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

Free Radic Biol Med. 2017 Dec:113:244-254. doi: 10.1016/j.freeradbiomed.2017.10.008. Epub 2017 Oct 7.

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.

Keywords: 5-methoxyindole-2-carboxylic acid (MICA); Chemical preconditioning; Dihydrolipoamide dehydrogenase; Ischemic stroke; Neuroprotection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Administration, Oral
  • Animals
  • Brain / blood supply
  • Brain / metabolism
  • Brain / pathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / enzymology
  • Brain Ischemia / genetics
  • Brain Ischemia / pathology
  • Cell Death / drug effects
  • Dihydrolipoamide Dehydrogenase / antagonists & inhibitors
  • Dihydrolipoamide Dehydrogenase / genetics*
  • Dihydrolipoamide Dehydrogenase / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Indoles / pharmacology*
  • Ischemic Preconditioning
  • Male
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / pathology
  • Mitochondrial Proteins / antagonists & inhibitors
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / agonists
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / genetics
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Signal Transduction
  • Stroke / drug therapy*
  • Stroke / enzymology
  • Stroke / genetics
  • Stroke / pathology

Substances

  • Indoles
  • Mitochondrial Proteins
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, rat
  • 5-methoxyindole-2-carboxylic acid
  • Adenosine Triphosphate
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, rat
  • Dihydrolipoamide Dehydrogenase