鞘磷脂酶 A2 预处理通过多种机制对手术诱导的脑损伤大鼠模型发挥神经保护作用。
Multiple mechanisms underlying neuroprotection by secretory phospholipase A2 preconditioning in a surgically induced brain injury rat model.
机构信息
Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Physiology, Jinan University School of Medicine, Guangzhou, Guangdong Province, China.
Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
出版信息
Exp Neurol. 2018 Feb;300:30-40. doi: 10.1016/j.expneurol.2017.10.022. Epub 2017 Oct 24.
BACKGROUND
Intra-operative bleeding, post-operative brain edema and neuroinflammation are major complications in patients with surgical brain injury (SBI). Phospholipase A2 (PLA2) is the upstream enzyme which initiates the PLA2, 5-lipoxygenase (5-LOX) and leukotriene B4 (LTB4) inflammatory pathway. We hypothesized PLA2preconditioning (PPC) prior to SBI can activate endogenous anti-inflammatory responses to protect against SBI. This study evaluated if PPC can ameliorate neurosurgical complications and elucidated PPC-mediated possible protective mechanisms in a rat SBI model.
METHODS
Total 105 adult male Sprague Dawley rats were used for this study. SBI was induced by partial resection of the right frontal lobe. PLA2 or 0.9% NaCl was injected via rats' tail vein for 3 consecutive days prior to SBI. For mechanism study, a selective PLA2 inhibitor, Manoalide and 5-LOX inhibitor, Zileuton were injected intravenously with PPC to elucidate the role of PLA2 and 5-LOX in PPC-mediated anti-inflammatory effects. Brain water content (BWC) and lung water content, neurological tests, ELISA, western blot, immunohistochemistry, white blood cells (WBC) count, and spectrophotometric assay for intra-operative hemorrhage volume were evaluated.
RESULTS
First, PPC reduced brain water content, intra-operative bleeding, and improved neurological function after SBI. Second, PPC decreased 5-LOX expression and brain leukocyte infiltration, while increasing glial fibrillary acidic protein (GFAP) expression in the peri-resection brain tissue after SBI. Third, PPC induced peripheral inflammation represented by mild pulmonary inflammation and increased peripheral blood WBC count and LTB4 level. Lastly, PPC increased blood glucose concentration and glucocorticoid levels after SBI. In addition, PPC mediated above-mentioned changes were partially reversed by administration of PLA2 inhibitor, Manoalide and 5-LOX inhibitor, Zileuton.
CONCLUSIONS
PPC conferred neuroprotection against SBI via multi-target involvement induced anti-inflammatory mechanisms.
背景
术中出血、术后脑水肿和神经炎症是手术性脑损伤（SBI）患者的主要并发症。磷脂酶 A2（PLA2）是启动 PLA2、5-脂氧合酶（5-LOX）和白三烯 B4（LTB4）炎症途径的上游酶。我们假设 SBI 前进行 PLA2 预处理（PPC）可以激活内源性抗炎反应，从而预防 SBI。本研究评估了 PPC 是否可以改善神经外科并发症，并在大鼠 SBI 模型中阐明了 PPC 介导的可能保护机制。
方法
本研究共使用 105 只成年雄性 Sprague Dawley 大鼠。通过部分切除右侧额叶诱导 SBI。在 SBI 前连续 3 天通过大鼠尾静脉注射 PLA2 或 0.9%NaCl。为了进行机制研究，在 PPC 中静脉注射选择性 PLA2 抑制剂 Manoalide 和 5-LOX 抑制剂 Zileuton，以阐明 PLA2 和 5-LOX 在 PPC 介导的抗炎作用中的作用。评估脑水含量（BWC）和肺水含量、神经学测试、ELISA、Western blot、免疫组织化学、白细胞（WBC）计数和术中出血量的分光光度测定。
结果
首先，PPC 降低了 SBI 后的脑水含量、术中出血并改善了神经功能。其次，PPC 降低了 5-LOX 表达和脑白细胞浸润，同时增加了 SBI 后切除脑组织周围的胶质纤维酸性蛋白（GFAP）表达。第三，PPC 诱导了以轻度肺炎症为代表的外周炎症，并增加了外周血 WBC 计数和 LTB4 水平。最后，PPC 在 SBI 后增加了血糖浓度和糖皮质激素水平。此外，PLA2 抑制剂 Manoalide 和 5-LOX 抑制剂 Zileuton 的给药部分逆转了 PPC 介导的上述变化。
结论
PPC 通过多靶点参与诱导抗炎机制对 SBI 提供神经保护作用。
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