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PubMed2006

Geographic isolates of atypical Parkinsonism and tauopathy in the tropics: possible synergy of neurotoxins.

Over the last 60 years an abnormally high prevalence of atypical Parkinsonism has been reported in 5 different geographic isolates. It was first described on Guam, later in New Guinea and in the Kii peninsula, on Guadeloupe, and in New Caledonia. We investigated the phenotype of atypical Parkinsonism in three of these foci and observed several similarities with dementia in most and amyotrophic lateral sclerosis in some. This disappearance of this disease in two places--Guam and New Guinea--suggested an environmental origin which has not been clarified before the disease ended. The exposure to annonaceae acetogenins and/or rotenone has been documented in four of these places, and experimental studies in animals demonstrated annonaceae acetogenins neurotoxicity, which is similar to rotenone neurotoxicity. Simultaneous exposure to acetogenins and rotenone could produce a synergistic toxicity on neurons.

Acetogenins↗
PubMed1994

Increased production of reactive oxygen species by rat liver mitochondria after chronic ethanol treatment.

Rat liver microsomes and, to a lesser extent, nuclei were previously shown to produce reactive oxygen species at elevated rates after chronic ethanol treatment. The ability of intact rat liver mitochondria to interact with iron and either NADH or NADPH, and the effects of ethanol treatment, on production of reactive oxygen intermediates was determined. In the presence of ferric-ATP, NADH or NADPH catalyzed mitochondrial lipid peroxidation. Rates were elevated two- to threefold with mitochondria from ethanol-fed rats with both reductants. Mitochondrial lipid peroxidation was insensitive to superoxide dismutase, catalase, or hydroxyl radical scavengers but was sensitive to GSH and anti-oxidants such as trolox. Mitochondrial generation of hydroxyl radical-like species (assayed by oxidation of chemical scavengers) was increased after chronic ethanol treatment, as was H2O2 production. Modifiers of mitochondrial metabolism such as rotenone, cyanide, or an uncoupling agent, had no effect on mitochondrial production of reactive oxygen intermediates. The membrane-impermeable thiol reagent, p-chloromercuribenzoate, was complete inhibitory with both mitochondrial preparations. The activity of the rotenone-insensitive NADH-cytochrome c reductase, an enzyme of the outer mitochondrial membrane, was increased 40 to 60% by the ethanol treatment. These results suggest that NADH acting via the outer membrane NADH reductase can catalyze an iron-dependent production of oxygen radicals by rat liver mitochondria. The outer mitochondrial membrane fraction, prepared by digitonin fractionation, displayed increased rotenone-insensitive NADH-cytochrome c reductase activity after ethanol treatment and was more reactive in catalyzing scission of pBR322 DNA from the supercoiled form to the open circular forms. Rates of oxygen radical production by mitochondria and the extent of increase produced by chronic ethanol treatment are similar to those previously found with microsomes when NADH is the cofactor. Oxidation of ethanol by alcohol dehydrogenase generates NADH, and NADH-dependent production of reactive oxygen species by various organelles is increased after chronic ethanol treatment. These acute metabolic interactions coupled to induction by chronic ethanol treatment may play an important role in the development of a state of oxidative stress in the liver by ethanol.

Animals↗
PubMed1998

Substrate and site specificity of hydrogen peroxide generation in mouse mitochondria.

