Roles of astrocytic sonic hedgehog production and its signal for regulation of the blood-brain barrier permeability

Sonic hedgehog (Shh) is a secreted glycopeptide belonging to the hedgehog family that is essential for morphogenesis during embryonic development. The Shh signal is mediated by two membrane proteins, Patched-1 (Ptch-1) and Smoothened (Smo), following the activation of transcription factors such as Gli. Shh decreases the permeability of the blood-brain barrier (BBB) and plays a key role in its function. In the damaged brain, BBB function is remarkably disrupted. The BBB disruption causes brain edema and neuroinflammation resulting from the extravasation of serum components and the infiltration of inflammatory cells into the cerebral parenchyma. Multiple studies have suggested that astrocyte is a source of Shh and that astrocytic Shh production is increased in the damaged brain. In various experimental animal models of acute brain injury, Shh or Shh signal activators alleviate BBB disruption by increasing tight junction proteins in endothelial cells. Furthermore, activation of astrocytic Shh signaling reduces reactive astrogliosis, neuroinflammation, and increases the production of vascular protective factors, which alleviates BBB disruption in the damaged brain. These findings suggest that astrocytic Shh and Shh signaling protect BBB function in the damaged brain and that target drugs for Shh signaling are expected to be novel therapeutic drugs for acute brain injuries.