Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury

Jinzi Wu, Rongrong Li, Wenjun Li, Ming Ren, Nopporn Thangthaeng, Nathalie Sumien, Ran Liu, Shaohua Yang, James W. Simpkins, Michael J. Forster, Liang-Jun Yan

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

The objective of this study was to investigate a possible role of mitochondrial dihydrolipoamide dehydrogenase (DLDH) as a chemical preconditioning target for neuroprotection against ischemic injury. We used 5-methoxyindole-2-carboxylic acid (MICA), a reportedly reversible DLDH inhibitor, as the preconditioning agent and administered MICA to rats mainly via dietary intake. Upon completion of 4 week's MICA treatment, rats underwent 1 h transient ischemia and 24 h reperfusion followed by tissue collection. Our results show that MICA protected the brain against ischemic stroke injury as the infarction volume of the brain from the MICA-treated group was significantly smaller than that from the control group. Data were then collected without or with stroke surgery following MICA feeding. It was found that in the absence of stroke following MICA feeding, DLDH activity was lower in the MICA treated group than in the control group, and this decreased activity could be partly due to DLDH protein sulfenation. Moreover, DLDH inhibition by MICA was also found to upregulate the expression of NAD(P)H-ubiquinone oxidoreductase 1(NQO1) via the Nrf2 signaling pathway. In the presence of stroke following MICA feeding, decreased DLDH activity and increased Nrf2 signaling were also observed along with increased NQO1 activity, decreased oxidative stress, decreased cell death, and increased mitochondrial ATP output. We also found that MICA had a delayed preconditioning effect four weeks post MICA treatment. Our study indicates that administration of MICA confers chemical preconditioning and neuroprotection against ischemic stroke injury.

Original languageEnglish
Pages (from-to)244-254
Number of pages11
JournalFree Radical Biology and Medicine
Volume113
DOIs
StatePublished - 1 Dec 2017

Fingerprint

Dihydrolipoamide Dehydrogenase
Ischemic Preconditioning
Stroke
Wounds and Injuries
5-methoxyindole-2-carboxylic acid
Rats
Brain
Brain Infarction
Control Groups
Ubiquinone
Oxidative stress
Cell death
NAD
Surgery

Keywords

  • 5-methoxyindole-2-carboxylic acid (MICA)
  • Chemical preconditioning
  • Dihydrolipoamide dehydrogenase
  • Ischemic stroke
  • Neuroprotection

Cite this

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title = "Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury",
abstract = "The objective of this study was to investigate a possible role of mitochondrial dihydrolipoamide dehydrogenase (DLDH) as a chemical preconditioning target for neuroprotection against ischemic injury. We used 5-methoxyindole-2-carboxylic acid (MICA), a reportedly reversible DLDH inhibitor, as the preconditioning agent and administered MICA to rats mainly via dietary intake. Upon completion of 4 week's MICA treatment, rats underwent 1 h transient ischemia and 24 h reperfusion followed by tissue collection. Our results show that MICA protected the brain against ischemic stroke injury as the infarction volume of the brain from the MICA-treated group was significantly smaller than that from the control group. Data were then collected without or with stroke surgery following MICA feeding. It was found that in the absence of stroke following MICA feeding, DLDH activity was lower in the MICA treated group than in the control group, and this decreased activity could be partly due to DLDH protein sulfenation. Moreover, DLDH inhibition by MICA was also found to upregulate the expression of NAD(P)H-ubiquinone oxidoreductase 1(NQO1) via the Nrf2 signaling pathway. In the presence of stroke following MICA feeding, decreased DLDH activity and increased Nrf2 signaling were also observed along with increased NQO1 activity, decreased oxidative stress, decreased cell death, and increased mitochondrial ATP output. We also found that MICA had a delayed preconditioning effect four weeks post MICA treatment. Our study indicates that administration of MICA confers chemical preconditioning and neuroprotection against ischemic stroke injury.",
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author = "Jinzi Wu and Rongrong Li and Wenjun Li and Ming Ren and Nopporn Thangthaeng and Nathalie Sumien and Ran Liu and Shaohua Yang and Simpkins, {James W.} and Forster, {Michael J.} and Liang-Jun Yan",
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Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury. / Wu, Jinzi; Li, Rongrong; Li, Wenjun; Ren, Ming; Thangthaeng, Nopporn; Sumien, Nathalie; Liu, Ran; Yang, Shaohua; Simpkins, James W.; Forster, Michael J.; Yan, Liang-Jun.

In: Free Radical Biology and Medicine, Vol. 113, 01.12.2017, p. 244-254.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury

AU - Wu, Jinzi

AU - Li, Rongrong

AU - Li, Wenjun

AU - Ren, Ming

AU - Thangthaeng, Nopporn

AU - Sumien, Nathalie

AU - Liu, Ran

AU - Yang, Shaohua

AU - Simpkins, James W.

AU - Forster, Michael J.

AU - Yan, Liang-Jun

PY - 2017/12/1

Y1 - 2017/12/1

N2 - The objective of this study was to investigate a possible role of mitochondrial dihydrolipoamide dehydrogenase (DLDH) as a chemical preconditioning target for neuroprotection against ischemic injury. We used 5-methoxyindole-2-carboxylic acid (MICA), a reportedly reversible DLDH inhibitor, as the preconditioning agent and administered MICA to rats mainly via dietary intake. Upon completion of 4 week's MICA treatment, rats underwent 1 h transient ischemia and 24 h reperfusion followed by tissue collection. Our results show that MICA protected the brain against ischemic stroke injury as the infarction volume of the brain from the MICA-treated group was significantly smaller than that from the control group. Data were then collected without or with stroke surgery following MICA feeding. It was found that in the absence of stroke following MICA feeding, DLDH activity was lower in the MICA treated group than in the control group, and this decreased activity could be partly due to DLDH protein sulfenation. Moreover, DLDH inhibition by MICA was also found to upregulate the expression of NAD(P)H-ubiquinone oxidoreductase 1(NQO1) via the Nrf2 signaling pathway. In the presence of stroke following MICA feeding, decreased DLDH activity and increased Nrf2 signaling were also observed along with increased NQO1 activity, decreased oxidative stress, decreased cell death, and increased mitochondrial ATP output. We also found that MICA had a delayed preconditioning effect four weeks post MICA treatment. Our study indicates that administration of MICA confers chemical preconditioning and neuroprotection against ischemic stroke injury.

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KW - Chemical preconditioning

KW - Dihydrolipoamide dehydrogenase

KW - Ischemic stroke

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SN - 0891-5849

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