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

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.