Recombinant human erythropoietin (rhEPO) alleviates early brain injury following subarachnoid hemorrhage in rats: possible involvement of Nrf2-ARE pathway.
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 20s. In SAH+rhEPO group, rhEPO was administered i.p. at 1000U/kg starting 5 min after the induction of SAH and repeated every 8h 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.
Zhang
Jian
J
Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu Province, PR China.
Zhu
Yun
Y
Zhou
Dai
D
Wang
Zhong
Z
Chen
Gang
G
D000818:Animals; D001483:Base Sequence; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology; D017931:DNA Primers; D004921:Erythropoietin / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013345:Subarachnoid Hemorrhage / Q000150:complications*
D017931:DNA Primers; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011994:Recombinant Proteins; D004921:Erythropoietin