The objective of this study was to elucidate the mechanisms of mitochondrial H2O2 generation in mouse organs by determining the nature of their differences in substrate utilization, inhibitor sensitivity, and the site specificity affecting H2O2 production. Mitochondria were isolated from heart, brain, and kidney and the rate of H2O2 generation was measured using the FADH-linked substrates succinate and alpha-glycerophosphate as well as the NADH-linked substrates pyruvate/malate, beta-hydroxybutyrate, and glutamate. Respiratory inhibitors, antimycin and rotenone, were added singly and sequentially to each substrate-supported H2O2 generation reaction mixture to determine the mitochondrial site(s) of generation and the optimal condition(s) for maximal rates of generation. Succinate supported the highest rate of mitochondrial H2O2 generation. Moreover, it was the preferred substrate for the heart mitochondria. alpha-Glycerophosphate is a poor substrate for H2O2 generation in heart mitochondria. Inhibitor studies showed that heart mitochondria were the most sensitive and responsive to antimycin, while brain was the most sensitive to rotenone. A surprising finding was that NADH-linked substrate-supported H2O2 generation in kidney mitochondria was not responsive to rotenone. The contribution from each of the three sites (ubiquinone, NADH dehydrogenase, and alpha-glycerophosphate dehydrogenase) of mitochondrial H2O2 generation to the total was both substrate and organ dependent. Results indicate that assay conditions must be considered before comparisons of sites and rates of mitochondrial H2O2 generation among different organs can be made.

Animals↗
PubMed1995

Metabolic inhibition and low internal ATP activate K-ATP channels in rat dopaminergic substantia nigra neurones.

The patch-clamp technique was used to study whole-cell currents of acutely dissociated rat substantia nigra (SN) neurones. In perforated-patch current-clamp recordings, inhibition of mitochondrial metabolism by rotenone (5 microM) produced a hyperpolarisation and inhibited electrical activity. These effects were reversed by the sulphonylureas tolbutamide (0.5 mM) or glibenclamide (0.5 microM). Under voltage-clamp conditions, rotenone induced a time- and voltage-independent K+ current which was selectively blocked by sulphonylureas. The glibenclamide-sensitive current reversed at -81.7 +/- 2.7 mV (n = 5) and showed marked inward rectification. Intracellular dialysis with 0.3 mM adenosine 5'-triphosphate (ATP), but not 2 mM or 5 mM ATP, in standard whole-cell recordings also resulted in activation of a sulphonylurea-sensitive K+ current with similar properties (reversal potential, -81.9 +/- 2.5 mV, n = 5). The close similarity in the properties of the ATP-sensitive K+ current observed in whole-cell recordings and the K+ current activated by metabolic inhibition in perforated-patch recordings suggest that they both result from activation of the same type of ATP-sensitive K+ channel. Sulphonylureas had no effect on electrical activity or membrane currents in the absence of rotenone in perforated-patch recordings, or in cells dialysed with 5 mM ATP, indicating that in SN neurones these drugs are selective for the ATP-sensitive K+ current.

Action Potentials↗
PubMed1993

NAD(P)H-ubiquinone oxidoreductases in plant mitochondria.

Plant (and fungal) mitochondria contain multiple NAD(P)H dehydrogenases in the inner membrane all of which are connected to the respiratory chain via ubiquinone. On the outer surface, facing the intermembrane space and the cytoplasm, NADH and NADPH are oxidized by what is probably a single low-molecular-weight, nonproton-pumping, unspecific rotenone-insensitive NAD(P)H dehydrogenase. Exogenous NADH oxidation is completely dependent on the presence of free Ca2+ with a K0.5 of about 1 microM. On the inner surface facing the matrix there are two dehydrogenases: (1) the proton-pumping rotenone-sensitive multisubunit Complex I with properties similar to those of Complex I in mammalian and fungal mitochondria. (2) a rotenone-insensitive NAD(P)H dehydrogenase with equal activity with NADH and NADPH and no proton-pumping activity. The NADPH-oxidizing activity of this enzyme is completely dependent on Ca2+ with a K0.5 of 3 microM. The enzyme consists of a single subunit of 26 kDa and has a native size of 76 kDa, which means that it may form a trimer.

Calcium↗
PubMed2003

Mitochondrial complex I inhibition produces selective damage to hippocampal subfield CA1 in organotypic slice cultures.

