magnesium in both cell types. Intracellular [Mg2+]i was 0.15 and 0.26 mM in undifferentiated and neutrophyl-like HL-60 cells, respectively. Stimuli that triggered magnesium efflux, such as db cAMP in undifferentiated and IFN-alpha in neutrophyl-like HL-60 cells, induced a slow but consistent increase of [Mg2+]i which was independent from Ca2+ movements. Overall, these data indicate that magnesium homeostasis is regulated by receptor-mediated magnesium efflux which was modified during differentiation of HL-60 cells. Stimulation of magnesium efflux is paralleled by an increase of [Mg2+]i which reflects a release of magnesium from the bound cation pool.

Adenosine Triphosphate↗
PubMed2003

Cytoprotective and anticancer properties of coenzyme Q versus capsaicin.

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and serves as an electron donor and acceptor in mitochondrial energy-linked respiration. CoQ1 was shown to prevent ROS formation and cell death in complex 1 inhibited cells. Low concentrations of capsaicin like CoQ1 inhibited ROS formation but CoQ1 was more effective at restoring the mitochondrial membrane potential collapse caused by complex 1 inhibitors such as rotenone. At low concentrations, capsaicin acts as a CoQ mimic by protecting against rotenone induced ROS formation and mitochondrial membrane potential collapse. Lipid peroxidation in isolated rat hepatocytes induced by cumene hydroperoxide and chloroacetaldehyde was also prevented. At higher concentrations, capsaicin and CoQ1 became cytotoxic. Hep G2 cells were more susceptible than hepatocytes. The cytotoxic mechanism for both capsaicin and CoQ1 was shown to involve a collapse of the mitochondrial membrane potential, however, only capsaicin caused ROS formation. The capsaicin side chain was required for capsaicin induced cytotoxicity. The anticancer properties of CoQ1 and capsaicin should prove useful for inducing tumor cell apoptosis.

Animals↗
PubMed2001

Hypoxia-induced upregulation of eNOS gene expression is redox-sensitive: a comparison between hypoxia and inhibitors of cell metabolism.

Several papers report a hypoxia-induced upregulation of the endothelial nitric oxide synthase (eNOS) mRNA expression. Since there is no known hypoxia-sensitive element binding site in the eNOS promoter, we reasoned that the effect of hypoxia could be simulated by a metabolically elicited alteration of the redox state. Therefore, cultured porcine aortic endothelial cells (PAEC) were exposed to hypoxia (1-10% O(2)) or inhibitors of cellular energy metabolism including rotenone, 2, 4 dinitrophenol (DNP) and 2-deoxyglucose for 6 to 24 h. Additionally, cells were treated with lactate and nicotinic acid to alter the cellular NAD(P)H/NAD(P) ratio without changes of energy supply. The cellular NAD(P)H/NAD(P) ratio was used as an index of the cellular redox state and determined using the MTT-assay. Hypoxia increased eNOS mRNA transcription and MTT-reduction in a manner inversely proportional to pO(2). Exposure to rotenone, DNP, and lactate increased the NAD(P)H/NAD(P) ratio, MTT-reduction, and eNOS mRNA also in parallel. In contrast, 2-deoxyglucose and nicotinic acid attenuated both MTT-reduction and eNOS mRNA expression. In order to study a potential role of the redox regulated transcription factor complex AP-1 in hypoxia-induced eNOS mRNA transcription, c-jun expression was determined and decoy experiments were performed. c-jun expression paralleled changes of eNOS mRNA expression and MTT-reduction. Furthermore, in the presence of oligodeoxynucleotides corresponding to the AP-1 binding sites of the eNOS promoter, the hypoxia and chemically induced eNOS mRNA expression was completely abolished. We propose that hypoxia, by altering cellular metabolism, leads to an increase in the cellular NAD(P)H/NAD(P) ratio which favors enhanced eNOS expression by redox-sensitive AP-1 mediated transcriptional control.

Animals↗
PubMed1979

Effect of metabolic inhibitors on vasopressin-stimulated transport systems in the toad bladder.

