Enhanced Neurogenesis and Collaterogenesis by Sodium Danshensu TreatmentAfter Focal Cerebral Ischemia in Mice

摘要

Ischemic stroke remains a serious threat to human life. There are limited effectivetherapies for the treatment of stroke. We have previously demonstrated that angiogenesisand neurogenesis in the brain play an important role in functional recovery followingischemic stroke. Recent studies indicate that increased arteriogenesis and collateralcirculation are determining factors for restoring reperfusion and outcomes of strokepatients. Danshensu, the root extract, is used intreatments of various human ischemic events in traditional Chinese medicine. Itstherapeutic mechanism, however, is not well clarified. Due to its proposed effect onangiogenesis and arteriogenesis, we hypothesized that danshensu could benefit strokerecovery through stimulating neurogenesis and collaterogenesis in the post-ischemia brain.Focal ischemic stroke targeting the right sensorimotor cortex was induced in wild-typeC57BL6 mice and transgenic mice expressing green fluorescent protein (GFP) to label smoothmuscle cells of brain arteries. Sodium danshensu (SDS, 700 mg/kg) was administeredintraperitoneally (i.p.) 10 min after stroke and once daily until animals were sacrificed.To label proliferating cells, 5-bromo-2′-deoxyuridine (BrdU; 50 mg/kg, i.p.) wasadministered, starting on day 3 after ischemia and continued once daily until sacrifice.At 14 days after stroke, SDS significantly increased the expression of vascularendothelial growth factor (VEGF), stromal-derived factor-1 (SDF-1), brain-derivedneurotrophic factor (BDNF), and endothelial nitric oxide synthase (eNOS) in theperi-infarct region. SDS-treated animals showed increased number of doublecortin(DCX)-positive cells. Greater numbers of proliferating endothelial cells and smooth musclecells were detected in SDS-treated mice 21 days after stroke in comparison with vehiclecontrols. The number of newly formed neurons labeled by NeuN and BrdU antibodies increasedin SDS-treated mice 28 days after stroke. SDS significantly increased the newly formedarteries and the diameter of collateral arteries, leading to enhanced local cerebral bloodflow recovery after stroke. These results suggest that systemic sodium danshensu treatmentshows significant regenerative effects in the post-ischemic brain, which may benefitlong-term functional recovery from ischemic stroke.