Introduction: Recently the sonic hedgehog (shh) signaling pathway has been shown to play an important role in regulating the repair and regenerative responses to brain injury, including ischemia. However, the precise cellular components that express and upregulate shh gene and the cellular components that respond to shh signaling remain to be identified.

Methods: A cortical ischemic stroke model was utilized in a series of mice in which conditional deletion of the shh gene was accomplished. Behavioral deficits were analyzed and compared to animals treated with post-stroke shh signaling agonist treatment to placebo. Cortical ischemia was accomplished via an middle cerebral artery occlusion model.

Results: Conditional deletion of the shh gene both in SVZ and in penumbra nestin-expressing cells lead to more severe behavioral deficits in shh iKO mice after cortical stroke (total distance traveled= 87.9+14.6% of prestroke level for wt mice and 48.9+6.3% of prestroke level for shh iKO mice, p=0.020; Total movement number= 67.7+6.8% of prestroke level in wt and 50.0+8.5% in shh iKO mice, p=0.014). In contrast, animals given post-stroke treatment of shh signaling agonist demonstrated less deficits in behavioral function compared to vehicle treated mice (pre stroke: total distance traveled=19630.4+1302.3cm for vehicle group and 20217.0+1386.4 cm for SAG treatment group, p=0.97; total movement number= 5316+200.7 for vehicle group and 5478.9+235.8 for SAG treatment group, p=0.88 and 7 days post stroke: total distance traveled=10461.7+864.2cm for vehicle group and 15368.1+1741.3 cm for SAG treatment group, p=0.02; total movement number= 3288.9+224.9 for vehicle group and 4317.3+396.8 for SAG treatment group, p=0.03).

Conclusions: In summary, our data demonstrates that shh signaling plays critical and ongoing roles in response to ischemic injury and modulation of shh signaling in vivo alters the functional outcome after cortical ischemic injury.

Patient Care: translational research leading to improved stroke treatment

Learning Objectives: discuss the potential role that shh gene activation plays in cerebral recovery following ischemic injury

References: Yu Luo. "Cell-based therapy for stroke", Journal of Neural Transmission, 10/14/2010 46. Bambakidis NC, Petrullis M, Kui X, Rothstein B, Karampelas I, Kuang Y, Selman WR, Lamanna JC, Miller RH. Improvement of neurological recovery and stimulation of neural progenitor cell proliferation by intrathecal administration of Sonic hedgehog. J Neurosurg 116:1114-20, 2012