Vasopressin increases the permeability of receptor cells to water and, in tissues such as toad bladder, to solutes such as urea. While cyclic AMP appears to play a major role in mediating the effects of vasopressin, there is evidence that activation of the water permeability system and the urea permeability system involves separate pathways. In the present study, we have shown that inhibitors of oxidative metabolism (rotenone, dinitrophenol, and methylene blue) selectively inhibit either vasopressin-stimulated water flow or vasopressin-stimulated urea transport. There was no inhibition, however, when exogenous cyclic AMP was substituted for vasopressin, and little to no inhibition when the potent analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) was employed. Rotenone had no effect on adenylate cyclase activity or cyclic AMP levels within the cell; dinitrophenol decreased adenylate cyclase activity minimally. Additional studies with vinblastine and nocodazole, inhibitors of microtubule assembly, demonstrated an inhibition of vasopressin and cyclic AMP-stimulated water flow but showed no effect on urea transport. We would conclude that water and urea transport, as examples of hormone-stimulated processes, have different links to cell metabolism, and that in addition to cyclic AMP, a non-nucleotide pathway may be involved in the action of vasopressin.

Adenylyl Cyclases↗
PubMed2001

Cell attachment modulation by radiation from a pulsed light diode (lambda = 820 nm) and various chemicals.

BACKGROUND AND OBJECTIVE: Adhesive interactions between cells and extracellular matrices play a regulative role in wound repair processes. The objective of this investigation is to study the mechanisms of light action on cellular adhesion in vitro. The adhesion of HeLa cells to a glass matrix is evaluated after irradiation with a pulsed near-infrared (IR) diode and treatment with various chemicals. STUDY DESIGN/MATERIALS AND METHODS: A semiconductor diode (820 +/- 10 nm, 10Hz, 16--120 J/m(2)) is used for irradiation of the cell suspension. In parallel experiments, various chemicals (mannitol, melatonin, ethanol, ascorbic acid, superoxide dismutase, catalase, rotenone, azide, dinitrophenol (DNP), methylene blue, and hydrogen peroxide) are added to the cell suspension before or after the irradiation procedure. The cell-glass adhesion is studied by using the adhesion assay technique (Lasers Surg. Med. 1996;18:171). RESULTS: It has been found that cell-glass adhesion increases in a dose-dependent manner after irradiation. The treatment of the cells with antioxidants (free radical scavengers), e.g., mannitol, melatonin, ethanol, and ascorbic acid, as well as with the ionophore DNP, eliminated the light effect. The respiratory chain inhibitors rotenone and azide strongly modified the light effect, depending on the dose. The oxidative agents hydrogen peroxide (in a low concentration) and methylene blue increased the cell adhesion. Superoxide dismutase did not modify the light effect. The effect of the catalase (stimulative or suppressive) was dependent on its concentration and treatment sequence. Preirradiation was found to decrease (or normalize to the control level) the suppressive effects of some chemicals. CONCLUSION: The results obtained are evidence that first, pulsed IR radiation with certain parameters modulates the cell-matrix attachment. second, free radical and redox processes are involved in the cell-matrix interaction, probably at some stage(s) of the photosignal transduction. Third, both types of the primary reactions in the respiratory chain, namely, the increase of the electron flow and production of the reactive oxygen species, cause a transient oxidative stress in the cytoplasm.

Ascorbic Acid↗
PubMed1998

Quantitative study of mitochondrial complex I in platelets of parkinsonian patients.

Activity of mitochondrial enzyme complex I (NADH-ubiquinone oxidoreductase) is reduced in the substantia nigra of patients with Parkinson's disease (PD). A less pronounced decrease in the activity of this enzyme has also been reported in platelets of PD patients. To obtain quantitative information on platelet complex I in PD, we studied platelet complex I in 16 PD patients and 16 age-matched controls by using a newly developed technique based on the binding of [3H]dihydrorotenone ([3H]DHR), an analog of the pesticide rotenone, to complex I. We also investigated the inhibitory effect of MPP+ (1-methyl-4-phenyl-pyridinium) on [3H]DHR specific binding to platelet complex I. PD patients and controls showed similar levels of [3H]DHR specific binding; preincubation of platelets with MPP+ caused the same degree of inhibition of [3H]DHR specific binding in the two groups. In PD patients, we observed a direct correlation between MPP+-induced inhibition of [3H]DHR specific binding and the daily intake of levodopa, which may be related to drug-induced changes in the transport of MPP+ into the platelet or in its binding to complex I. These findings demonstrate that the reported reduction in complex I activity in platelets of PD patients can not be accounted for by an abnormality at the level of the rotenone binding site (putatively the ND-1 gene product), although they do not exclude differences in complex I activity between PD patients and controls.

