Adropin Reduces Early Brain Injury and Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage in a Mouse Model.

BACKGROUND: Delayed cerebral ischemia remains a major cause of morbidity after aneurysmal subarachnoid hemorrhage (SAH), and effective therapies beyond nimodipine are lacking. Adropin, an endogenous peptide that regulates endothelial function and nitric oxide signaling, has shown neurovascular protective effects in experimental SAH. However, its efficacy when administered at clinically relevant delayed time points and in severe SAH remains unclear. METHODS: A severe double-injection SAH model was induced in male C57BL/6 mice. Synthetic adropin or vehicle was administered beginning 6 or 12 hours after SAH, with repeat dosing according to experimental end points. Outcomes included eNOS (endothelial nitric oxide synthase) signaling, blood-brain barrier integrity, cerebral vasospasm, microvascular thrombosis, neuronal apoptosis, and neurobehavioral performance. Additional studies were conducted in energy homeostasis-associated knockout mice and tamoxifen-induced brain endothelial-specific adropin deletion. Statistical analyses were performed using Prism 10. RESULTS: Endogenous adropin expression and eNOS signaling were reduced 24 hours after SAH. Adropin administration restored total eNOS expression. Adropin preserved tight junction integrity, selectively restoring occludin expression, and significantly reduced microvascular thrombosis. When administered 6 hours after SAH, adropin attenuated delayed cerebral vasospasm, reduced neuronal apoptosis, improved recognition memory and mitigated anxiety-like behavior at 1 month post SAH. In contrast, adropin administered 12 hours after SAH conferred partial and inconsistent behavioral benefit and did not significantly reverse vasospasm. Adropin attenuated vasospasm and improved behavioral outcomes in energy homeostasis-associated knockout mice. Endothelial-specific adropin deletion did not exacerbate vasospasm, and systemic adropin administration did not further improve vessel diameter in this model. CONCLUSIONS: Adropin confers robust neurovascular protection after severe SAH when administered within a clinically relevant early therapeutic window. These findings highlight adropin as a promising candidate for mitigating endothelial dysfunction, vasospasm, and long-term neurological deficits following SAH, with timing of intervention playing a critical role in therapeutic efficacy.