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Poststroke Sonic Hedgehog Agonist Treatment Improves Functional Recovery by Enhancing Neurogenesis and Angiogenesis

Background and Purpose— Because of the limitation in treatment window of the r-tPA (recombinant tissue-type plasminogen activator), the development of delayed treatment for stroke is needed. In this study, we examined the efficacy of delayed poststroke treatment (post 3–8 days) of the sonic hedgehog pathway agonist on functional recovery and the underlying mechanisms. Methods— We evaluated functional recovery at 1 month after stroke using locomotion analysis and Barnes maze test for cognitive function. We used a genetically inducible neural stem cell–specific reporter mouse line (nestin-CreERT2-R26R-YFP) to label and track their proliferation, survival, and differentiation in ischemic brain. Brain tissue damage, angiogenesis, and cerebral blood flow recovery was evaluated using magnetic resonance imaging techniques and immunostaining. Results— Our results show that delayed treatment of sonic hedgehog pathway agonist in stroke mice results in enhanced functional recovery both in locomotor function and in cognitive function at 1 month after stroke. Furthermore, using the Nestincre-ERT2-YFP mice, we showed that poststroke sonic hedgehog pathway agonist treatment increased surviving newly born cells derived from both subventricular zone and subgranular zone neural stem cells, total surviving DCX+ (Doublecortin) neuroblast cells, and neurons (NeuN+/YFP+) in the ischemic brain. Sonic hedgehog pathway agonist treatment also improved the brain tissue repair in ischemic region supported by our T2-weighted magnetic resonance imaging, cerebral blood flow map by arterial spin labeling, and immunohistochemistry (&agr;-smooth muscle actin and CD31 immunostaining). Conclusions— These data confirm an important role for the hedgehog pathway in poststroke brain repair and functional recovery, suggesting a prolonged treatment window for potential treatment strategy to modulate sonic hedgehog pathway after stroke.