1-Methyl-4-phenylpyridinium↗
PubMed2002

The effects of phytochemical pesticides on the growth of cultured invertebrate and vertebrate cells.

A range of cultured cells of invertebrate and vertebrate origin was grown in the presence of a number of phytochemical pesticides to test the effect of the latter on cell proliferation. The main observation was that azadirachtin was a potent inhibitor of insect cell replication, with an EC50 of 1.5 x 10(10) M against Spodoptera cells and of 6.3 x 10(9) M against Aedes albopictus cells, whilst affecting mammalian cells only at high concentrations (> 10(-4) M). As expected, the other phytochemical pesticides, except for rotenone, had little effect on the growth of the cultured cells. Rotenone was highly effective in inhibiting the growth of insect cells (EC50:10(-8) M) but slightly less toxic towards mammalian cells (EC50:2 x 10(-7) M). Neem terpenoids other than azadirachtin and those very similar in structure significantly inhibited growth of the cell cultures, but to a lesser degree. The major neem seed terpenoids, nimbin and salannin, for example, inhibited insect cell growth by 23% and 15%, respectively.

Animals↗
PubMed1995

Reactive oxygen species produced by liver mitochondria of rats in sepsis.

Reactive oxygen species (ROS) can be generated in experimental shock states through several different mechanisms. We measured ROS production in metabolically active liver mitochondria from rats rendered septic by cecal ligation and puncture. By polarography, the State 4 and State 3 respiration rates of liver mitochondria isolated from septic animals were no different from control organelles. During oxidation of succinate, however, nonenzymatic hydroxylation of salicylic acid to 2,3-dihydroxybenzoic acid by mitochondria from septic rats was increased, indicating generation of hydroxyl radical (OH.). Inhibition of electron transport at Complex I with rotenone had no effect on this pattern of OH. production, but rotenone and cyanide abolished the differences in OH. formation between control and septic liver mitochondria. Measurements of H2O2 release suggested that septic mitochondria will increase rates of H2O2 production in the presence of succinate. Additional investigations revealed no difference in the release of iron between septic and control mitochondria. When referenced to respiration rate, both OH. and H2O2 production were greater in septic liver mitochondria. The reproducible effect of sepsis on generation of reactive oxygen species by liver mitochondria utilizing FAD-linked but not NAD-linked substrates suggests that enhanced mitochondrial oxidative stress in sepsis is related to alterations in the activity of Complex II of the electron transport chain.

Animals↗
PubMed1995

Dexamethasone induces resistance to the lethal consequences of electron transport inhibition in cultured hepatocytes.

Pretreatment of cultured rat hepatocytes with 1 microM dexamethasone protected against cell killing by 5 microM rotenone and 1 mM cyanide. Simultaneous treatment (no pretreatment) was ineffective, as was pretreatment with 10 microM of sex hormones or the mineralocorticoid aldosterone. Protection by dexamethasone was blocked by 10 microM of glucocorticoid receptor antagonist, RU486, and by 1 microM of the inhibitor of protein synthesis, cycloheximide. Cells pretreated with dexamethasone for 6, 12, and 18 h showed increasing degrees of protection. Pretreatment with dexamethasone had no effect on either the decline of cellular ATP or the loss of the mitochondrial membrane potential. In addition, dexamethasone did not prevent the mitochondrial permeability transition. By contrast, dexamethasone prevented the increased release of [3H]arachidonic acid from phospholipids produced by cyanide. These data describe an inductive effect of dexamethasone in protecting cultured hepatocytes against inhibition of electron transport by rotenone and cyanide. It is concluded that pretreatment with dexamethasone prevents cell killing by inhibiting a mechanism that couples the mitochondrial permeability transition to the accelerated degradation of plasma membrane phospholipids.

