Cell‐free hemoglobin and heme in the subarachnoid space disrupt endothelial cell function. This occurs by generating reactive oxygen species and decreasing nitric oxide (NO) production.6 In summary, these events lead to significant endothelial dysfunction resulting in DCI most strongly correlates with the 3‐month outcome.7
The only current proven treatment for post‐SAH DCI is prophylactic nimodipine driven by data from a single large clinical trial.8 However, a Cochrane worst‐case‐scenario meta‐analysis showed no statistically significant difference between nimodipine and placebo, casting doubt on its benefit.9 Even with nimodipine, up to 30% of patients will suffer cerebral infarction.10 This leaves a significant gap in the treatment of post‐SAH DCI.
Adropin is a potential therapeutic to bridge the current gap in treatments for post‐SAH DCI. It is a 4.5 kDa peptide encoded by the energy homeostasis‐associated (ENHO) gene, discovered in 2008 by Kumar et al. as a regulator of lipid metabolism and insulin sensitivity, that is highly expressed in the liver and brain tissue of mice.11 Adropin has a direct effect on endothelial cell function by increasing VEGFR2 (vascular endothelial growth factor receptor 2) expression12 and by regulating of NO bioavailability through stimulation of eNOS (endothelial NO synthase) phosphorylation at Ser1177.13 Our laboratory has demonstrated that adropin is protective against both early and delayed brain injury following a single injection of the SAH model in mice.14 However, its efficacy when administered at a clinically relevant time point, with a severe double‐injection SAH model, has not yet been evaluated. The median time from SAH symptoms to treatment is 169 minutes, making a therapeutic with efficacy at a delayed time point critical.15 In this study, we seek to investigate the therapeutic effects of adropin in severe double‐injection SAH (compared with mild single blood injection), including its efficacy in a mouse model within a clinically relevant time window.