Abstract
Delayed cerebral injury (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is a preventable injury that would improve patient’s outcomes if an effective treatment can be developed. The most common long-term disability in SAH patients is cognitive dysfunction. Contrary to the common theory that damage from DCI originates solely from ischemia caused by cerebral vasospasm, inflammation has been shown to be important independent mediator of DCI. Neutrophil activation in the meninges is a critical step to developing late spatial memory deficits in a murine model of SAH. Importantly, myeloperoxidase (MPO) null mice do not develop meningeal neutrophilia and are protected from spatial memory deficits. In this study, WT C57BL/6J mice administered a single dose of the myeloperoxidase inhibitor (MPOi) AZD5904 (180mM/kg) have fewer neutrophils in the meninges 6 days after the hemorrhage and have fewer neutrophils leave the meningeal blood vessels to enter the meninges (79 ± 20 vs 28 ± 24, p < 0.01). Interestingly, the intraperitoneal (IP) route of administration had a larger effect than the intrathecal route suggesting that MPO mediated neutrophil extravasation occurs in the luminal blood vessel. Second, mice administered AZD5904 (20mM/kg) intraperitoneally (IP) for 4 consecutive days starting 2 days after the hemorrhage do not develop delayed spatial memory dysfunction (multiple-comparisons analysis, p < 0.001 F (2, 22) = 10.11). In conclusion, MPOi given systemically prevents neutrophil entry into the meninges and prevents spatial memory dysfunction in mice. MPOi is a promising strategy for translation to patients with aneurysmal SAH.