Limon Safiye, Coulibaly Aminata P, Provencio Jose Javier
Department of Neurology, University of Virginia, Charlottesville, VA, 22908, USA.
Department of Neuroscience, West Virginia University, Morgantown, WV, 26506, USA.
Neurocrit Care. 2024 Dec 10. doi: 10.1007/s12028-024-02169-x.
Delayed cerebral injury (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is a preventable injury that would improve patient outcomes if an effective treatment can be developed. The most common long-term disability in patients with SAH 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 an important independent mediator of DCI.
Neutrophil infiltration of the meninges is a critical step in developing late spatial memory deficits in a murine model of SAH and may serve as a surrogate marker for disease progression. Importantly, myeloperoxidase (MPO) null mice do not develop meningeal neutrophilia and are protected from spatial memory deficits.
In this study, wildtype mice administered a single dose of the MPO inhibitor (MPOi) AZD5904 at peak neutrophil entry day have a higher percentage of neutrophils that remain in the meningeal blood vessel 6 days after the hemorrhage suggesting neutrophil extravasation into the meninges is inhibited (79 ± 20 vs. 28 ± 24, p < 0.01). Interestingly, the intraperitoneal route of administration has a larger effect than the intrathecal route suggesting that MPO inhibition is best administered systemically not in the central nervous system. Second, mice administered AZD5904 intraperitoneal for 4 consecutive days starting 2 days after the hemorrhage do not develop delayed spatial memory dysfunction (two-way analysis of variance, p > 0.001 F [2, 22] = 10.11).
Systemic MPOi prevents neutrophil entry into the meninges and prevents spatial memory dysfunction. MPOi is a promising strategy for translation to patients with aneurysmal SAH.
动脉瘤性蛛网膜下腔出血（SAH）后的迟发性脑损伤（DCI）是一种可预防的损伤，如果能开发出有效的治疗方法，将改善患者的预后。SAH患者最常见的长期残疾是认知功能障碍。与DCI损伤仅源于脑血管痉挛引起的缺血这一普遍理论相反，炎症已被证明是DCI的一个重要独立介质。
在SAH小鼠模型中，脑膜中性粒细胞浸润是导致晚期空间记忆缺陷的关键步骤，可作为疾病进展的替代标志物。重要的是，髓过氧化物酶（MPO）基因敲除小鼠不会出现脑膜嗜中性粒细胞增多，并且可免受空间记忆缺陷的影响。
在本研究中，在中性粒细胞进入高峰期给予单剂量MPO抑制剂（MPOi）AZD5904的野生型小鼠，出血后6天留在脑膜血管中的中性粒细胞百分比更高，这表明中性粒细胞向脑膜的渗出受到抑制（79±20 vs. 28±24，p<0.01）。有趣的是，腹腔给药途径比鞘内给药途径的效果更大，这表明MPO抑制最好通过全身给药而非中枢神经系统给药。其次，出血后2天开始连续4天腹腔注射AZD5904的小鼠不会出现延迟性空间记忆功能障碍（双向方差分析，p>0.001，F[2, 22]=10.11）。
全身MPOi可防止中性粒细胞进入脑膜并预防空间记忆功能障碍。MPOi是一种有望应用于动脉瘤性SAH患者的策略。
