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Introduction: Ischemic injury induces neurogenesis in the subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of dentate gyrus (DG), and it promotes the migration of neuroblasts, guided by blood vessels, into the ischemic damaged area. Recently, we have shown that docosahexaenoic acid (DHA; 22:6n-3) therapy improves functional and histological outcomes following experimental stroke. The objective, hence, is to determine whether DHA administration enhances endogenous neurogenesis after cerebral ischemia.Methods: Twenty-one male SD rats were anesthetized with isoflurane and subjected to 2 h of middle cerebral artery occlusion (MCAo) by intraluminal filament. DHA (5 mg/kg, n=10) or saline (n=11) was administered intravenously at 3 h after onset of MCAo (n = 7-10 per group). BrdU was injected on days 4, 5 and 6. DCX (doublecortin), NeuN (a marker for mature neurons), ki-67 (marker for cell proliferation) have been used to test the proliferation, migration and differentiation of neural precursor cells. Behavioral tests were conducted on days 1, 2 and 3 and weeks 1 and 2. Immunohistochemistry with BrdU and ki-67, DCX or NeuN, and histopathology were performed on day 14.Results: DHA-treated animals showed improved neurologic scores compared to the saline group during the two-week survival period. Total, cortical and subcortical infarct areas in the DHA-treated group were significantly attenuated at multiple bregma levels as well as total, cortical and subcortical infarct volumes by 42.4 %, by 47.5 %, and by 31.2 % compared to the vehicle-treated group. The number of BrdU+/ki-67+ cells in DHA-treated rats was increased in cortex by 88 %, SVZ by 40 % and DG by 270 % compared to saline-treated rats. DHA treatment increased the number of BrdU+/DCX+ cells in the cortex by 65 %, the SVZ by 29 % and the DG (by 58 %) compared to saline-treated group. In addition, the numbers of BrdU+/NeuN+ cells were increased in the cortex by 49 %, SVZ by 28 % and DG by 48% compared to vehicle treatment.Conclusion: DHA increased neurogenesis by proliferation, differentiation and migration of neural stem cells in the DG, SVZ and peri-infarct area two weeks after ischemic stroke. In addition, DHA promoted neurobehavioral recovery and reduced infarct volume.