Xie Cuicui, Zhou Kai, Wang Xiaoyang, Blomgren Klas, Zhu Changlian
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
Perinatal Center, Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden; Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
PLoS One. 2014 Sep 11;9(9):e107192. doi: 10.1371/journal.pone.0107192. eCollection 2014.
We have previously shown that lithium treatment immediately after hypoxia-ischemia (HI) in neonatal rats affords both short- and long-term neuroprotection. The aim of this study was to evaluate possible therapeutic benefits when lithium treatment was delayed 5 days, a time point when most cell death is over.
Eight-day-old male rats were subjected to unilateral HI and 2 mmol/kg lithium chloride was injected intraperitoneally 5 days after the insult. Additional lithium injections of 1 mmol/kg were administered at 24 h intervals for the next 14 days. Brain injury was evaluated 12 weeks after HI. Serum cytokine measurements and behavioral analysis were performed before sacrificing the animals.
Brain injury, as indicated by tissue loss, was reduced by 38.7%, from 276.5±27.4 mm3 in the vehicle-treated group to 169.3±25.9 mm3 in the lithium-treated group 12 weeks after HI (p<0.01). Motor hyperactivity and anxiety-like behavior after HI were normalized by lithium treatment. Lithium treatment increased neurogenesis in the dentate gyrus as indicated by doublecortin labeling. Serum cytokine levels, including IL-1α, IL-1β, and IL-6, were still elevated as late as 5 weeks after HI, but lithium treatment normalized these cytokine levels.
Delayed lithium treatment conferred long-term neuroprotection in neonatal rats after HI, and this opens a new avenue for future development of treatment strategies for neonatal brain injury that can be administered after the acute injury phase.
我们之前已经表明，新生大鼠缺氧缺血（HI）后立即进行锂治疗可提供短期和长期神经保护。本研究的目的是评估在HI后5天延迟进行锂治疗的潜在治疗益处，这是大多数细胞死亡已经结束的时间点。
8日龄雄性大鼠接受单侧HI，损伤后5天腹腔注射2 mmol/kg氯化锂。在接下来的14天里，每隔24小时额外注射1 mmol/kg锂。HI后12周评估脑损伤情况。在处死动物前进行血清细胞因子测量和行为分析。
HI后12周，与对照组相比，锂治疗组的组织损失所表明的脑损伤减少了38.7%，从对照组的276.5±27.4 mm³降至169.3±25.9 mm³（p<0.01）。锂治疗使HI后的运动亢进和焦虑样行为恢复正常。双皮质素标记显示，锂治疗增加了齿状回中的神经发生。血清细胞因子水平，包括IL-1α、IL-1β和IL-6，在HI后5周仍升高，但锂治疗使这些细胞因子水平恢复正常。
延迟锂治疗对新生大鼠HI后具有长期神经保护作用，这为急性损伤期后可应用的新生儿脑损伤治疗策略的未来发展开辟了一条新途径。