The effects of mitochondrial respiratory chain inhibitors and the excitotoxin N-methyl-D-aspartate (NMDA) on cell death in hippocampal subfields CA1 and CA3 were examined in hippocampal organotypic slice cultures. Slice cultures, 2-3 week old, were exposed for 1 h to either the Complex I inhibitors, rotenone or 1-methyl-4-phenylpyridium (MPP+), the Complex II inhibitor 3-nitropropionic acid (3-NP), or the excitotoxin NMDA. Cell death was examined 24 and 48 h following treatment, by measuring propidium iodide (PI) fluorescence. Treatment with 1 micro M Rotenone caused greater cell death in hippocampal subfield CA1 than CA3. Exposure of hippocampal slice cultures to 10 micro M rotenone, to MPP+ or to NMDA resulted in damage to both CA1 and CA3 subfields. 3-NP produced little damage in either subfield. The data suggest that mitochondrial Complex I inhibition can produce selective cell damage in hippocampus and in this regard is similar to that observed following hypoxia/ischemia.

1-Methyl-4-phenylpyridinium↗
PubMed2006

Inhibition of specific electron transport pathways leads to oxidative stress and decreased Candida albicans proliferation.

Candida parapsilosis mitochondria contain three respiratory chains: the classical respiratory chain (CRC), a secondary parallel chain (PAR) and an "alternative" oxidative pathway (AOX). We report here the existence of similar pathways in C. albicans. To observe the capacity of each pathway to sustain yeast growth, C. albicans cells were cultured in the presence of inhibitors of these pathways. Antimycin A and KCN totally abrogated yeast growth, while rotenone did not prevent proliferation. Furthermore, rotenone promoted only partial respiratory inhibition. Lower concentrations of KCN that promote partial inhibition of respiration did not inhibit yeast growth, while partial inhibition of respiration with antimycin A did. Similarly, AOX inhibitor BHAM decreased O(2) consumption slightly but completely stunted cell growth. Reactive oxygen species production and oxidized glutathione levels were enhanced in cells treated with antimycin A or BHAM, but not rotenone or KCN. These findings suggest that oxidative stress prevents C. albicans growth.

Antimycin A↗
PubMed1991

Acetoacetate and malate effects on succinate and energy production by O2-deprived liver mitochondria supplied with 2-oxoglutarate.

Acetoacetate provision to Ca(2+)-loaded liver mitochondria (less than 40 micrograms-ion Ca2+ x g protein-1), supplied with 2 mM Pi and 2-oxoglutarate as substrate, was found to prevent the mitochondrial deenergization and Ca2+ release induced by either rotenone during aerobic incubations or by O2 deprivation. Under the latter condition, the acetoacetate-promoted Ca2+ retention was entirely supported by ATP produced anaerobically at the succinylthiokinase step of the tricarboxylic acid cycle and was therefore abolished by addition of oligomycin. Surprisingly, oligomycin was also found to trigger Ca2+ release in rotenone-inhibited mitochondria in the presence of acetoacetate under aerobic conditions, unless a Pi acceptor was supplied. ADP deprivation at the succinylthiokinase step is likely to be involved. As estimated from rates of succinate production in O2-deprived mitochondria or from respiration rates in rotenone-inhibited mitochondria at supramaximal acetoacetate concentrations (above 1.2 mM) in the presence of a Pi acceptor, ATP production by substrate-level phosphorylation was close to 10 mumol.g protein-1.min-1 and appeared to be limited by rates of ketone body transport across the inner membrane. The rates of anaerobic energy production obtained by coupling 2-oxoglutarate oxidation to acetoacetate reduction were markedly higher than those obtained by reactions involved in the anaerobic metabolism of amino acids, simulated by providing 2-oxoglutarate and malate to mitochondria. Energy production was limited by rates of oxidant equivalent generation under the latter condition. Our data suggest that acetoacetate could effectively contribute to sustaining anaerobic energy production from endogenous substrates in liver tissue.

Acetoacetates↗
PubMed1988

Uncoupler-inhibitor titrations of ATP-driven reverse electron transfer in isolated rat-liver mitochondria.