Adenosine Triphosphate↗
PubMed1999

Activation of Glut1 glucose transporter in response to inhibition of oxidative phosphorylation.

We have previously shown that exposure of Clone 9 cells to hypoxia, cyanide, or azide results in an acute stimulation of glucose transport that is largely mediated by "activation" of glucose transporter (Glut1) sites preexisting in the plasma membrane. However, it is not known whether inhibition of oxidative phosphorylation only at its terminal step, or at any of its steps, leads to the glucose transport response. Hence, the effect of azide (5 mM), rotenone (1 microM), rotenone (1 microM) plus thenoyltrifluoroacetone (TTFA) (5 microM), antimycin A (0.3 microM), dinitrophenol (0.25 mM), carbonyl cyanide m-chlorophenylhydrazone (CCCP) (2.5 microM), and oligomycin B (0.15 microM) on glucose transport was determined. All of the above agents elicited a similar approximately 4-fold stimulation of cytochalasin B (CB)-inhibitable 3-O-methyl glucose (3-OMG) uptake in Clone 9 cells. The stimulatory effect of azide on 3-OMG uptake was not inhibited by antioxidants 2-mercaptopropionyl glycine (1.2 mM) and 1,10-phenanthroline (40 microM), while, in contrast, the antioxidants attenuated the stimulation of glucose transport in response to 250 microM H(2)O(2) by approximately 50%. To differentiate between an increase in the number of functional Glut1 sites in the plasma membrane (in the absence of "translocation") versus an increase in the "intrinsic activity" of Glut1, the effect of azide on the energy of activation (E(a)) of glucose transport was measured. The E(a) was determined by measuring the rate of CB-inhibitable 3-OMG uptake at 24.0, 28.0, 35. 0, and 40 degrees C. The E(a) of control Clone 9 cells and of cells exposed to 10 mM azide for 2 h was 32,530 +/- 1830 and 31,220 +/- 600 J/mol, respectively (P > 0.1), while the rate of CB-inhibitable 3-OMG uptake was 9.3 +/- 0.7-fold higher in azide-treated cells. It is concluded that (i) inhibition of oxidative phosphorylation, at any of its steps, leads to a stimulation of glucose transport, and (ii) the mechanism of stimulation of glucose transport in response to azide appears to be predominately mediated by an apparent increase in the number of functional Glut1 sites in the plasma membrane (instead of an increase in their "intrinsic activity"), suggesting an "unmasking" mechanism.

Animals↗
PubMed1994

Lactate oxidation coupled to energy production in mitochondria like particles from Setaria digitata, a filarial parasite.

In the filarial parasite, Setaria digitata, the mitochondria like particles (MLP) show NAD reduction with sodium lactate. The MLP also reduces dye and ferricyanide with lactate. The ferricyanide reduction by lactate is found to be sensitive to the cytochrome o inhibitor orthohydroxy diphenyl (OHD) and complex I inhibitor rotenone, modulated by ADP (+) and ATP (-) and inhibited by pyruvate and oxaloacetate. MLP shows lactate oxidation sensitive to OHD, rotenone and sodium malonate. Thus, the lactate utilizing complex system, consisting of an NADH generating MLP bound lactate dehydrogenase and a lactate flavocytochrome reductase tightly linked to complex I and cytochrome o, produces ATP in functional association with fumarate reductase complex and other enzyme systems. Hence, this study provides new dimensions to the study of metabolism in filarial parasites.

Animals↗
PubMed1995

Heat shock-induced accumulation of 70-kDa stress protein (HSP70) can protect ATP-depleted tumor cells from necrosis.

