Abstract TP274: Post-stroke Treatment With Docosanoids Promote Functional Recovery, Neurogenesis and Angiogenesis, Attenuate Blood-brain Barrier After Experimental Ischemic Stroke

Abstract

Objective: Ischemic injury induces neurogenesis in the subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of dentate gyrus (DG) promotes the migration of neuroblasts, guided by blood vessels, into the ischemic damaged area. Neurogenesis leads the functional and histological recovery in the ischemic-damaged brain through the proliferation, migration, differentiation and integration of newly generated neural cells into the existing neural circuit. Recently, we have shown that Docosahexaenoic acid (DHA) and Neuroprotectin D1 (NPD1) therapy improves functional and histological outcomes following experimental stroke. It has also been shown that DHA promotes neurite outgrowth of immature neurons, such as embryonic hippocampal cells and embryonic cortical cells. The objective of this study was to explore underlying mechanisms of docosanoid neuroprotection after cerebral ischemia. Methods: Male Sprague-Dawley rats were anesthetized with isoflurane/nitrous oxide, underwent 2h of middle cerebral artery occlusion (MCAo) and treated with DHA (5mg/kg, IV) or NPD1 (5μg/per rat, ICV) and vehicles 1h after. Neuro-behavioral assessments were conducted on days 1, 2, 3 and on weeks 1, 2, 3 or 4. BrdU was injected on days 4, 5 and 6, immunohistochemistry was performed on week 2 or 4, MRI on day 7 and lipidomic analysis at 4 and 5h after onset of stroke. Results: DHA improved short- and long-term behavioral functions and reduced cortical, subcortical and total infarct volumes (by 42%, 47% and 31%, respectively) after 2 weeks and reduced tissue loss by 50% after 4 weeks. DHA increased the number of BrdU + /Ki-67 + , BrdU + /DCX + and BrdU + /NeuN + cells in the cortex, subventricular zone and dentate gyrus and potentiated NPD1 synthesis in the penumbra at 5h after MCAo. NPD1 improved behavior, reduced lesion volumes, protected ischemic penumbra, increased NeuN, GFAP, SMI-71 positive cells and vessels, axonal regeneration in the penumbra and attenuated blood-brain barrier (BBB) after MCAo. Conclusion: We conclude that docosanoid administration increases neurogenesis, angiogenesis, activates NPD1 synthesis in the penumbra and diminishes BBB, which correlates to long-term neurobehavioral recovery after experimental ischemic stroke.