Uncoupler-inhibitor titrations of ATP-driven reverse electron transfer across the first site of the respiratory chain were performed in isolated rat-liver mitochondria, and the experimental results were compared with the predictions of a simple delocalized chemiosmotic mechanism. The rates of ATP hydrolysis (Jp) and reverse electron transfer (-J0) were measured at different uncoupler (S-13) concentrations, either in the absence or in the presence of rotenone. When the rates -J0 and Jp measured at different uncoupler concentrations were expressed as percentages of the activity at zero uncoupler concentration, it was found that the efficiency of S-13 to uncouple the reverse electron transfer and to stimulate ATP hydrolysis was not significantly changed upon partial inhibition with rotenone. These results are in contrast with data from a study of uncoupler-inhibitor titrations in submitochondrial particles published previously, in which a higher effectiveness of several uncouplers to inhibit ATP-driven reverse electron transfer was observed in the presence of rotenone.

Acetoacetates↗
PubMed1992

Effects of calcium antagonists on glycolysis of rat brain synaptosomes.

The effects of calcium antagonists nimodipine, nicardipine and flunarizine on lactate production and specific activities of some enzymes regulating glycolytic flux have been evaluated in synaptosomes isolated from rat whole brain and submitted to in vitro chemical hypoxia induced by rotenone, an inhibitor of mitochondrial respiration. The following enzymes have been tested; hexokinase (ATP: D-hexose-6-phosphotransferase, EC2.7.1.1), phosphofructokinase (ATP: D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) and pyruvate kinase (ATP: pyruvate 2-O-phosphotransferase, EC 2.7.1.40). The results show that rotenone increases by about eight times the production of lactate; nicardipine and nimodipine, starting from a concentration of 10(-4) M, were able to counteract the rotenone-induced stimulation of glycolysis, but flunarizine was without effect. The dihydropyridines but not flunarizine decreased the maximum activity of phosphofructokinase. This effect was already detectable at a concentration of 10(-5) M. Neither hexokinase nor pyruvate kinase were affected by any of the drugs studied.

Animals↗
PubMed1994

Effect of methyl methacrylate on mitochondrial function and structure.

1. Treatment of isolated rat liver mitochondria with methyl methacrylate (MM) produced membrane disruption as evidenced by the release of citrate synthase, and changes in the ultrastructure of mitochondria. 2. At concentration 0.1%, MM uncoupled oxidative phosphorylation as evidenced by stimulation of state 4 respiration supported either by pyruvate plus malate or succinate (+rotenone) and ATP-ase activity in intact mitochondria. 3. At concentration 1% MM stimulated ATP-ase activity in intact mitochondria and succinate (+ rotenone) oxidation at state 4 and was without effect on this substrate oxidation at state 3. 4. MM inhibited pyruvate plus malate oxidation either at state 3 or in the presence of uncoupling agents. 5. MM inhibited the NADH oxidase of electron transport particles at a concentration which failed to inhibit either succinic oxidase or the NADH-ferricyanide reductase activity. 6. The data presented suggest that in the isolated mitochondria MM inhibits NADH oxidation in the vicinity of the rotenone sensitive site of complex I. 7. The general conclusion is that MM may block an electron transport and to uncouple oxidative phosphorylation in rat liver mitochondria. The overall in vitro effect would be to prevent ATP synthesis which could result in cell death under in vivo conditions.

Adenosine Triphosphatases↗
PubMed1991

The response of intact Strongyloides ratti infective (L3) larvae to substrates and inhibitors of respiratory electron transport.

