Abstract
Oxygen glucose deprivation-reoxygenation (OGD-R) causes the production of reactive oxygen species (ROS) and oxidative injury in neuronal cells. We tested the potential neuroprotective function of compound 13 (C13), a novel AMP-activated protein kinase (AMPK) activator, against OGD-R. We show that C13 pretreatment protected SH-SY5Y neuronal cells and primary hippocampal neurons from OGD-R. C13 activated AMPK signaling in SH-SY5Y cells and primary neurons. It significantly inhibited OGD-R-induced apoptosis activation in neuronal cells. Conversely, AMPKα1 shRNA or knockout reversed C13-mediated neuroprotection against OGD-R. C13 potently inhibited OGD-R-induced ROS production and oxidative stress in SH-SY5Y cells and primary neurons. Furthermore, C13 induced Keap1 downregulation and Nrf2 activation, causing Nrf2 stabilization, nuclear accumulation, and expression of Nrf2-dependent genes. Nrf2 silencing or knockout in SH-SY5Y cells abolished C13-mediated neuroprotection against OGD-R. In conclusion, C13 activates AMPK-Nrf2 signaling to protect neuronal cells from OGD-R.
Highlights
In the pathogenesis of stroke, ischemia-reperfusion leads to significant oxidative injury, causing severe damage to neurons [1, 2]
We show that compound 13 (C13) activates AMP-activated protein kinase (AMPK) signaling to attenuate oxygen glucose deprivation (OGD)-R-induced oxidative injury in neuronal cells
Assaying of cell death by measuring medium lactate dehydrogenase (LDH) release further demonstrated that Oxygen glucose deprivation-reoxygenation (OGD-R) induced significant SH-SY5Y cell death (Figure 1C), and this effect was significantly inhibited by pretreatment with C13 (5–25 μM; Figure 1C)
Summary
In the pathogenesis of stroke, ischemia-reperfusion leads to significant oxidative injury, causing severe damage to neurons [1, 2]. Ischemia-reperfusion is mimicked by oxygen glucose deprivation (OGD)-reoxygenation (OGD-R) [3,4,5,6]. OGD-R induces the production of reactive oxygen species (ROS), resulting in neuronal cell death and apoptosis [5, 7]. ROS inhibition (i.e., by adding antioxidants) can protect neuronal cells from OGD-R [5, 7]. AMP-activated protein kinase (AMPK) is a master energy sensor. Its activation is vital for energy and metabolism homeostasis [8]. Recent studies have shown that forced activation of AMPK, by genetic and/or pharmacological methods, will promote cell survival under different stress conditions [11]. The prosurvival function of AMPK is achieved through regulation of AMPK’s downstream effectors
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