resolvin-d2 and Brain-Injuries

Early brain injury (EBI) is the early phase of secondary complications arising from subarachnoid hemorrhage (SAH). G protein-coupled receptor 18 (GPR18) can exert neuroprotective effects during ischemia. In this study, we investigated the roles of GPR18 in different brain regions during EBI using a GPR18 agonist, resolvin D2 (RvD2). Location and dynamics of GPR18 expression were assessed by immunohistochemistry and western blotting in a rat model of SAH based on endovascular perforation. RvD2 was given intranasally at 1 h after SAH, and SAH grade, brain water content and behavior were assayed before sacrifice. TUNEL and dihydroethidium staining of the cortex were performed at 24 h after SAH. Selected brain regions were also examined for pathway related proteins using immunofluorescence and Western blotting. We found that GPR18 was expressed in meninges, hypothalamus, cortex and white matter before EBI. After SAH, GPR18 expression was increased in meninges and hypothalamus but decreased in cortex and white matter. RvD2 improved neurological scores and brain edema after SAH. RvD2 attenuated mast cell degranulation and reduced expression of chymase and tryptase expression in the meninges. In the hypothalamus, RvD2 attenuated inflammation, increased expression of proopiomelanocortin and interleukin-10, as well as decreased expression of nerve peptide Y and tumor necrosis factor-α. In cortex, RvD2 alleviated oxidative stress and apoptosis, and protected the blood-brain barrier. RvD2 also ameliorated white matter injury by elevating myelin basic protein and suppressing amyloid precursor protein. Our results suggest that GPR18 may help protect multiple brain regions during EBI, particularly in the cortex and hypothalamus. Upregulating GPR18 by RvD2 may improve neurological functions in different brain regions via multiple mechanisms.

Topics: Animals; Apoptosis; Brain Edema; Brain Injuries; Docosahexaenoic Acids; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Subarachnoid Hemorrhage

Ischemic stroke is an acute and severe neurological disease, resulting in disability and death. Reperfusion to an ischemic brain is a means to reverse brain damage after stroke; however, this causes secondary tissue damage induced by inflammation responses, called ischemia/reperfusion (I/R) injury. Adhesion of neutrophils to endothelial cells underlies the initiation of inflammation in I/R. Inspired by this interaction, we report a drug delivery system comprised of neutrophil membrane-derived nanovesicles loaded with Resolvin D2 (RvD2) that can enhance resolution of inflammation, thus protecting brain damage during ischemic stroke. In the study, the middle cerebral artery occlusion (MCAO) mouse model was developed to mimic ischemic stroke. Using intravital microscopy of a live mouse brain, we visualized the binding of nanovesicles to inflamed brain vasculature for delivery of therapeutics to ischemic stroke lesions in real-time. We also observed that RvD2-loaded nanovesicles dramatically decreased inflammation in ischemic stroke and improved mouse neurological functions. Our study provides a strategy to inhibit neuroinflammation using neutrophil-derived nanovesicles for ischemic stroke therapy.

Topics: Animals; Brain Injuries; Cell Adhesion; Cell Membrane; Disease Models, Animal; Docosahexaenoic Acids; Drug Carriers; Drug Delivery Systems; Endothelial Cells; Infarction, Middle Cerebral Artery; Inflammation; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Neutrophils; Reperfusion Injury; Stroke