Live, intact third-stage larvae (L3s) of Strongyloides ratti in the absence of exogenous substrates consumed oxygen at a rate (E-QO2) of 181.8 +/- 12.4 ng atoms min-1 mg dry weight-1 at 35 degrees C. Respiratory electron transport (RET) Complex I inhibitor rotenone (2 microM) produced 33 +/- 6.5% inhibition of the E-QO2. Unusually the rotenone-induced inhibition was not relieved by 5 mM-succinate. The E-QO2 of intact L3s was refractory to RET Complex III inhibitor antimycin A at 2 microM; 4 microM-antimycin inhibited less than or equal to 10% of the E-QO2. The electron donor couple ascorbate/TMPD augmented the E-QO2 in the presence of rotenone (2 microM) and antimycin A (4 microM) by 110%. Azide (1 mM) stimulated the antimycin A refractory QO2 by 36.6 +/- 7.2% which was only partially inhibited by 1.0 mM-KCN (IC50 = 0.8 mM). The data suggest the presence of classical (CPW) and alternate (APW) electron transport pathways in S. ratti L3s.

Animals↗
PubMed1993

Hypotonic fragility of outer membrane and activation of external pathway of NADH oxidation in rat liver mitochondria are increased with age.

Great importance is attached to structural and functional deterioration of mitochondria as a reason for ageing of an organism; the attention of many scientists has been concentrated on such questions as age changes in the system of oxidative phosphorylation, damage of mitochondrial DNA by free radicals generated in the respiratory chain and inclusion of some fragments of mitochondrial DNA into the nuclear genome. Mitochondrial high amplitude swelling in a cell under some extreme conditions can possibly play a very important role in mechanisms of deterioration of energy transformation function, in activation of lipid peroxidation and mitochondrial DNA damage as a result of outer membrane disruption and release of enzymes from the intermembrane space (e.g. superoxide dismutase amd adenylate kinase). In this work the age changes of the hypotonic fragility of the outer membrane of rat liver mitochondria and the activation of the external, rotenone-insensitive pathway of NADH oxidation have been examined. It is shown that the obligatory condition for activation of rotenone-insensitive NADH oxidation is a break in the outer membrane and that the rate of NADH oxidation substantially increases in the presence of physiological concentrations of Mg2+ which cause a multiple increase in the affinity of the inner membrane to cytochrome c. Research on the rate of rotenone-insensitive NADH oxidation with respect to the osmotic pressure, the ionic strength of the medium, the presence of Mg2+ ions and cytochrome c in the medium has demonstrated a considerable increase in the hypotonic fragility of the outer membrane of liver mitochondria with age in male rats. In female rats the age changes were insignificant. It is supposed that the damage to the outer membrane of mitochondria in cells can serve as one of the possible explanations of both decrease in the reliability of an aged organism under extreme conditions and sex differences of life-span.

Aging↗
PubMed1992

Uptake of organic anions by isolated rat hepatocytes. A classification in terms of ATP-dependency.

Uptake of organic anions into isolated rat hepatocytes was studied to examine their ATP dependency. In the presence of rotenone (0.2 microM), the initial velocity of the uptake (Vo) of dibromosulfophthalein (DBSP; 10 microM), 1-anilino-8-naphthalenesulfonate (ANS; 10 microM) and benzylpenicillin (PCG; 0.02 microM) was reduced to 60-70% of the control value, while that of bromosulfophthalein (BSP; 10 microM), rose bengal (RB; 10 microM) and bromophenol blue (BPB; 10 microM) was not affected. Furthermore, we examined the inhibitory effect of rotenone on the uptake at equilibrium of non-metabolizable ligands (DBSP, BPB and RB). The uptake of these ligands reached equilibrium at 30 min with a cel-to-medium concentration ratio (C/M ratio) of 75, 37 and 126, respectively. The C/M ratio at equilibrium of DBSP was reduced by rotenone to approx. 60% of the control value, while that of BPB and RB was not reduced. Other metabolic inhibitors such as sodium azide (10 mM) and carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP; 10 microM) also reduced the Vo of DBSP and PCG, while the uptake of BSP and RB was not reduced by these inhibitors. These results indicate that organic anions can be classified into two groups according to whether they are taken up by hepatocytes in an ATP-dependent manner, i.e., via active transport or in an ATP-independent manner, i.e., via facilitated diffusion. DBSP, PCG and ANS belong to the former group, whereas BSP, BPB and RB belong to the latter.

