Protein Information

Name lactate dehydrogenase (protein family or complex)
Synonyms LDH; lactate dehydrogenase; lactate dehydrogenases

Compound Information

Name rotenone
CAS

Reference List

PubMed Abstract RScore(About this table)
20026743 Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K, Dorn C, Hellerbrand C, Kastenberger M, Kunz-Schughart LA, Oefner PJ, Andreesen R, Gottfried E, Kreutz MP: Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol. 2010 Feb 1;184(3):1200-9. Epub 2009 Dec 21.

Blocking of glycolysis by 2-deoxyglucose strongly inhibited TNF secretion, whereas suppression of oxidative phosphorylation by rotenone had little effect.
Blocking synthesis of tumor-derived lactate by oxamic acid, an inhibitor of lactate dehydrogenase, reversed the suppression of TNF secretion in this coculture model.
1(0,0,0,1) Details
16424801 Lecour S, Van der Merwe E, Opie LH, Sack MN: Ceramide attenuates hypoxic cell death via reactive oxygen species signaling. J Cardiovasc Pharmacol. 2006 Jan;47(1):158-63.

Pretreatment with ceramide reduced lactate dehydrogenase release at the end of the simulated ischemia but this cytoprotective effect was lost in the presence of MPG.
Incubation of ceramide with cyclooxygenase-2 inhibitor, NS 398 (10 microM), or with a mitochondrial respiratory chain inhibitor, rotenone (10 microM) reduced the cytoprotective effect of ceramide in parallel with a partial diminution in ROS generation.
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7428947 Berry MN, Grivell AR, Wallace PG: Energy-dependent regulation of the steady-state concentrations of the components of the lactate dehydrogenase reaction in liver. FEBS Lett. 1980 Oct 6;119(2):317-22.

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17643412 Choi JH, Kim DH, Yun IJ, Chang JH, Chun BG, Choi SH: Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes. Eur J Pharmacol. 2007 Oct 1;571(2-3):106-15. Epub 2007 Jul 4.

H2O2-induced oxidative cytotoxicity was measured grossly by monitoring lactate dehydrogenase (LDH) release, and was found to be associated with lysosomal acridine orange relocation, lysosomal cathepsin D release into cytosol, and reduced mitochondrial potentials.
Zaprinast was found to inhibit sphingosine-induced lysosomal acridine orange relocation and the induced decrease in mitochondrial potential, but zaprinast had no effect on rotenone-induced mitochondrial collapse, which was not associated with lysosomal destabilization.
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16573651 Casarejos MJ, Menendez J, Solano RM, Rodriguez-Navarro JA, Garcia de Yebenes J, Mena MA: Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline. J Neurochem. 2006 May;97(4):934-46. Epub 2006 Mar 29.

These compounds were inactive in ROT-naive cultures but PD98059 slightly increased cellular necrosis, as measured by lactate dehydrogenase levels, caused by ROT, without changing mitochondrial activity.
1(0,0,0,1) Details
6530010 Szczesna-Kaczmarek A, Litwinska D, Popinigis J: Oxidation of NADH via an "external" pathway in skeletal-muscle mitochondria and its possible role in the repayment of lactacid oxygen debt. Int J Biochem. 1984;16(12):1231-5.

Mitochondria isolated from skeletal muscle of rat catalyse oxidation of the external NADH (in the presence of rotenone, antimycin A and cytochrome c) at a rate of 15 natoms O2/min/mg protein by a pathway sensitive to mersalyl.
In a medium supplemented with commercial lactate dehydrogenase, or when mitochondria were incubated in the presence of a cytoplasm, the NADH oxidation could be arrested by pyruvate.
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10874983 Lofrumento DD, Panaro MA, Mitolo V: Modulation between aerobic and anaerobic metabolism in the mutant cell line CdtR-Q. Boll Soc Ital Biol Sper. 1998 Jul-Aug;74(7-8):67-74.

