Recombinant human erythropoietin (rhEPO) alleviates early brain injury following subarachnoid hemorrhage in rats: Possible involvement of Nrf2–ARE pathway

Abstract

Recombinant human erythropoietin (rhEPO) has demonstrated beneficial effects against vasospasm and brain damage at the late stage of subarachnoid hemorrhage (SAH); however few investigations have been done about the effect of rhEPO on SAH-induced early brain injury (EBI) and also the underlying mechanisms remain unclear. This study was undertaken to evaluate the influence of rhEPO on the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2–ARE) pathway and early brain injury in rats after SAH. Adult male SD rats were divided into four groups: (1) control group ( n = 18); (2) SAH group ( n = 18); (3) SAH + vehicle group ( n = 18); and (4) SAH + rhEPO group ( n = 18). The rat SAH model was induced by injection of 0.3 ml fresh arterial, non-heparinized blood into the prechiasmatic cistern in 20 s. In SAH + rhEPO group, rhEPO was administered i.p. at 1000 U/kg starting 5 min after the induction of SAH and repeated every 8 h for 48 h. Brain samples were extracted at 48 h after SAH. As a result, we found that treatment with rhEPO markedly increased expressions of Nrf2–ARE pathway related agents, such as Nrf2, heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO1), and glutathione S-transferase α-1 (GST-α1). Administration of rhEPO following SAH significantly ameliorated EBI, such as cortical apoptosis, brain edema, and blood–brain barrier (BBB) impairment. In conclusion, post-SAH rhEPO administration may attenuate EBI in this SAH model, possibly through activating Nrf2–ARE pathway and modulating cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.