Adenosine Triphosphate↗
PubMed1993

Alkoxyl and methyl radical formation during cleavage of tert-butyl hydroperoxide by a mitochondrial membrane-bound, redox active copper pool: an EPR study.

The cleavage of tert-butyl hydroperoxide by submitochondrial particles yielded two distinctive radicals, alkoxyl and methyl radicals, detected by the electron paramagnetic resonance technique in conjunction with the spin trap 5,5'-dimethyl-1-pyrrolyne-N-oxide. Free radical formation was partly sensitive to bathocuproine disulfonate and was augmented upon supplementation of the mitochondrial membranes with copper, thus suggesting that a redox active copper pool in mitochondrial membranes participated actively in the cleavage of the O-O bond of tert-butyl hydroperoxide. This view was experimentally substantiated by the following: first, observation of the maximal EPR signal intensity required the presence of exogenous electron donors, such as succinate or reduced nicotinamide adenine dinucleotide (NADH). Second, copper reduction was accomplished partly by a superoxide radical-dependent mechanism as indicated by the sensitivity of the electron paramagnetic resonance (EPR) signal to superoxide dismutase. Third, the enhancing effect of the respiratory chain inhibitors, antimycin A and rotenone, on free radical yield assessed in the presence of superoxide dismutase pointed to the occurrence of two potential loci in the respiratory chain involved in direct electron transfer to membrane-bound copper: one located between NADH and the rotenone-sensitive site and another, quantitatively less important, between the rotenone- and antimycin-sensitive sites. These results support the notion that a redox pool of copper tightly bound to the mitochondrial membrane contributes significantly to the reductive cleavage of organic peroxides associated with free radical production.

Animals↗
PubMed2004

Cd2+ versus Ca2+-produced mitochondrial membrane permeabilization: a proposed direct participation of respiratory complexes I and III.

A comparison of Cd2+ and Ca2+ effects on in vitro rat liver mitochondria function and a further study of their interaction were conducted. Similarity and distinction in action of rotenone, oligomycin, N-ethylmaleimide, dithiothreitol, catalase, dibucaine, ruthenium red, cyclosporin A (CsA), and ADP on Cd2+ and/or Ca2+-induced mitochondrial dysfunction were revealed. We found that rotenone exerted a strong protective action both against Ca2+ and Cd2+-produced mitochondrial membrane permeabilization (MMP). In contrast to Ca2+, catalase and dibucaine did not influence on main Cd2+ effects. In NH4NO3 medium N-ethylmaleimide (NEM) at low concentrations increased markedly Cd2+-produced swelling of non-energized mitochondria, whereas it exhibited a partial reversal effect following energization. In sucrose medium low [NEM] did not change Cd2+-produced mitochondrial swelling. High [NEM] promoted synergistic increase of the Cd2+-produced swelling in NH4NO3 medium; all above effects were reversed (and prevented) by dithiothreitol, DTT. We shown also that when exogenous Ca2+ and Pi were simultaneously present in NH4NO3 medium, DTT reversed only partially Cd2+-produced swelling of succinate plus rotenone-energized mitochondria, while DTT recovery action was complete when either Ca2+ or Pi were separately administered to the Cd2+-treated mitochondria. Besides, DTT added following a low Cd2+ pulse in KCl medium containing exogenous Ca2+ induced a substantial enhancing of sustained Cd2+ stimulation of mitochondrial basal respiration and the stimulation was CsA-sensitive, while the activation promoted by low [Cd2+] alone was totally eliminated by DTT supplement. We observed the similar respiratory activation earlier when high concentrations of Cd2+ in the absence of added Ca2+ were used but it was completely CsA-insensitive. A possible involvement of respiratory chain components, namely complex I (P-site) and complex III (S-site) in Cd2+ and/or Ca2+-produced MMP was discussed.

