Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Heilongjiang.
The Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai; and.
J Neurosurg. 2017 Oct;127(4):716-724. doi: 10.3171/2016.7.JNS152995. Epub 2016 Oct 14.
OBJECTIVE Inflammation and apoptosis are two key factors contributing to secondary brain injury after intracerebral hemorrhage (ICH). The objective of this study was to evaluate the effects of lithium posttreatment on behavior, brain atrophy, inflammation, and perihematomal cell death. Furthermore, the authors aimed to determine the role of the pro-apoptotic glycogen synthase kinase-3β (GSK-3β) after experimental ICH. METHODS Male Sprague-Dawley rats (n = 108) were subjected to intracerebral infusion of semicoagulated autologous blood. Window of opportunity and dose optimization studies of lithium on ICH-induced injury were performed by measuring neurological deficits. Animals with ICH received vehicle administration or lithium posttreatment (60 mg/kg) for up to 21 days. Hemispheric atrophy was evaluated. Perihematomal cell death was quantified through terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL). The number of myeloperoxidase (MPO)-positive neutrophils and OX42-positive microglia in the perihematomal areas were calculated. Western blotting was used for the quantification of GSK-3β, heat shock protein 70 (HSP70), nuclear factor-κB p65 (NF-κB p65), and cy-clooxygenase-2 (COX-2). RESULTS Lithium, at a dose of 60 mg/kg initiated from 2 hours after injury, exhibited the best effects of improving neurological outcomes 3, 5, 7, 14, 21, and 28 days after ICH, reduced the hemispheric atrophy at 42 days after surgery, and reduced the number of TUNEL-positive cells, MPO-positive neutrophils, and OX42-positive microglia in the perihematomal areas. Furthermore, lithium posttreatment modulated GSK-3β, increased HSP70, and decreased NF-κB p65 and COX-2 expression in the ipsilateral hemisphere. CONCLUSIONS Lithium posttreatment at a dose of 60 mg/kg, initiated beginning 2 hours after injury, improves functional and morphological outcomes, and inhibits inflammation and perihematomal cell death in a rat model of semicoagulated autologous blood ICH through inactivation of GSK-3β.
炎症和细胞凋亡是导致脑出血（ICH）后继发性脑损伤的两个关键因素。本研究旨在评估锂治疗对行为、脑萎缩、炎症和血肿周围细胞死亡的影响。此外，作者旨在确定实验性 ICH 后促凋亡糖原合酶激酶-3β（GSK-3β）的作用。
雄性 Sprague-Dawley 大鼠（n = 108）接受半凝固自体血脑内输注。通过测量神经功能缺损来进行锂对 ICH 损伤的治疗窗和剂量优化研究。ICH 动物接受载体或锂治疗（60mg/kg），最长可达 21 天。评估半球萎缩。通过末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记（TUNEL）定量检测血肿周围细胞死亡。计算血肿周围区髓过氧化物酶（MPO）阳性中性粒细胞和 OX42 阳性小胶质细胞的数量。Western 印迹用于定量测定 GSK-3β、热休克蛋白 70（HSP70）、核因子-κB p65（NF-κB p65）和环氧化酶-2（COX-2）。
剂量为 60mg/kg 的锂，于损伤后 2 小时开始给药，在 ICH 后 3、5、7、14、21 和 28 天改善神经功能预后的效果最佳，术后 42 天减轻半球萎缩，减少血肿周围区 TUNEL 阳性细胞、MPO 阳性中性粒细胞和 OX42 阳性小胶质细胞的数量。此外，锂治疗后调节 GSK-3β，增加 HSP70，降低同侧半脑 NF-κB p65 和 COX-2 的表达。
剂量为 60mg/kg 的锂治疗，于损伤后 2 小时开始给药，可改善功能和形态学预后，并通过抑制 GSK-3β 的活性，抑制大鼠半凝固自体血 ICH 模型中的炎症和血肿周围细胞死亡。
