Resolvin D2 protects against cerebral ischemia/reperfusion injury in rats

Gang Zuo,Haiying Li,Haitao Shen,Xiang Li,Rutao Mu,Gang Chen,Zhong Wang,Dongping Zhang

doi:10.1186/s13041-018-0351-1

Abstract

Cerebral ischemia/reperfusion (I/R) injury is a critical factor leading to a poor prognosis for ischemic stroke patients. ω-3 fatty acid supplements taken as part of a daily diet have been shown to improve the prognosis of patients with ischemic stroke. In this study, we aimed to investigate the potential effects of resolvin D2 (RvD2), a derivative of ω-3 fatty acids, and its possible advantage on cerebral I/R injury in rats. Cerebral I/R caused by middle cerebral artery occlusion and reperfusion (MCAO/R) was established in Sprague-Dawley rats. First, in rats fed a regular diet, the MCAO/R stimulus led to a significant decrease in endogenous production of RvD2. Exogenous supply of RvD2 via intraperitoneal injection reversed MCAO/R-induced brain injury, including infarction, inflammatory response, brain edema, and neurological dysfunction. Meanwhile, RvD2 reversed the MCAO/R-induced decrease in the protein level of GPR18, which has been identified as a receptor for RvD2, especially in neurons and brain microvascular endothelial cells (BMVECs). Furthermore, RvD2 exerted rescue effects on MCAO/R-induced neuron and BMVEC death. Moreover, GPR18 antagonist O-1918 could block the rescue effects of RvD2, possibly at least partially though the GPR18-ERK1/2-NOS signaling pathway. Finally, compared with ω-3 fatty acid supplements, RvD2 treatment had a better rescue effect on cerebral infarction, which may be due to the MCAO/R-induced decrease in 5-lipoxygense phosphorylation and subsequent RvD2 generation. In conclusion, compared with ω-3 fatty acids, RvD2 may be an optimal alternative and complementary treatment for ischemic stroke patients with recanalization treatment.

Highlights

Ischemic stroke is a common cause of long-term disability and is the second leading cause of death worldwide
Middle cerebral artery occlusion (MCAO)/R led to a significant decrease in the endogenous production of Resolvin D2 (RvD2) In order to elucidate the endogenous production of RvD2 after I/R, we detected the RvD2 level in brain tissue after middle cerebral artery occlusion and reperfusion (MCAO/R) by enzyme-linked immunosorbent assay (ELISA) in rats fed a regular diet
The results revealed that the endogenous RvD2 levels were significantly decreased in the MCAO/R group compared with the sham group (Fig. 1a)

Summary

Introduction

Ischemic stroke is a common cause of long-term disability and is the second leading cause of death worldwide. BMVECs represent main targets for the reactive oxygen species (ROS) and inflammatory response produced during cerebral I/R [4]. Neuronal apoptosis and necrosis are other central pathological processes in I/R-induced brain injury. Inflammatory cytokines such as tumor necrosis factor α (TNF-α) and Resolvin D2 (RvD2), a member of the resolvin family, is produced from ω-3 polyunsaturated fatty acids after a series of catalyzed reactions by lipoxygenases [6]. Ω-3 fatty acids are able to cross the BBB effectively via its receptors to enter brain tissue [7]. It has been shown that both RvD2 and resolvin D1 can regulate the chronic inflammatory process that occurs in the adipose tissue of obese patients [8]. Aging rats treated with DHA were found to exhibit improved

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