Smoothened Agonist Treatment Mitigates Vasogenic Edema, Neuroinflammation, and Neurological Dysfunction Following Traumatic Brain Injury in Mice

Traumatic brain injury (TBI)-a serious brain damage caused by accidents, falls, and sports-causes vasogenic edema, neuroinflammation, and neurological dysfunction resulting from blood-brain barrier disruption. Sonic hedgehog (Shh), a secretory protein belonging to the hedgehog family, protects cerebrovascular and neuronal function via the patched-1 (Ptch-1)-smoothened (Smo)-Gli pathway. In this study, we investigated the effects of Smo agonists (Shh and SAG) and antagonist (Jervine) on vasogenic edema, neuroinflammation, and neurological dysfunction in mice following TBI. Male ddy mice (8 weeks old) were used to minimize the influence of gonadal hormones on the results. A TBI model was established by inflicting a fluid percussion injury (FPI) on mouse cerebrum or cultured cells. Shh expression increased in mouse cerebrums and cultured astrocytes after FPI. Vasogenic edema was assessed by Evans blue extravasation into brain tissue and increased brain water content. Evans blue extravasation and brain water content increased after FPI. Repeated intracerebroventricular administration of recombinant Shh reduced Evans blue extravasation and brain water content in the cerebrum after FPI, whereas treatment with Jervine, an Smo antagonist, aggravated these conditions. Recombinant Shh administration also decreased the expression of inflammatory cytokines and chemokines in the cerebrum after FPI. Notably, repeated intravenous administration of SAG, a small-molecule Smo agonist, reduced FPI-induced vasogenic edema and neuroinflammation, and improved neurological dysfunction in mice. Furthermore, SAG treatment increased the expression of vascular protective factors and tight junction proteins. These results suggest that Smo agonists are promising therapeutic agents for TBI.