Effect of DJ-1 on the neuroprotection of astrocytes subjected to cerebral ischemia/reperfusion injury

Abstract

Abstract: Astrocytes are involved in neuroprotection, and DJ-1 is an important antioxidant protein that is abundantly expressed in reactive astrocytes. However, the role of DJ-1 in astrocytes’ neuroprotection in cerebral ischemia/reperfusion injury and its potential mechanism is unclear. Thus, to explore effects and mechanisms of DJ-1 on the neuroprotection of astrocytes, we used primary co-cultures of neurons and astrocytes under oxygen and glucose deprivation/reoxygenation in vitro and transient middle cerebral artery occlusion/reperfusion in vivo to mimic ischemic reperfusion insult. Lentiviral was used to inhibit and upregulate DJ-1 expression in astrocytes, and DJ-1 siRNA blocked DJ-1 expression in rats. Inhibiting DJ-1 expression led to decreases in neuronal viability. DJ-1 knockdown also attenuated total and nuclear Nrf2 and glutathione (GSH) levels in vitro and vivo. Similarly, loss of DJ-1 decreased Nrf2/ARE-binding activity and expression of Nrf2/ARE pathway-driven genes. Overexpression of DJ-1 yielded opposite results. This suggests that the mechanism of action of DJ-1 in astrocyte-mediated neuroprotection may involve regulation of the Nrf2/ARE pathway to increase GSH after cerebral ischemia/reperfusion injury. Thus, DJ-1 may be a new therapeutic target for treating ischemia/reperfusion injury. Key Messages: Astrocytes protect neurons in co-culture after OGD/RDJ-1 is upregulated in astrocytes and plays an important physiological roles in neuronal protection under ischemic conditionsDJ-1 protects neuron by the Nrf2/ARE pathway which upregulates GSH.