Administration of 5-methoxyindole-2-carboxylic Acid That Potentially Targets Mitochondrial Dihydrolipoamide Dehydrogenase Confers Cerebral Preconditioning Against Ischemic Stroke Injury

Overview

Journal Free Radic Biol Med

Specialties Biochemistry
Biology
General Medicine

Date 2017 Oct 12

PMID 29017857

Citations 13

Authors

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

Affiliations

Soon will be listed here.

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 1h transient ischemia and 24h 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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