On the other hand, NADH-cytochrome c oxido-reductase activity, insensitive to rotenone, is more than doubled in Don Q.
In these cells the activity of lactate dehydrogenase is very high, being able to oxidise more than 3,000 nmoles of NADH/min/mg of protein.
1(0,0,0,1) Details
838718 Van Dop C, Hutson SM, Lardy HA: Pyruvate metabolism in bovine epididymal spermatozoa. . J Biol Chem. 1977 Feb 25;252(4):1303-8.

The results indicate that the intramitochondrial lactate dehydrogenase X, which is unique to spermatozoa, allows the NADH resulting from pyruvate oxidation to reduce other pyruvate molecules to lactate.
Treating bovine epididymal spermatozoa with rutamycin or rotenone inhibited both respiration and motility supported by endogenous substrates.
1(0,0,0,1) Details
3876033 Norris SH, Hersey SJ: Stimulation of pepsinogen secretion in permeable isolated gastric glands. Am J Physiol. 1985 Sep;249(3 Pt 1):G408-15.


Criteria for permeabilization were the release of lactate dehydrogenase in response to digitonin as well as the finding that calcium stimulation and spermine inhibition required the presence of digitonin.
1(0,0,0,1) Details
16917840 Imamura K, Takeshima T, Kashiwaya Y, Nakaso K, Nakashima K: D-beta-hydroxybutyrate protects dopaminergic SH-SY5Y cells in a rotenone model of Parkinson's disease. J Neurosci Res. 2006 Nov 1;84(6):1376-84.

We evaluated cellular oxidation reduction by the alamarBlue assay, viability by lactate dehydrogenase (LDH) assay, and survival/death ratio by live/dead assays.
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15659109 Liu HQ, Zhu XZ, Weng EQ: Intracellular dopamine oxidation mediates rotenone-induced apoptosis in PC12 cells. Acta Pharmacol Sin. 2005 Jan;26(1):17-26.

METHODS: Cell viability was assessed by detecting the leakage of lactate dehydrogenase (LDH) into the medium.
1(0,0,0,1) Details
12097231 Li C, Wright MM, Jackson RM: Reactive species mediated injury of human lung epithelial cells after hypoxia-reoxygenation. Exp Lung Res. 2002 Jul-Aug;28(5):373-89.

Rotenone and myxothiazole increased DCF oxidation more in hypoxic than in normoxic cells, suggesting that mitochondrial electron transport complex I may have been altered by hypoxia preexposure.
Lung epithelial cells preexposed to hypoxia released more lactate dehydrogenase (LDH) than normoxic controls in response to increased O (2)(-) production.
1(0,0,0,1) Details
3688218 Murphy E, LeFurgey A, Lieberman M: Biochemical and structural changes in cultured heart cells induced by metabolic inhibition. Am J Physiol. 1987 Nov;253(5 Pt 1):C700-6.


We examined the relationship between ionic homeostasis, ATP, and irreversible cell injury in cultured embryonic chick heart cells treated with rotenone (10 (-4) M) alone or in combination with iodoacetate (IAA) (10 (-3) M), in the presence of extracellular calcium (Ca0) (2.7 mM) and its nominal absence.
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1313342 Piwnica-Worms D, Chiu ML, Kronauge JF: Divergent kinetics of 201Tl and 99mTc-SESTAMIBI in cultured chick ventricular myocytes during ATP depletion. Circulation. 1992 Apr;85(4):1531-41.

METHODS AND RESULTS: To better understand the mechanistic responses of these tracers to myocellular injury, cultured chick embryo cardiac myocytes were metabolically inhibited in iodoacetate (1 mM) and rotenone (10 microM) for up to 2 hours, and initial uptake rates of each agent were determined at successive intervals along with correlative cellular contents of ATP, sodium, and potassium and lactate dehydrogenase release.
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2174736 Modica-Napolitano JS, Joyal JL, Ara G, Oseroff AR, Aprille JR: Mitochondrial toxicity of cationic photosensitizers for photochemotherapy. Cancer Res. 1990 Dec 15;50(24):7876-81.


