Nanshan Hospital, The First Affiliated Hospital of Guangzhou University of Chinese Medicine (Shenzhen Nanshan Hospital of Chinese Medicine), Shenzhen 518052, China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Brain Res Bull. 2024 Oct 15;217:111084. doi: 10.1016/j.brainresbull.2024.111084. Epub 2024 Sep 18.
Subarachnoid hemorrhage (SAH) is a severe neurological event lacking of effective therapy. Early brain injury (EBI) and delayed neurological dysfunction are important cause in the poor prognosis of patients with SAH. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation has been implicated in many inflammatory lesion pathogeneses including SAH. Dl-3-n-butylphthalide (NBP) has been reported to possess substantial anti-inflammatory properties, which is beneficial for various neurodegenerative diseases. However, the effect and molecular mechanisms of NBP on SAH have not been clearly identified. We designed this study to investigate the effect of NBP against EBI and delayed neurological dysfunction after SAH and to reveal the possible underlying mechanism. The adult mice were subjected to endovascular perforation SAH model or sham operation. Mice were randomized to sham group, SAH group, or SAH+NBP group. The EBI (short-term study) was studied at 48 h post-SAH and delayed neurological dysfunction (long-term study) at 21 days post-SAH. The results suggested that NBP evidently alleviated the EBI in mice at 48 h post-SAH, as shown by elevating neurological score, reducing brain edema, blood-brain barrier disruption, neuronal loss, and astrocyte aggregation, as well as ameliorating cerebral vasospasm. Moreover, NBP was able to improve long-term neurobehavioral functions and decrease neuronal apoptosis at 21 days after SAH. Significantly, NBP treatment also inhibited the expressions of NLRP3, ASC, caspase-1, cleaved-caspase-1, IL-1β, IL-18, GSDMD and GSDMD-N in both EBI and delayed neurological dysfunction induced by SAH. Our findings suggested that NBP treatment exerts a profound neuroprotective effect against early brain injury and delayed neurological dysfunction induced by SAH, at least partially through regulating NLRP3 inflammasome signaling pathway and its related inflammation and pyroptosis.
蛛网膜下腔出血（SAH）是一种缺乏有效治疗方法的严重神经事件。早期脑损伤（EBI）和迟发性神经功能障碍是 SAH 患者预后不良的重要原因。核苷酸结合寡聚化结构域（NOD）样受体含pyrin 结构域 3（NLRP3）炎性小体的激活与包括 SAH 在内的许多炎症损伤的发病机制有关。二氢-α-生育三烯酚（NBP）已被报道具有实质性的抗炎特性，对各种神经退行性疾病有益。然而，NBP 对 SAH 的作用和分子机制尚不清楚。我们设计了这项研究，以探讨 NBP 对 SAH 后 EBI 和迟发性神经功能障碍的影响，并揭示可能的潜在机制。成年小鼠接受血管内穿孔 SAH 模型或假手术。将小鼠随机分为假手术组、SAH 组和 SAH+NBP 组。SAH 后 48 小时进行 EBI（短期研究），SAH 后 21 天进行迟发性神经功能障碍（长期研究）。结果表明，NBP 明显减轻了 SAH 后 48 小时小鼠的 EBI，表现为神经评分升高、脑水肿减轻、血脑屏障破坏、神经元丢失和星形胶质细胞聚集减轻，以及脑血管痉挛改善。此外，NBP 还能改善 SAH 后 21 天的神经行为功能，减少神经元凋亡。值得注意的是，NBP 治疗还抑制了 NLRP3、ASC、caspase-1、cleaved-caspase-1、IL-1β、IL-18、GSDMD 和 GSDMD-N 在 EBI 和 SAH 诱导的迟发性神经功能障碍中的表达。我们的研究结果表明，NBP 治疗对 SAH 引起的早期脑损伤和迟发性神经功能障碍具有显著的神经保护作用，至少部分是通过调节 NLRP3 炎性小体信号通路及其相关炎症和细胞焦亡。
