Morin and isoquercitrin protect against ischemic neuronal injury by modulating signaling pathways and stimulating mitochondrial biogenesis

ABSTRACT

Objetive: The search for the etiology of Alzheimer’s disease has revealed dysregulation of amyloid protein precursors, β-secretase, mitophagy, apoptosis, and Tau protein genes after ischemic brain injury. Due to this and the fact that some flavonoids have demonstrated anti-amyloidogenic effects on AD targets, we aimed to investigate whether they are effective against an ischemic neuronal injury not only by its antioxidant effects and clarify their mechanism.

We simulated the energy depletion that characterizes ischemic processes using iodoacetic acid on HT22 cells. In vitro ischemic assays were also performed under OXPHOS inhibition using inhibitors of the different mitochondrial complexes and intracellular ATP, NADH and NADPH levels were determined. The signaling pathways of MAP kinase (MAPK) and of the PI3K/Akt mTOR were analyzed for its close association with post-ischemic survival.

Results: Morin and isoquercitrin showed a significant neuroprotective effect against IAA toxicity, favored the activity of the mitochondrial complexes and prevented the decrease in ERK phosphorylation and activation of the stress proteins JNK and p38 caused by IAA treatment, as well as prevented satisfactorily mTOR and p70 dephosphorylation. They provide a considerable resistance to ischemic brain injury by modulating signaling pathways that stimulate mitochondrial biogenesis and promoting the activity of electron transport chain.

Highlights

• Morin and isoquercitrin showed a significant neuroprotective effect against IAA toxicity.

• Morin and isoquercitrin favor the activity of the mitochondrial complexes I, III and V.

• Morin and isoquercitrin prevent the decrease in ERK phosphorylation caused by IAA.

• Morin shows a better profile avoiding Akt dephosphorylation than isoquercetrin.

• Morin and isoquercitrin prevent dephosphorylation of mTOR and p70.

GRAPHICAL ABSTRACT

KEYWORDS:

• Morin
• isoquercitrin
• HT22 cells
• ischemia
• ATP
• OXPHOS

Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Notes on contributors

Vanesa Carmona Mata

Vanesa Carmona Mata, PhD is adjunct Professor at the Pharmacology, Pharmacognosy & Botany Department of Pharmacy School of Complutense University of Madrid. Currently working as a Public Health Inspector (Regional Ministry of Health of Madrid), previously worked at The Spanish Agency of Medicines and Medical Devices.

Joshua Goldberg

Joshua Goldberg, Ph.D. is a research scientist at ActivX Biosciences, a fully owned subsidiary of Kyorin Pharmaceutical Co., Ltd. This work was conducted while a postdoctoral researcher at the Salk Institute for Biological Sciences.