Inhibition of microRNA‐148b‐3p alleviates oxygen‐glucose deprivation/reoxygenation‐induced apoptosis and oxidative stress in HT22 hippocampal neuron via reinforcing Sestrin2/Nrf2 signalling

Abstract

MicroRNAs (miRNAs) have emerged as crucial regulators of neuronal injury during cerebral ischaemia/reperfusion injury. Various miRNAs are dysregulated during this pathological process; however, the precise role of these miRNAs in regulating neuronal injury remains largely unknown. In the current study, we explored the potential function of microRNA‐148b‐3p (miR‐148b‐3p) in regulating neuronal injury induced by oxygen‐glucose deprivation/reoxygenation (OGD/R) in vitro, a cellular model for mimicking cerebral ischaemia/reperfusion injury. We found that miR‐148b‐3p expression was significantly decreased in neurons in response to OGD/R exposure. Importantly, miR‐148b‐3p overexpression decreased cell viability and exacerbated apoptosis and reactive oxygen species (ROS) production in OGD/R‐exposed neurons. By contrast, miR‐148b‐3p inhibition improved cell viability and decreased apoptosis and ROS production in OGD/R‐exposed neurons. Notably, Sestrin2, a cytoprotective gene, was identified as a miR‐148b‐3p target gene. miR‐148b‐3p inhibition markedly increased Sestrin2 expression as well as the activation of nuclear factor erythroid‐2‐related factor 2 (Nrf2) antioxidant signalling. Moreover, silencing of Sestrin2 or Nrf2 significantly reversed the miR‐148‐3p‐inhibition‐mediated protective effect in OGD/R‐injured neurons. Overall, these results demonstrate that miR‐148b‐3p inhibition protects neurons from OGD/R‐induced apoptosis and ROS production through reinforcing Nrf2 antioxidant signalling via upregulation of Sestrin2. Our study indicates that the miR‐148b‐3p/Sestrin2/Nrf2 axis plays an important role in regulating neuronal injury and may serve as a potential therapeutic target for providing neuroprotection during cerebral ischaemia/reperfusion injury.

MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress

“…Mitogen-activated protein kinase (MAPK) (Liu et al , 2019a, Ola-Davies et al , 2019 and mammalian target of rapamycin (mTOR) (Qiao et al , 2019, Yuan et al , 2019 can act as upstream mediators of the Nrf2 signaling pathway. Based on these studies, we can conclude that Nrf2 pathway may be a down-stream mediator of the miRs (Chi et al , 2019, Du et al , 2019, Qin et al , 2019, Wu et al , 2019a.…”

Sestrin2 protects against traumatic brain injury by reinforcing the activation of Nrf2 signaling

“…24 Moreover, the up-regulation of SESN2 protects neurons from oxygen-glucose deprivation/re-oxygenation-induced apoptosis and oxidative stress in vitro . 15,25 These studies suggest a considerable neuroprotective function of SESN2. Consistently, in this study, we found that SESN2 expression was induced in cortical neurons injured by scratch, an in vitro model of TBI.…”

Sestrin2 as a gatekeeper of cellular homeostasis: Physiological effects for the regulation of hypoxia‐related diseases

“…SESN2 is closely associated with these processes, especially oxygen free radical damage. A study by Du et al 85 demonstrated that SESN2 alleviated oxygen‐glucose deprivation and reoxygenation‐induced apoptosis via the NRF2 pathway. Besides, SESN2 overexpression markedly decreased cerebral I/R injury by upregulating NRF2 in the nucleus 86 .…”