The phenomenon of cell resistance to prolonged energy deprivation after mild thermal stress was studied in vitro. Murine P3O1 myeloma and Ehrlich ascites carcinoma cells were treated with rotenone (an inhibitor of respiration) in glucose-free medium to block ATP generation. ATP rapidly decreased in these cells to 3-6% of the initial level that resulted in powerful aggregation of cytoskeletal proteins, blebbing, and necrotic death of 60-70% cells within 2 h. Prior heat shock (43 degrees C for 10 min) with a subsequent 3-h recovery in a rich medium considerably suppressed the rotenone-induced actin aggregation and rate of necrosis in the energy-deprived cells without effecting the ATP drop in them. Using [14C]leucine labeling, gel electrophoresis, and fluorography, stimulation of the heat-shock protein (HSP) synthesis and total suppression of any other translation were revealed in the cells during recovery after the heat pretreatment. Significantly elevated levels of HSP70 but not HSP90 and HSP27 were found by means of immunoblotting in both cell cultures rendered resistant to necrosis under ATP-depleting conditions. Inhibition of the thermo-induced HSP synthesis by cycloheximide fully prevented development of the tolerance to energy deprivation. A novel function of HSP70 consisting of protection of ATP-deprived cells from "lethal" aggregation of cytoskeletal proteins is suggested.

Adenosine Triphosphate↗
PubMed1994

Induction of heat-shock protein synthesis and thermotolerance in EL-4 ascites tumor cells by transient ATP depletion after ischemic stress.

The effect of a short-term energy deprivation (ischemia) on thermoresistance and heat-shock protein (HSP) synthesis in murine ascites EL-4 thymoma cells was studied in vitro. The incubation of the cells in glucose-free medium with rotenone (respiratory inhibitor) for 10 min caused rapid ATP depletion (to 9% of the initial level). After recovery, the synthesis of HSP70 and HSP90 was stimulated in the cells and they became greatly more resistant to hyperthermia than the control cells. The simultaneous rotenone and thermal treatment significantly decreased cell viability. The transition of HSP70 to Triton X-100-insoluble cell fraction was found in the ATP-depleted cells as well as in the heat-shocked cells, and 1 mM ATP fully reversed such insolubilization when it was added in Triton extraction buffer. The data obtained reveal that transient ATP depletion per se is sufficient to result in the HSP70 insolubilization, thus being conducive to induction of HSP synthesis and thermotolerance in the cells which recovered after energy deprivation. A novel mechanism of protein aggregation in ATP-deficient cells and a possible role of transient ischemia in development of tumor thermotolerance in vivo are discussed.

2,4-Dinitrophenol↗
PubMed1997

Role of oxidative metabolism on endothelium-dependent vascular relaxation of isolated vessels.

The obligatory role of endothelium in mediating vasodilator response to numerous humoral agents has been definitely accepted. However, the chemical identity of endothelium-derived relaxing factor(s) (EDRF) and the mechanisms underlying its synthesis and release remain unclear. Much evidence suggests a compartmentalization of ATP into cells, such that ATP derived from glycolysis or from oxidative metabolism is used for different cellular functions. To investigate which energy source (i.e. oxidative v glycolytic metabolism) is preferentially used for the biosynthesis and/or release of EDRF, rings of rabbit thoracic aorta were studied in organ chambers. After preconstriction with PGF2 alpha, inhibition of glycolysis with either iodoacetate (300 microM) (n = 6) or 2-deoxyglucose (20 mM) (n = 6) did not affect concentration-response curve to the endothelium-dependent agent acetylcholine. In contrast, inhibition of oxidative metabolism with either 1 mM amytal or 5 microM rotenone markedly impaired relaxation to acetylcholine. In fact, maximal relaxation was 75 +/- 5% in control rings (n = 6), and 42 +/- 7% (P < 0.01) in amytal-treated rings (n = 6), whereas rotenone converted acetylcholine relaxation into constriction (n = 6; P < 0.001). The effect of amytal on endothelium-dependent relaxation was reversible, suggesting that endothelial cells were not damaged by the inhibitor. Amytal also markedly reduced endothelium-mediated relaxation to ADP (37 +/- 6%; P < 0.05; n = 5), as well as to the calcium ionophore A23187. Neither mitochondrial inhibitor affected relaxation to nitroglycerin, an endothelium-independent agent. Finally, amytal did not affect relaxation to S-nitrosocysteine (a recently proposed EDRF) (n = 5), suggesting that the effects on acetylcholine and ADP responses were not due to non-specific interferences with EDRF once released from endothelial cells. In conclusion, our data demonstrate that the active process of biosynthesis and/or release of EDRF requires energy derived mainly from mitochondrial oxidative metabolism.

