PEGylated Erythropoietin Protects against Brain Injury in the MCAO-Induced Stroke Model by Blocking NF-κB Activation
Jun Hyung Im1,†, In Jun Yeo1,†, Chul Ju Hwang1, Kyung Sun Lee2 and Jin Tae Hong1,*
1College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160,
2R&D Center, Ts Corporation, Incheon 22300, Republic of Korea
*E-mail: jinthong@chungbuk.ac.kr
Tel: +82-43-261-2813, Fax: +82-43-268-2732
The first two authors contributed equally to this work.
Received: September 9, 2019; Revised: October 12, 2019; Accepted: October 28, 2019; Published online: December 9, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Cerebral ischemia exhibits a multiplicity of pathophysiological mechanisms. During ischemic stroke, the reactive oxygen species (ROS) concentration rises to a peak during reperfusion, possibly underlying neuronal death. Recombinant human erythropoietin (EPO) supplementation is one method of treating neurodegenerative disease by reducing the generation of ROS. We investigated the therapeutic effect of PEGylated EPO (P-EPO) on ischemic stroke. Mice were administered P-EPO (5,000 U/kg) via intravenous injection, and middle cerebral artery occlusion (MCAO) followed by reperfusion was performed to induce in vivo ischemic stroke. P-EPO ameliorated MCAO-induced neurological deficit and reduced behavioral disorder and the infarct area. Moreover, lipid peroxidation, expression of inflammatory proteins (cyclooxygenase-2 and inducible nitric oxide synthase), and cytokine levels in blood were reduced by the P-EPO treatment. In addition, higher activation of nuclear factor kappa B (NF-κB) was found in the brain after MCAO, but NF-κB activation was reduced in the P-EPO-injected group. Treatment with the NF-κB inhibitor PS-1145 (5 mg/kg) abolished the P-EPO-induced reduction of infarct volume, neuronal death, neuroinflammation, and oxidative stress. Moreover, P-EPO was more effective than EPO (5,000 U/kg) and similar to a tissue plasminogen activator (10 mg/kg). An in vitro study revealed that P-EPO (25, 50, and 100 U/ml) treatment protected against rotenone (100 nM)-induced neuronal loss, neuroinflammation, oxidative stress, and NF-κB activity. These results indicate that the administration of P-EPO exerted neuroprotective effects on cerebral ischemia damage through anti-oxidant and anti-inflammatory properties by inhibiting NF-κB activation.
Keywords: PEGylated erythropoietin, Nuclear factor kappa B, Reactive oxygen species, Stroke, Inflammation


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