Oxidative Stress-mediated Sprouty-related Protein with an EVH1 Domain 1 Down-regulation Contributes to Resisting Oxidative Injury in Microglia

Abstract

Microglia play an ambiguous role in injury or repair after ischemia–reperfusion, and the induced oxidative stress serves as an important signal, mediates direct toxicity to nerve cells, and eventually simulates complex physiological processes such as activation of microglia to repair the damaged area. Herein, we show that sprouty-related protein with an EVH1 domain 1 (SPRED1) may act as a regulatory node in this phenomenon. The ischemic brain of an ischemia–reperfusion rat model constructed by middle cerebral artery occlusion (MCAO) showed an increase in oxidative stress and downregulation of SPRED1 expression. Hydrogen peroxide (H2O2)-simulated oxidative damage exerted a fluctuating regulatory effect on SPRED1 level in BV2 microglia, which is highly consistent with its regulatory effect on nuclear factor kappa B (NF-κB) transcription factor p65. Interestingly, SPRED1 overexpressed in BV2 cells did not exert any regulatory effect on p38 mitogen-activated protein kinase (MAPK), NF-κB p65, and pro-inflammatory cytokines. However, treatment of BV2 cells overexpressing SPRED1 with H2O2 led to significant changes in the above phenomena as well as their viability and apoptosis. In the absence of H2O2 induction, SPRED overexpression alone did not mediate such an effect. These findings indicate that SPRED1 tends to maintain intracellular homeostasis of signals, but the oxidative stress derived from ischemia-reperfusion can easily degrade SPRED1 and consequently re-activate these restricted signals and alter the behavior of microglia. Thus, our study reveals a novel role of SPRED1 in microglia in response to cerebral ischemia-induced oxidative stress.