Department of Neurosurgery, University Hospital Basel, Basel, Switzerland.
Department of Neurosurgery, Kantonsspital Aarau, Tellstrasse, 5001, Aarau, Switzerland.
Transl Stroke Res. 2021 Oct;12(5):894-904. doi: 10.1007/s12975-020-00880-3. Epub 2021 Jan 6.
Early brain injury (EBI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia (DCI) are common complications of subarachnoid hemorrhage (SAH). Inflammatory processes in the cerebrospinal fluid (CSF) are one of the causes for such complications. Our aim to study the effects of an IL-6 receptor antagonist (Tocilizumab) examines the occurrence of DCVS, neuronal cell death, and microclot formation in an acute SAH rabbit model. Twenty-nine New Zealand white rabbits were randomized into one of three groups as the SAH, SAH + Tocilizumab, and sham groups. In SAH groups, hemorrhage was induced by extracranial-intracranial arterial blood shunting from the subclavian artery into the cisterna magna under intracranial pressure (ICP) monitoring. In the second group, Tocilizumab was given once intravenously 1 h after SAH induction. Digital subtraction angiography was performed, and CSF and blood were sampled before and after (day 3) SAH induction. IL-6 plasma and CSF levels were measured. TUNEL, FJB, NeuN, and caspase-3 immunostaining were used to assess cell apoptosis, neurodegeneration, and neuronal cell death, respectively. Microclot formation was detected by fibrinogen immunostaining. Between baseline and follow-up, there was a significant reduction of angiographic DCVS (p < 0.0001) in the Tocilizumab compared with the SAH group. Tocilizumab treatment resulted in decreased neuronal cell death in the hippocampus (p = 0.006), basal cortex (p = 0.001), and decreased microclot formation (p = 0.02). Tocilizumab reduced DCVS, neuronal cell death, and microclot formation in a rabbit SAH model, and could be a potential treatment to prevent DCVS and DCI in SAH patients.
早期脑损伤 (EBI)、迟发性脑血管痉挛 (DCVS) 和迟发性脑缺血 (DCI) 是蛛网膜下腔出血 (SAH) 的常见并发症。脑脊液 (CSF) 中的炎症过程是这些并发症的原因之一。我们的目的是研究白细胞介素 6 受体拮抗剂 (托珠单抗) 对急性蛛网膜下腔出血兔模型中 DCVS、神经元细胞死亡和微栓形成的影响。29 只新西兰白兔随机分为三组：SAH 组、SAH+托珠单抗组和假手术组。在 SAH 组中，通过锁骨下动脉向脑池内颅内压 (ICP) 监测下的蛛网膜下腔外-颅内动脉分流，诱导出血。在第二组中，在 SAH 诱导后 1 小时静脉内给予托珠单抗一次。进行数字减影血管造影，并在 SAH 诱导前后 (第 3 天) 采集 CSF 和血液样本。测量 IL-6 血浆和 CSF 水平。TUNEL、FJB、NeuN 和 caspase-3 免疫染色分别用于评估细胞凋亡、神经退行性变和神经元细胞死亡。纤维蛋白原免疫染色检测微栓形成。与基线相比，在托珠单抗组中，血管造影 DCVS 明显减少（p<0.0001）。托珠单抗治疗导致海马（p=0.006）、基底皮质（p=0.001）神经元细胞死亡减少，微栓形成减少（p=0.02）。托珠单抗可减少兔蛛网膜下腔出血模型中的 DCVS、神经元细胞死亡和微栓形成，可能是预防 SAH 患者 DCVS 和 DCI 的潜在治疗方法。
