Resolvin D2 protects against cerebral ischemia/reperfusion injury in rats

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.

Lipoxin and Resolvin Receptors Transducing the Resolution of Inflammation in Cardiovascular Disease

“…These results reveal that adding to the pro-resolving effect of DRV2/GPR18 on immune cells, the receptor participates in the healing of tissues through the activation of the Gαi protein in endothelial cells. In a rat model of cerebral ischemia/reperfusion injury, Zuo et al (2018) observed that the middle cerebral artery occlusion and reperfusion stimulus led to a significant decreased in RvD2 production and DRV2/GPR18 expression. Exogenous administration of RvD2 reversed the effect especially on neurons and brain microvascular endothelial cells ( Zuo et al, 2018 ).…”

“…In a rat model of cerebral ischemia/reperfusion injury, Zuo et al (2018) observed that the middle cerebral artery occlusion and reperfusion stimulus led to a significant decreased in RvD2 production and DRV2/GPR18 expression. Exogenous administration of RvD2 reversed the effect especially on neurons and brain microvascular endothelial cells ( Zuo et al, 2018 ). These effects were partly mediated by increased ERK1/2 phosphorylation and the increased production of neuronal NOS (nNOS) and endothelial NOS (eNOS).…”

“…These effects were partly mediated by increased ERK1/2 phosphorylation and the increased production of neuronal NOS (nNOS) and endothelial NOS (eNOS). When pretreated with O-1918, the RvD2 function was partly abolished ( Zuo et al, 2018 ).…”

Docosahexaenoic acid, 22:6n‐3: Its roles in the structure and function of the brain

“…They induce remote functional recovery after brain damage (Bisicchia et al, 2018). Resolvin D2 and aspirin‐triggered resolvin D2 protect from cerebral ischemic injury through ERK1/2 phosphorylation followed by stimulation of nNOS or eNOS to inhibit programmed neuronal cell death and increase zonula occludens‐1 for the maintenance of blood‐brain barrier integrity (Zuo et al, 2018). Resolvin D3, resolvin D5, aspirin‐triggered resolvin D3, and aspirin‐triggered resolvin D5 halt neuroinflammatory process (Dalli et al, 2013; Hong et al, 2005).…”

Resolution of Inflammation in Neurodegenerative Diseases: The Role of Resolvins

“…The activation of the DRV2/GRP18 axis has been reported to reduce neutrophil infiltration in a mouse model of hind limb ischemia/reperfusion [26]. In a mouse model of cerebral ischemia/reperfusion injury, exogenous administration of RvD2 reduced infarction area, inflammatory response, and brain edema [27]. In kidney ischemia/reperfusion injury, RvD1 administration reduced infiltrating leukocytes and preserved glomerular function [28].…”