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.

Reexploring 5-methoxyindole-2-carboxylic acid (MICA) as a potential antidiabetic agent

“…During our studies of mitochondrial dysfunction in stroke injury, we stumbled upon a chemical called 5-methoxyindole-2-carboxylic acid (MICA) ( Figure 1 ), which exhibits a potential role in neuroprotection against stroke injury when applied as either a preconditioning or postconditioning agent. 4 , 5 MICA is often regarded as a biomarker for malignant melanoma, 6 but intriguingly, a quick literature search indicates that MICA is actually also a hypoglycemic agent. 7 , 8 In fact, this chemical, having an indole nucleus core structure that is known to possess antidiabetic properties, 9 , 10 was studied extensively in 1960s and 1970s in terms of its glucose-lowering ability.…”

“…It should be noted that MICA inhibition of the conversion of pyruvate to acetyl-CoA occurs not only just in the liver but also in many other tissues such as adipose, testis, brain, and kidney. 5 , 12 , 19 , 20 The establishment that MICA inhibits DLDH is based on the evidence that the cofactor lipoic acid instead of other cofactors such as thiamine and thiamine pyrophosphate can reverse MICA inhibition of DLDH. 14 …”

“…In particular, we and others have demonstrated that different administration routes could be important to minimize MICA’s toxic effects and get beneficial results. 4 , 5 , 7 , 8…”

“…Additionally, as MICA targets nearly all tissues in the body and has a variety of effects on protein expression and cellular pathways in numerous experimental settings or disease models, 4 , 5 , 12 , 15 , 20 , 25 – 27 its potential effect on pancreatic β-cell function and insulin secretion in the context of diabetes should also be investigated. Moreover, a comprehensive evaluation of MICA on glucose metabolism, in particular, gluconeogenesis in cultured hepatocytes should also be performed.…”

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“…Elevated extracellular LDH is a biomarker of oxidative stress and disrupted cell sincerity throughout the lipid peroxidation and oxidative stress. Tao 74 reported that increased level production of LDH cause Aβ accumulation is probably involved in the pathophysiology of AD. Administration of Gb and Ph to AD groups caused a pronounced reduction in the elevated activity of LDH as compared with Alzheimer's group.…”