Abstract
Kaempferol has been shown to protect cells against cerebral ischemia/reperfusion injury through inhibition of apoptosis. In the present study, we sought to investigate whether ferroptosis is involved in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuronal injury and the effects of kaempferol on ferroptosis in OGD/R-treated neurons. Western blot, immunofluorescence, and transmission electron microscopy were used to analyze ferroptosis, whereas cell death was detected using lactate dehydrogenase (LDH) release. We found that OGD/R attenuated SLC7A11 and glutathione peroxidase 4 (GPX4) levels as well as decreased endogenous antioxidants including nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and superoxide dismutase (SOD) in neurons. Notably, OGD/R enhanced the accumulation of lipid peroxidation, leading to the induction of ferroptosis in neurons. However, kaempferol activated nuclear factor-E2-related factor 2 (Nrf2)/SLC7A11/GPX4 signaling, augmented antioxidant capacity, and suppressed the accumulation of lipid peroxidation in OGD/R-treated neurons. Furthermore, kaempferol significantly reversed OGD/R-induced ferroptosis. Nevertheless, inhibition of Nrf2 by ML385 blocked the protective effects of kaempferol on antioxidant capacity, lipid peroxidation, and ferroptosis in OGD/R-treated neurons. These results suggest that ferroptosis may be a significant cause of cell death associated with OGD/R. Kaempferol provides protection from OGD/R-induced ferroptosis partly by activating Nrf2/SLC7A11/GPX4 signaling pathway.
Highlights
Ischemic stroke is a major cause of mortality and serious disability worldwide, accounting for about 80% of stroke
To determine whether oxygen-glucose deprivation/reperfusion (OGD/R)-induced injury was associated with ferroptosis in neuron, we investigated protein levels of SLC7A11, Glutathione peroxidase 4 (GPX4), and nuclear factor-E2-related factor 2 (Nrf2) by Western blots
Kaempferol strikingly elevated GPX4 activity in neurons subjected to OGD/R insult
Summary
Ischemic stroke is a major cause of mortality and serious disability worldwide, accounting for about 80% of stroke. Ischemic stroke occurs when a blood vessel is blocked, leading to acute disrupted cerebral blood flow and oxygen delivery to the brain. Ferroptosis is described as an iron-dependent form of cell death mediated by excess accumulation of lipid peroxides [1,2]. Inactivation of GPX4 or depletion of GSH causes the accumulation of lipid hydroperoxides, eventually leading to the induction of ferroptosis [3,5,6]. Neuron-specific GPX4 depletion in the forebrain elevates lipid peroxidation, increases ferroptosis, and triggers neurodegeneration [7]. Inhibition of SLC7A11, the light chain of system xc - , attenuates GSH levels and GPX4 activity, resulting in the accumulation of lethal lipid peroxides and the induction of ferroptosis [2,9].
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