Clarithromycin Ameliorates Early Brain Injury After Subarachnoid Hemorrhage via Suppressing Periostin-Related Pathways in Mice.

Abstract

Subarachnoid hemorrhage (SAH) remains a life-threatening disease, and early brain injury (EBI) is an important cause of poor outcomes. The authors have reported that periostin, a matricellular protein, is one of key factors of post-SAH EBI. Clarithromycin (CAM) is a worldwide antibiotic that can inhibit periostin expression. This study aimed to investigate whether CAM suppressed EBI after experimental SAH, focusing on blood-brain barrier (BBB) disruption, an important pathology of EBI. C57BL/6 male adult mice underwent endovascular perforation SAH modeling (n=139) or sham operation (n=30). Different dosages (25, 50, or 100mg/kg) of CAM or the vehicle (n=16, 52, 13, and 58, respectively) were randomly administered by an intramuscular injection 5min after SAH induction. Post-SAH 50mg/kg CAM treatment most effectively improved neurological scores and brain water content at 24 and 48h and reduced immunoglobulin G extravasation at 24h compared with vehicle-treated SAH mice (p<0.01). Western blotting showed that post-SAH BBB disruption was associated with increased expressions of periostin, phosphorylated signal transducer and activator of transcription 1 and 3, matrix metalloproteinase-9, and the consequent degradation of zonula occludens-1, which were suppressed by 50mg/kg CAM treatment (p<0.05, respectively, versus vehicle-treated SAH mice). Periostin and its related molecules were upregulated in capillary endothelial cells and neurons after SAH. An intracerebroventricular injection of recombinant periostin blocked the neuroprotective effects of CAM in SAH mice (n=6, respectively; p<0.05). In conclusion, this study first demonstrated that CAM improved post-SAH EBI in terms of BBB disruption at least partly via the suppression of periostin-related pathways.