With photoirradiation VB-BO was also shown to inhibit rotenone-sensitive NADH-cytochrome c reductase activity, but it had no effect on succinate-cytochrome c reductase activity.
0(0,0,0,0) Details
1696124 Breitbart H, Wehbie R, Lardy HA: Calcium transport in bovine sperm mitochondria: effect of substrates and phosphate. Biochim Biophys Acta. 1990 Jul 9;1026(1):57-63.


In the presence of succinate, glutamate stimulates calcium uptake 3-fold, and this effect is not inhibited by rotenone.
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2163215 Dickman KG, Mandel LJ: Differential effects of respiratory inhibitors on glycolysis in proximal tubules. Am J Physiol. 1990 Jun;258(6 Pt 2):F1608-15.

Compared with antimycin A, treatment with rotenone or FCCP resulted in less cell injury [measured by lactate dehydrogenase (LDH) release] and greater preservation of cell K+ and ATP contents. 2-Deoxyglucose blocked lactate production by 50% in the presence of rotenone and increased LDH release, suggesting that glycolytic ATP is partially protective.
31(0,1,1,1) Details
8736490 Virmani MA, Biselli R, Spadoni A, Rossi S, Corsico N, Calvani M, Fattorossi A, De Simone C, Arrigoni-Martelli E: Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors. Pharmacol Res. 1995 Dec;32(6):383-9.

It appears that L-carnitine and its acetylated form, acetyl-L-carnitine, can attenuate the cell damage, as assessed by lactate dehydrogenase (LDH) release, evoked by the uncoupler, p-(trifluoromethoxy) phenylhdyrazone (FCCP), or by the inhibitors, 3-nitropropionic acid (3-NPA) or rotenone.
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2003584 Del Castillo JR, Ricabarra B, Sulbaran-Carrasco MC: Intermediary metabolism and its relationship with ion transport in isolated guinea pig colonic epithelial cells. Am J Physiol. 1991 Mar;260(3 Pt 1):C626-34.


Oxygen consumption (QO2) measured after the sequential addition of the following drugs showed that oligomycin inhibited QO2 by 67%, carbonyl cyanide p-trifluoromethoxyphenylhydrazone increased QO2 by approximately 70% of the basal consumption, and rotenone inhibited QO2 by 90%.
0(0,0,0,0) Details
20169778 Radad K, Moldzio R, Rausch WD: Minocycline protects dopaminergic neurons against long-term rotenone toxicity. Can J Neurol Sci. 2010 Jan;37(1):81-5.

RESULTS: Treatment of cultures with 5 and 20 nM of rotenone significantly decreased the survival of tyrosine hydroxylase immunoreactive neurons by 27 and 31% and increased the release of lactate dehydrogenase into the culture medium by 31 and 236%, respectively compared to untreated controls.
13(0,0,2,3) Details
19120153 Moldzio R, Piskernik C, Radad K, Rausch WD: Rotenone damages striatal organotypic slice culture. Ann N Y Acad Sci. 2008 Dec;1148:530-5.

Lactate dehydrogenase activity was elevated by 167% at 1 mM of rotenone.
6(0,0,1,1) Details
16580092 Radad K, Rausch WD, Gille G: Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration. Neurochem Int. 2006 Sep;49(4):379-86. Epub 2006 Mar 31.

Consistent with the cytotoxic effect of rotenone as evidenced by dopaminergic cell loss, it significantly increased the release of lactate dehydrogenase into the culture medium, the number of necrotic cells in the culture and the number of nuclei showing apoptotic features.
6(0,0,1,1) Details
684877 Vdovichenko LM: [Properties of lactate dehydrogenase of brain mitochondria] . Ukr Biokhim Zh. 1978 Jul-Aug;50(4):489-93.

