Department of Neurosurgery, Kuwana City Medical Center, 3-11 Kotobuki-cho, Kuwana, Mie 511-0061, Japan.
Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Oxid Med Cell Longev. 2021 Nov 11;2021:9739977. doi: 10.1155/2021/9739977. eCollection 2021.
Blood-brain barrier (BBB) disruption is a common and critical pathology following subarachnoid hemorrhage (SAH). We investigated the BBB disruption property of secreted protein acidic and rich in cysteine (SPARC) after SAH. A total of 197 rats underwent endovascular perforation to induce SAH or sham operation. Small interfering ribonucleic acid (siRNA) for SPARC or scrambled siRNA was administered intracerebroventricularly to rats 48 h before SAH. Anti-SPARC monoclonal antibody (mAb) 236 for functional blocking or normal mouse immunoglobulin G (IgG) was administered intracerebroventricularly 1 h after SAH. Selective integrin V3 inhibitor cyclo(-RGDfK) or phosphate-buffered saline was administered intranasally 1 h before SAH, along with recombinant SPARC treatment. Neurobehavior, SAH severity, brain edema, immunohistochemical staining, and Western blot were evaluated. The expression of SPARC and integrin V3 was upregulated after SAH in the endothelial cells. SPARC siRNA and anti-SPARC mAb 236 prevented neuroimpairments and brain edema through protection of BBB as measured by IgG extravasation 24 and 72 h after SAH. Recombinant SPARC aggravated neuroimpairments and cyclo(-RGDfK) suppressed the harmful neurological effects via inhibition of activated c-Jun N-terminal kinase, p38, and matrix metalloproteinase-9 followed by retention of endothelial junction proteins. SPARC may induce post-SAH BBB disruption via integrin V3 signaling pathway.
血脑屏障（BBB）破坏是蛛网膜下腔出血（SAH）后的一种常见且关键的病理。我们研究了 SAH 后分泌富含半胱氨酸的酸性蛋白（SPARC）的 BBB 破坏特性。共有 197 只大鼠接受血管内穿孔以诱导 SAH 或假手术。在 SAH 前 48 小时，通过脑室内给予 SPARC 的小干扰核糖核酸（siRNA）或乱序 siRNA。在 SAH 后 1 小时，通过脑室内给予 SPARC 功能阻断的单克隆抗体（mAb）236 或正常小鼠免疫球蛋白 G（IgG）。在 SAH 前 1 小时，通过鼻腔给予整合素 V3 选择性抑制剂环（RGDfK）或磷酸盐缓冲盐水，同时给予重组 SPARC 治疗。评估神经行为、SAH 严重程度、脑水肿、免疫组织化学染色和 Western blot。在血管内皮细胞中，SPARC 和整合素 V3 的表达在 SAH 后上调。SPARC siRNA 和抗 SPARC mAb 236 通过保护 BBB，防止 IgG 漏出，从而防止神经损伤和脑水肿，在 SAH 后 24 和 72 小时进行测量。重组 SPARC 加重了神经损伤，环（RGDfK）通过抑制激活的 c-Jun N-末端激酶、p38 和基质金属蛋白酶-9 抑制有害的神经作用，从而保留内皮连接蛋白。SPARC 可能通过整合素 V3 信号通路诱导 post-SAH BBB 破坏。
