Peripheral Neuropathy in Rats Exposed to Dichloroacetate

Calcutt, Nigel A.; López, Verónica; Bautista, Arjel D.; Mizisin, Leah M.; Torres, Brenda R.; Shroads, Albert L.; Mizisin, Andrew P.; Stacpoole, Peter W.

doi:10.1097/nen.0b013e3181b40217

Cited by 45 publications

(40 citation statements)

References 35 publications

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“…DCA treatment for 8 weeks induced mild weight loss (control ϭ 282 Ϯ 5 versus DCA ϭ 259 Ϯ 3 g; mean Ϯ S.E.M., p Ͻ 0.001 by unpaired t test) and peripheral neuropathy, as illustrated by slowing of motor nerve conduction velocity (control ϭ 50.3 Ϯ 1.9 versus DCA ϭ 42.5 Ϯ 1.1 m/s; p Ͻ 0.01) and paw thermal hypoalgesia (control ϭ 10.35 Ϯ 0.62 versus DCA ϭ 13.34 Ϯ 0.72 s; p Ͻ 0.001), as has been reported for rats treated with a similar dose of DCA (Calcutt et al, 2009).…”

Section: Resultssupporting

confidence: 54%

“…ALDH1A1 is a cytosolic and inducible isoform of the aldehyde dehydrogenase family that catalyzes the oxidation of medium-chain aliphatic aldehydes, including 4-hydroxynonenal and malondialdehyde (Alnouti and Klaassen, 2008). This is noteworthy because elevated levels of these indices of lipid peroxidation have been found in the sciatic nerves of rats treated with the same dose of DCA as used in the present study (Calcutt et al, 2009). Furthermore, increased production of reactive oxygen species and lipid peroxidation have been demonstrated in the livers of mice treated with high doses of DCA (Larson and Bull, 1992;Hassoun et al, 2010).…”

Section: Mitochondrion As a Site Of Dichloroacetate Biotransformation 91mentioning

confidence: 49%

“…Adult female Sprague-Dawley (SD) rats were treated by gavage with tap water vehicle (n ϭ 9, control group) or 500 mg/kg/day DCA (n ϭ 11, DCA-treated group) for 8 weeks. Neuropathy was confirmed by measuring sciatic motor nerve conduction velocity and paw thermal response latency exactly as described elsewhere followed by sacrifice by decapitation (Calcutt et al, 2009). Studies were performed after approval by the local Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

Li¹,

James²,

McKenzie³

et al. 2010

J Pharmacol Exp Ther

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Dichloroacetate (DCA) is a potential environmental hazard and an investigational drug. Repeated doses of DCA result in reduced drug clearance, probably through inhibition of glutathione transferase 1 (GSTZ1), a cytosolic enzyme that converts DCA to glyoxylate. DCA is known to be taken up by mitochondria, where it inhibits pyruvate dehydrogenase kinase, its major pharmacodynamic target. We tested the hypothesis that the mitochondrion was also a site of DCA biotransformation. Immunoreactive GSTZ1 was detected in liver mitochondria from humans and rats, and its identity was confirmed by liquid chromatography/tandem mass spectrometry analysis of the tryptic peptides. Study of rat submitochondrial fractions revealed GSTZ1 to be localized in the mitochondrial matrix. The specific activity of GSTZ1-catalyzed dechlorination of DCA was 2.5-to 3-fold higher in cytosol than in whole mitochondria and was directly proportional to GSTZ1 protein expression in the two compartments. Rat mitochondrial GSTZ1 had a 2.5-fold higher App K m for glutathione than cytosolic GSTZ1, whereas the App K m values for DCA were identical. Rats administered DCA at a dose of 500 mg/kg/day for 8 weeks showed reduced hepatic GSTZ1 activity and expression of ϳ10% of control levels in both cytosol and mitochondria. We conclude that the mitochondrion is a novel site of DCA biotransformation catalyzed by GSTZ1, an enzyme colocalized in cytosol and mitochondrial matrix.