Rotenone and Ca2+ have no effect on the activity of lactate dehydrogenase in the both preparations, KCN inhibits it.
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8828812 Zboril P, Wernerova V: The isolation and some properties of the membrane-bound lactate dehydrogenase of Paracoccus denitrificans. Biochem Mol Biol Int. 1996 Jun;39(3):595-605.

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1516736 Szczesna-Kaczmarek A: Regulating effect of mitochondrial lactate dehydrogenase on oxidation of cytoplasmic NADH via an "external" pathway in skeletal muscle mitochondria. Int J Biochem. 1992 Apr;24(4):657-61.

The specific activity of mitochondrial LDH in skeletal muscle mitochondria was almost equal to the activity of rotenone-insensitive NADH-cytochrome c reductase. 3.
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1980165 Kim NP, Akhmerov RN, Makhmudov ES: [Oxidation of lactate in isolated rat heart mitochondria] . Ukr Biokhim Zh. 1990 Sep-Oct;62(5):67-72.

In unwashed mitochondria the oxidation of L-lactate (with NAD+) proceeds in presence of the added lactate dehydrogenase.
Oxidation of lactate with NAD+ is inhibited by rotenone.
2(0,0,0,2) Details
2721587 Miyazaki M, Utsumi K, Sato J: Mechanisms responsible for long-term survival of adult rat hepatocytes in the presence of phenobarbital in primary culture. Exp Cell Res. 1989 Jun;182(2):415-24.

PB effectively reduced the leakage of lactate dehydrogenase from hepatocytes caused by chenodeoxycholic acid in primary culture.
Rotenone and amobarbital, which act repressively on the PB-sensitive site in the respiratory chain and are known to inhibit the mitochondrial formation of active oxygen species with NAD-linked substances, effectively prolonged the hepatocyte survival in primary culture.
1(0,0,0,1) Details
17880998 Yitzhaki S, Hochhauser E, Porat E, Shainberg A: Uridine-5'-triphosphate (UTP) maintains cardiac mitochondrial function following chemical and hypoxic stress. J Mol Cell Cardiol. 2007 Nov;43(5):653-62. Epub 2007 Aug 7.

In the in vitro model, cultured cardiomyocytes were pretreated with 50 microM UTP prior to hypoxic and/or chemical stress with rotenone or sodium azide.
Pretreatment with UTP maintained increased ATP levels as well as mitochondrial membrane potential and reduced lactate dehydrogenase (LDH) release.
1(0,0,0,1) Details
2379665 Szczesna-Kaczmarek A: L-lactate oxidation by skeletal muscle mitochondria. . Int J Biochem. 1990;22(6):617-20.

Mitochondria isolated from rat skeletal muscle possess lactate dehydrogenase which is involved in direct oxidation of L-lactate in the presence of external NAD. 2.
Mitochondrial lactate oxidation is sensitive to oxamate-inhibitor of LDH, alpha-cyano-3-hydroxy-cinnamate-pyruvate translocase inhibitor and respiratory chain inhibitors (rotenone, antimycin A, KCN). 4.
1(0,0,0,1) Details
14643754 Kannurpatti SS, Sanganahalli BG, Mishra S, Joshi PG, Joshi NB: Glutamate-induced differential mitochondrial response in young and adult rats. Neurochem Int. 2004 Apr;44(5):361-9.

The treatment of slices with mitochondrial inhibitors rotenone and oligomycin inhibited ROS formation and LDH release substantially.
However, the formation of reactive oxygen species (ROS) and lactate dehydrogenase (LDH) release were significantly higher in adult rats as compared to young rats.
1(0,0,0,1) Details
19488053 Torres S, Salgado-Ceballos H, Guizar-Sahagun G, Torres JL, Orozco-Suarez S, Diaz-Ruiz A, Vazquez ME, Collado C, Rios C: Deleterious versus neuroprotective effect of metabolic inhibition after traumatic spinal cord injury. Spinal Cord. 2009 Oct;47(10):745-50. Epub 2009 Jun 2.