Adenosine Diphosphate↗
PubMed2005

Mode of mitochondrial Ca2+ clearance and its influence on secretory responses in stimulated chromaffin cells.

To study the role of mitochondrial Ca(2+) clearance in stimulated cells, changes in free Ca(2+) concentration in the cytosol, [Ca(2+)](c) and that in mitochondria, [Ca(2+)](m) along with secretory responses were observed using chromaffin cells co-loaded with Fura-2 and Rhod-2 in the perfused rat adrenal medulla. When the cells were stimulated with 40 mM K(+) in the perfusate, the duration of [Ca(2+)](m) response markedly increased with prolongation of the stimulation period, exhibiting a mean half-decay time of 21 min with 30s stimulation, whereas its amplitude was not altered with stimulations of 10-30s. A computer simulation analysis showed that such a mode of [Ca(2+)](m) response can be produced if excess Ca(2+) taken up by mitochondria precipitates as calcium phosphate (Pi) salt. In the presence of 5 microM rotenone plus 10 microM oligomycin, a decrease in the duration of [Ca(2+)](m) response and a slight but significant increase (24%) in the secretory response to 30s stimulation with 40 mM K(+) were observed. Simulation analyses suggested that this effect of rotenone may be due to reduction in mitochondrial Ca(2+) uptake induced by rotenone-elicited partial depolarization of the mitochondrial membrane potential. In chromaffin cells transsynaptically stimulated through the splanchnic nerve, the intensity of NAD(P)H autofluorescence changed with time courses similar to those of [Ca(2+)](m) responses. The temporal profiles of those two responses were prolonged in a similar manner by application of an inhibitor of mitochondrial Na(+)/Ca(2+) exchanger, CGP37157. Thus, due to the unique Ca(2+) buffering mechanism, [Ca(2+)](m) responses associated with massive mitochondrial Ca(2+) uptake may occur within a limited concentration range in which Ca(2+)-sensitive dehydrogenases are activated to control the mitochondrial redox state in stimulated chromaffin cells.

Animals↗
PubMed2006

Cytoprotection by lithium and valproate varies between cell types and cellular stresses.

Despite much evidence that lithium and valproate, two commonly used mood stabilizers, exhibit neuroprotective properties against an array of insults, the pharmacological relevance of such effects is not clear because most of these studies examined the acute effect of these drugs in supratherapeutic doses against insults which were of limited disease relevance to bipolar disorder. In the present study, we investigated whether lithium and valproate, at clinically relevant doses, protects human neuroblastoma (SH-SY5Y) and glioma (SVG and U87) cells against oxidative stress and endoplasmic reticulum stress in a time-dependent manner. Pretreatment of SH-SY5Y cells for 7 days, but not 1 day, with 1 mM of lithium or 0.6 mM of valproate significantly reduced rotenone and H2O2-induced cytotoxicity, cytochrome c release and caspase-3 activation, and increased Bcl-2 levels. Conversely, neither acute nor chronic treatment of SH-SY5Y cells with lithium or valproate elicited cytoprotective responses against thapsigargin-evoked cell death and caspase-3 activation. Moreover, inhibitors of glycogen synthase kinase-3 (GSK-3), kenpaullone and SB216763, abrogated rotenone-induced, but not H2O2-induced, cytotoxicity. Thus the cytoprotective effects of lithium and valproate against H2O2-induced cell death is likely independent of GSK-3 inhibition. On the other hand, chronic lithium or valproate treatment did not ameliorate cytotoxicity induced by rotenone, H2O2, and thapsigargin in SVG astroglial and U87 MG glioma cell lines. Our results suggest that lithium and valproate may decrease vulnerability of human neural, but not glial, cells to cellular injury evoked by oxidative stress possibly arising from putative mitochondrial disturbances implicated in bipolar disorder.

Antimanic Agents↗