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Section: Resultssupporting

confidence: 54%

Section: Mitochondrion As a Site Of Dichloroacetate Biotransformation 91mentioning

confidence: 49%

Section: Methodsmentioning

confidence: 99%

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Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

Li¹,

James²,

McKenzie³

et al. 2010

J Pharmacol Exp Ther

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“…This study therefore has demonstrated that by increasing the metabolic flexibility of the hyperthyroid heart, the response to increased levels of thyroid hormone is altered and cardiac hypertrophy is reduced. The side effects associated with DCA treatment, ie, pain, numbness, and peripheral neuropathy, 45,46 prevent DCA from being a viable treatment for hyperthyroidism; however, our data suggest that alternative metabolic interventions may relieve some of the more serious symptoms associated with this disease and therefore warrant further investigation.…”

Section: Effects Of Dichloroacetic Acid Treatment On the Hyperthyroidmentioning

confidence: 61%

Role of Pyruvate Dehydrogenase Inhibition in the Development of Hypertrophy in the Hyperthyroid Rat Heart

et al. 2011

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Background-Hyperthyroidism increases heart rate, contractility, cardiac output, and metabolic rate. It is also accompanied by alterations in the regulation of cardiac substrate use. Specifically, hyperthyroidism increases the ex vivo activity of pyruvate dehydrogenase kinase, thereby inhibiting glucose oxidation via pyruvate dehydrogenase. Cardiac hypertrophy is another effect of hyperthyroidism, with an increase in the abundance of mitochondria. Although the hypertrophy is initially beneficial, it can eventually lead to heart failure. The aim of this study was to use hyperpolarized magnetic resonance spectroscopy to investigate the rate and regulation of in vivo pyruvate dehydrogenase flux in the hyperthyroid heart and to establish whether modulation of flux through pyruvate dehydrogenase would alter cardiac hypertrophy. Methods and Results-Hyperthyroidism was induced in 18 male Wistar rats with 7 daily intraperitoneal injections of freshly prepared triiodothyronine (0.2 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ). In vivo pyruvate dehydrogenase flux, assessed with hyperpolarized magnetic resonance spectroscopy, was reduced by 59% in hyperthyroid animals (0.0022Ϯ0.0002 versus 0.0055Ϯ0.0005 second Ϫ1 ; Pϭ0.0003), and this reduction was completely reversed by both short-and long-term delivery of dichloroacetic acid, a pyruvate dehydrogenase kinase inhibitor. Hyperpolarized [2-13 C]pyruvate was also used to evaluate Krebs cycle metabolism and demonstrated a unique marker of anaplerosis, the level of which was significantly increased in the hyperthyroid heart. Cine magnetic resonance imaging showed that long-term dichloroacetic acid treatment significantly reduced the hypertrophy observed in hyperthyroid animals (100Ϯ20 versus 200Ϯ30 mg; Pϭ0.04) despite no change in the increase observed in cardiac output.Conclusions-This work has demonstrated that inhibition of glucose oxidation in the hyperthyroid heart in vivo is mediated by pyruvate dehydrogenase kinase. Relieving this inhibition can increase the metabolic flexibility of the hyperthyroid heart and reduce the level of hypertrophy that develops while maintaining the increased cardiac output required to meet the higher systemic metabolic demand. (Circulation. 2011;123:2552-2561.)Key Words: hyperthyroidism Ⅲ magnetic resonance spectroscopy Ⅲ pyruvate dehydrogenase complex T hyroid hormones regulate many aspects of growth, development, and energy metabolism, and are critical for normal cell function in multiple organs. [1][2][3] The heart is particularly sensitive to the action of thyroid hormones, with thyroid dysfunction having detrimental effects on the cardiovascular system. Minimal alterations in circulating thyroid hormone concentrations significantly alter many cardiac parameters. For instance, an increase in circulating thyroid hormone markedly increases heart rate, contractility, and cardiac output. 4 -7 Furthermore, hyperthyroid patients often develop hypertrophy, tachycardia, palpitations, fatigue, and atrial arrhythmias. 8 Clinical Perspective on p 2561Hyperthyroidism is acc...

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“…DCA neuropathy was induced by daily injection (1.0 g/kg i.p.) throughout the study (43,81). Local exposure to gp120 (product 1021, ImmunoDX) was used to model HIV neuropathy (44).…”

Section: Methodsmentioning

confidence: 99%

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Calcutt¹,

Smith²,

Frizzi³

et al. 2017

Journal of Clinical Investigation

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Peripheral Neuropathy in Rats Exposed to Dichloroacetate

Cited by 45 publications

References 35 publications

Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

Role of Pyruvate Dehydrogenase Inhibition in the Development of Hypertrophy in the Hyperthyroid Rat Heart

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

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