METHODS: Animals were divided into five groups: one sham and four with TSCI, including no treatment, rotenone (inhibitor of mitochondrial complex I), sodium azide (inhibitor of mitochondrial complex IV) and pyrophosphate of thiamine or non-degradable cocarboxylase as a metabolic reactivator.
RESULTS: After TSCI, the metabolic inhibition with sodium azide treatment diminished the lipid peroxidation process (malondialdehyde levels by spectrophotometric procedures) and the damage to the spinal cord tissue (morphometric analysis), and increased the activity of creatine kinase and lactate dehydrogenase enzymes (P <0.05) (measured by spectrophotometric procedures 24 h after TSCI as well as after the functional recovery of the hind limb (evaluated weekly for 2 months by the BBB (Basso, Beattie and Bresnahan) scale)) when compared with the TSCI group without treatment.
1(0,0,0,1) Details
10515594 Bailey SM, Pietsch EC, Cunningham CC: Ethanol stimulates the production of reactive oxygen species at mitochondrial complexes I and III. Free Radic Biol Med. 1999 Oct;27(7-8):891-900.

Reactive oxygen species production was detected using the 2',7'-dichlorofluorescein fluorescence assay and cell injury was determined by lactate dehydrogenase release.
Rotenone, a mitochondrial complex I inhibitor that allows electron flow through the flavin mononucleotide (FMN), but prevents electron flow to complex III, significantly increased reactive oxygen species production in untreated cells, but decreased reactive oxygen species production in antimycin plus ethanol-treated cells.
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18385062 He Y, Leung KW, Zhang YH, Duan S, Zhong XF, Jiang RZ, Peng Z, Tombran-Tink J, Ge J: Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants. Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1447-58.

Primary TM cultures were treated with one of the following mitochondrial respiratory chain inhibitors: rotenone (ROT, complex I inhibitor), thenoyltrifluoroacetone (TTFA, complex II inhibitor), myxothiazol or antimycin A (MYX, AM-complex III inhibitors); mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA); and antioxidants vitamin E (Vit E) or N-acetylcysteine (NAC).
Reactive oxygen species (ROS) level, determined by H (2)-DCF-DA, and cell death, measured by lactate dehydrogenase activity and Annexin V-FITC labeling, were also examined.
1(0,0,0,1) Details
7082719 Mita M, Hall PF: Metabolism of round spermatids from rats: lactate as the preferred substrate. Biol Reprod. 1982 Apr;26(3):445-55.

Synthesis of ATP with lactate and with pyruvate is inhibited by rotenone, rutamycin or 2,4-dinitrophenol.
Post-mitochondrial supernate from spermatids showed that high concentration of pyruvate (greater than 1 mM) inhibit lactate dehydrogenase with pyruvate as substrate and that with lactate as substrate, pyruvate behaves as a competitive inhibitor of lactate dehydrogenase.
1(0,0,0,1) Details
7945357 Sivan VM, Raj RK: Lactate oxidation coupled to energy production in mitochondria like particles from Setaria digitata, a filarial parasite. Biochem Biophys Res Commun. 1994 Oct 14;204(1):17-22.

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.
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.
1(0,0,0,1) Details
10844979 Obungu VH, Kiaira JK, Olembo NK, Njogu MR: Pathways of glucose catabolism in procyclic Trypanosoma congolense. Indian J Biochem Biophys. 1999 Oct;36(5):305-11.

Studies of respiration on glucose in procyclic Trypanosoma congolense in the presence of rotenone, antimycin, cyanide, salicylhydroxamic acid and malonate have indicated the presence of NADH dehydrogenase, cytochrome b-c1, cytochrome aa3, trypanosome alternate oxidase and NADH fumarate reductase/succinate dehydrogenase pathway that contributes electrons to coenzyme Q of the respiratory chain.
Activities of lactate dehydrogenase, NAD (+)-linked malic enzyme and pyruvate kinase were less than 6 nanomoles/min/mg protein suggesting that they play a minor role in energy metabolism of the parasite.
1(0,0,0,1) Details
14960150 De Bari L, Atlante A, Valenti D, Passarella S: Partial reconstruction of in vitro gluconeogenesis arising from mitochondrial l-lactate uptake/metabolism and oxaloacetate export via novel L-lactate translocators. Biochem J. 2004 May 15;380(Pt 1):231-42.


