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【文献研读】石杉碱甲通过抑制内皮细胞焦亡改善自发性蛛网膜下腔出血后的神经功能缺损
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【概要描述】该研究表明，石杉碱甲注射液可抑制内皮细胞焦亡、抗氧化应激，改善蛛网膜下腔出血（SAH）后的早期脑损伤。
【文献研读】石杉碱甲通过抑制内皮细胞焦亡改善自发性蛛网膜下腔出血后的神经功能缺损
【概要描述】该研究表明，石杉碱甲注射液可抑制内皮细胞焦亡、抗氧化应激，改善蛛网膜下腔出血（SAH）后的早期脑损伤。
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- 日期：2024-06-03
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近期《Huperzine A ameliorates neurological deficits after spontaneous subarachnoid hemorrhage through endothelial cell pyroptosis inhibition》在 Acta Biochimica et Biophysica Sinica（生物化学与生物物理学报）发表。该研究由西湖大学医学院附属杭州市第一人民医院神经外科和体检中心团队完成。该研究表明，石杉碱甲注射液可抑制内皮细胞焦亡、抗氧化应激，改善蛛网膜下腔出血（SAH）后的早期脑损伤。
背景介绍
Subarachnoid hemorrhage (SAH) is a severe stroke type [1,2] mainly caused by aneurysm rupture and is characterized by high morbidity and mortality [3]. Additionally, survivors often have cognitive impairments affecting patients’ daily functionality, labor capacity, and quality of life [4]. Early brain injury within 72 h is considered to be the main cause of poor prognosis in SAH patients [5]. Alleviating early brain damage contributes to the improvement on survival rate and prognosis of SAH patients [6,7]. Therefore, inhibiting early brain damage in SAH patients is an important therapeutic strategy for improving the prognosis of SAH patients. It has been revealed that neuronal apoptosis and blood-brain barrier (BBB) destruction are the hallmark events of early brain injury after SAH, are closely related to irreversible acute brain injury after SAH, and are important factors for poor prognosis in SAH patients [8,9]. In addition, the increased permeability of the BBB allows immune molecules to migrate to the brain parenchyma, which further exacerbates brain injury. It is suggested that inhibiting BBB dysfunction can effectively ameliorate early brain injury after SAH and is an important therapeutic method for improving the prognosis of SAH patients.
蛛网膜下腔出血（SAH）是一种严重的脑卒中类型[1,2]，主要由颅内动脉瘤破裂引起，其特点是高致残率和高死亡率[3]。此外，幸存者通常存在认知障碍，影响患者的日常功能、劳动能力和生活质量[4]。SAH后72 小时内的早期脑损伤被认为是影响SAH 患者预后不良的主要原因之一[5]。减轻早期脑损伤有助于改善 SAH 患者的生存率和预后[6,7]。因此，抑制 SAH 患者早期脑损伤是改善 SAH 患者预后的重要治疗策略。研究表明，神经元凋亡和血脑屏障（BBB）破坏是 SAH后早期脑损伤的标志性事件，与 SAH后不可逆的急性脑损伤密切相关，是 SAH 患者预后不良的重要因素[8,9]。此外，血脑屏障的通透性增加使免疫分子迁移到脑实质，这进一步加剧了脑损伤。研究表明，抑制血脑屏障功能障碍可有效改善 SAH后的早期脑损伤，是改善 SAH 患者预后的重要方法。
材料和方法
Animal handling
SPF male SD rats were fed according to standard animal care proposal. After one week of adaptive feeding, the following treatments were carried out: (1) sham group: SD rats were subjected to a sham operation; (2) model group: SD rats were treated for SAH, and saline was applied intraperitoneally; and (3) treatment group: SD rats were treated for SAH, and Huperzine A (0.1 mg/kg, WEPON, Drug Approval Number: H20183340) was applied intraperitoneally. The procedure was as follows: after the SD rats were anesthetized, 0.35 mL of fresh autologous blood (20 s) without heparin was slowly injected into the anterior cistern of the optic chiasm, and the animals were kept head down at 30℃ for 20 min. The rats were immediately injected with 2 mL of normal saline and returned to the cage alone. The body temperature was maintained at 37°C. In the sham group, the SD rats (male, 250 -300 g) were injected with normal saline instead of autologous blood; in the model group and treatment group, the placebo (saline) and Huperzine A were administered intraperitoneally 12 h after autologous blood injection.
SPF 雄性 SD 大鼠按照标准动物饲养方案进行饲养。适应性饲养一周后，进行以下处理：（1）假手术组：SD 大鼠进行假手术操作；（2）模型组：SD 大鼠诱导蛛网膜下腔出血（SAH），腹腔注射生理盐水；（3）治疗组：SD 大鼠诱导 SAH， 腹腔注射石杉碱甲（0.1 mg/kg，南宫28制药集团有限公司，药品批准号：H20183340）。操作步骤如 下：SD 大鼠麻醉后，缓慢注入不含肝素的新鲜自体血（20 s，0.35 mL）至视交叉前池，将动物头向下保持在 30°C 下20 分钟。立即注射2 mL生理盐水， 将大鼠单独放回笼中，体温维持在 37°C。假手术组中，SD大鼠（雄性，250-300 g）注射生理盐水代替自体血。在模型组和治疗组中，大鼠自体血注射后 12 小时分别经腹腔注射安慰剂（生理盐水）和石杉碱甲。
研究结果
一、石杉碱甲改善 SAH 大鼠神经功能缺陷和脑组织神经元凋亡。
二、石杉碱甲通过改善 SAH 大鼠紧密连接蛋白的表达来抑制 BBB 功能障碍。
三、石杉碱甲改善了 SAH 大鼠脑组织内皮细胞的焦亡。
四、石杉碱甲改善了 SAH 大鼠脑组织的氧化应激，抑制了氧化应激介导的内皮细胞焦亡。
五、石杉碱甲抑制 SAH 大鼠脑组织内皮细胞 NF-κB 通路的激活。
结论：植物单体石杉碱甲在肥胖相关的认知障碍[32]、阿尔茨海默病和其他形式的痴呆[33]以及重复性创伤性脑损伤[34]中起神经保护作用。在这项研究中，我们发现石杉碱甲可以显著改善 SAH 大鼠的神经功能缺损评分和平衡评分。据报道，石杉碱甲对神经损伤的改善作用与其对神经元凋亡的抑制作用有关[17,18]。在这项研究中，我们发现石杉碱甲可以显着降低脑组织中神经元凋亡的水平。我们的结果表明，石杉碱甲可以抑制神经细胞凋亡，改善 SAH 后的早期神经功能缺损。石杉碱甲已在多项临床研究中被证明是安全的。本研究补充了石杉碱甲在神经损伤疾病中的神经保护功能，为 SAH 后早期脑损伤提供了新的潜在疗法。
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