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 MessagesAstrocytes 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
Highlights
During cerebral ischemia/reperfusion (I/R) injury, oxidative stress is thought to be an important mediator of pathogenesis [1]
We analyzed the changes of DJ-1 in ischemic rats with increasing reperfusion time (Fig. 2a, d) and showed higher levels of DJ-1 at reperfusion 24 h when compared with the sham group, and there were no differences among the other treatment groups
These results suggest that DJ-1 expression is upregulated when co-cultured cells are subjected to oxygen and glucose deprivation/reoxygenation (OGD/R), and the maximal effect was observed in the 5-h group
Summary
During cerebral ischemia/reperfusion (I/R) injury, oxidative stress is thought to be an important mediator of pathogenesis [1]. Previous studies have shown that astrocytes protect neurons against oxidative stress and affect neuronal survival in some neurodegenerative diseases [2, 4]. Studying astrocyte-neuron interactions and identifying astrocytederived neuroprotective molecules may help treat cerebral ischemia/reperfusion injury. DJ-1 is a multifunctional protein that regulates transcription [6, 7], antioxidant stress [8, 9], and anti-apoptotic processes [6, 10]. It is abundantly expressed in reactive astrocytes
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