In the light of the occurrence of L-lactate dehydrogenase inside the mitochondrial matrix, we looked at whether isolated rat liver mitochondria can take up and metabolize L-lactate, and provide oxaloacetate outside mitochondria, thus contributing to a partial reconstruction of gluconeogenesis in vitro.
1(0,0,0,1) Details
2360621 Weinberg JM, Davis JA, Abarzua M, Kiani T, Kunkel R: Protection by glycine of proximal tubules from injury due to inhibitors of mitochondrial ATP production. Am J Physiol. 1990 Jun;258(6 Pt 1):C1127-40.

We have determined whether glycine or glutathione can protect rabbit proximal tubules damaged by chemical inhibitors of oxidative phosphorylation: antimycin A, rotenone, cyanide, oligomycin, or carbonyl cyanide m-chlorophenylhdrazone (CCCP).
All the agents severely depleted cell ATP levels within 15 min and caused lethal cell injury, as quantified by lactate dehydrogenase (LDH) release.
1(0,0,0,1) Details
14653820 Jasso-Chavez R, Moreno-Sanchez R: Cytosol-mitochondria transfer of reducing equivalents by a lactate shuttle in heterotrophic Euglena. Eur J Biochem. 2003 Dec;270(24):4942-51.

To assess the expression and physiological role of the mitochondrial NAD (+)-independent lactate dehydrogenase (iLDH) in Euglena gracilis, cells were grown with different carbon sources, and the d- and l-iLDH activities and several key metabolic intermediates were examined. iLDH activity was significant throughout the growth period, increasing by three- to fourfold from latency to the stationary phase.
Oxalate, an inhibitor of iLDH, strongly inhibited oligomycin-sensitive respiration and growth, whereas rotenone, an inhibitor of respiratory complex I, only slightly affected these parameters in lactate-grown cells.
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12860476 Molina-Jimenez MF, Sanchez-Reus MI, Benedi J: Effect of fraxetin and myricetin on rotenone-induced cytotoxicity in SH-SY5Y cells: comparison with N-acetylcysteine. Eur J Pharmacol. 2003 Jul 4;472(1-2):81-7.

The viability of cells was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and cytotoxicity was assayed by lactate dehydrogenase (LDH) released into the culture medium.
1(0,0,0,1) Details
838719 Hutson SM, Van Dop C, Lardy HA: Mitochondrial metabolism of pyruvate in bovine spermatozoa. . J Biol Chem. 1977 Feb 25;252(4):1309-15.

As in intact cells, intramitochondrial lactate dehydrogenase competes successfully with the electron transport system for the NADH generated by pyruvate metabolism.
Rutamycin or rotenone increased both the rate of pyruvate use and the delta lactate/deltapyruvate ratio.
1(0,0,0,1) Details
9070626 Sriram K, Pai KS, Boyd MR, Ravindranath V: Evidence for generation of oxidative stress in brain by MPTP: in vitro and in vivo studies in mice. Brain Res. 1997 Feb 21;749(1):44-52.

Pretreatment of mouse brain slices, in vitro, with GSH or GSH isopropyl ester attenuated MPTP toxicity as assessed by the tissue activity of the mitochondrial enzyme, NADH-dehydrogenase (NADH-DH), and by leakage of the cytosolic enzyme, lactate dehydrogenase (LDH), from the slice into the medium.
In the striatum significant inhibition of rotenone-sensitive NADH ubiquinone-1 oxido-reductase (Complex 1) was observed transiently 1 h after MPTP administration.
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