Acetylcholine↗
PubMed2001

Modulation of the extracellular divalent cation-inhibited non-selective conductance in cardiac cells by metabolic inhibition and by oxidants.

The effect of metabolic inhibition and oxidative stress on the monovalent cation-permeable, extracellular divalent cation-inhibited non-selective conductance was investigated in ventricular myocytes at 22 degrees C. Under whole-cell voltage-clamp, with L-type Ca2+ channels blocked by nifedipine, and K+ currents blocked by Cs+ substitution for K+, removal of Ca2+(o)and Mg2+(o) induced a non-selective current (I(NS-(Ca)o)) in mouse, rabbit and rat cells. Removal of glucose increased I(NS-(Ca)o)in the absence of Ca2+(o) and Mg2+(o), but failed to induce this current in the presence of the divalent cations. Further inhibition of glycolysis by 2-deoxyglucose (DOG; 10 mM, in zero glucose) or of mitochondrial function by rotenone (10 microM) or NaCN (5 mM) also failed to induce I(NS-(Ca)o)in the presence of Ca2+(o) and Mg2+(o). Even when given together, DOG and rotenone did not induce I(NS-(Ca)o) in the presence of divalent cations. Preactivated I(NS-(Ca)o) was increased by the oxidants thimerosal (50 microM), diamide (500 microM) and pCMPS (50 microM). However, none of these drugs nor NEM (1 mM) did elicit I(NS-(Ca)o)in the presence of Ca2+(o) and Mg2+(o). Exposure of rat myocytes to Ag+ induced a current resembling I(NS-(Ca)o) (reversing at -5 mV; blocked by 100 microM Gd3+) even in the presence of divalent cations. The data indicate that metabolic inhibition only regulates activated I(NS-(Ca)o)but does not induce the opening of closed channels, and that small oxidants like Ag+ may induce I(NS-(Ca)o) activation by accessing at sites unavailable for larger molecules.

Action Potentials↗
PubMed2003

Animal models of Parkinson's disease in rodents induced by toxins: an update.

The development of animal models of Parkinson's disease is of great importance in order to test substitutive or neuroprotective strategies for Parkinson's disease. Such models should reproduce the main characteristics of the disease, such as a selective lesion of dopaminergic neurons that evolves over time and the presence of neuronal inclusions known as Lewy bodies. Optimally, such models should also reproduce the lesion of non-dopaminergic neurons observed in a great majority of patients with Parkinson's disease. From a behavioral point of view, a parkinsonian syndrome should be observed, ideally with akinesia, rigidity and rest tremor. These symptoms should be alleviated by dopamine replacement therapy, which may in turn lead to side effects such as dyskinesia. In this review, we analyze the main characteristics of experimental models of Parkinson's disease induced by neurotoxic compounds such as 6-hydroxydopamine, MPTP and rotenone. We show that, whereas MPTP and 6-hydroxydopamine induce a selective loss of catecholaminergic neurons that in most cases evolves over a short period of time, rotenone infusion by osmotic pumps can induce a chronically progressive degeneration of dopaminergic neurons and also of non-dopaminergic neurons in both the basal ganglia and the brainstem.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

On the mechanism of inhibition of NADH oxidase by ubiquinone-3.

The combined effects of rotenone and ubiquinone-3 on the kinetics of NADH dehydrogenase and NADH oxidase have been investigated. The two inhibitors do not show additivity; on the other hand, ubiquinone-3, when preincubated with the enzyme, partially removes rotenone sensitivity. The inhibition of NADH oxidase by ubiquinone-3 is the result of at least two combined effects: the competition of the less active ubiquinone-3 with endogenous ubiquinone-10 in the acceptor site of the dehydrogenase, and a nonspecific action on the structure of complex I. The latter effect is perhaps mediated by a physical change of the phospholipid bilayer similar to that observed with agents such as butanol, perturbing lipid-protein interactions in the membrane.

Animals↗