Post-stroke estradiol treatment enhances neurogenesis in the subventricular zone of rats after permanent focal cerebral ischemia

Pretreatment with estrogen has been shown to increase subventricular zone (SVZ) neurogenesis and improve neurological outcome after cerebral ischemia reperfusion injury in mice. However, the potential of post-stroke estrogen administration to enhance neurogenesis is largely unknown. In this study, we explored whether post-stroke estradiol administration had any effect on SVZ neurogenesis in a rat model of permanent focal cerebral ischemia and elucidated the potential mechanism of its effects. Male Sprague-Dawley rats (250-280 g) were divided into sham-operated (n=10), control (n=40), and estradiol-treated (n=40) groups. 5-Bromo-2-deoxyuridine (BrdU) was used to label proliferating cells. Immunohistochemistry was used to detect neurogenesis in the ischemic ipsilateral SVZ at 1, 3, 7 and 14. days following ischemia. The protein levels of hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) in ischemic ipsilateral SVZ were determined by Western blotting at 6, 12, 24 and 72. h after ischemia. Improved behavioral deficits and reduced infarct size were seen in estradiol-treated rats (P<0.05). Post-stroke estradiol administration increased BrdU-labeled cells, nestin-positive cells, doublecortin (DCX)-positive cells and BrdU+/DCX+ cells in the ischemic ipsilateral SVZ at all time points (P<0.05). Treatment with estradiol also increased HIF-1α and VEGF protein levels in the ischemic ipsilateral SVZ at all time points examined (P<0.05). These findings indicate that post-stroke estradiol administration promotes SVZ neurogenesis in rats, probably by increasing HIF-1α and VEGF protein expression.