N-乙酰神经氨酸脑蛋白水解物II饮品对新生鼠脑损伤的保护作用及早期安全性研究

摘要/Abstract

摘要： 目的：考察N-乙酰神经氨酸脑蛋白水解物II饮品的早期安全性，探索其对新生鼠感染性脑损伤和新生鼠缺氧缺血性脑病的治疗作用。方法：早期安全性实验中，不同剂量N-乙酰神经氨酸脑蛋白水解物Ⅱ饮品给药组连续灌胃28 d，通过小鼠体重、脏器系数、血生化毒性指标和组织病理切片研究其早期安全性。构建新生鼠感染性脑损伤模型，检测给药后脑组织皮层炎症因子水平变化；检测造模后4周的抑郁样行为。建立新生大鼠缺氧缺血性脑病模型，观察造模后3 d的体重变化、短期行为学以及皮层炎症因子水平变化；测定造模后4周的长期神经行为学指标。结果：早期安全性实验显示，与对照组相比，不同剂量N-乙酰神经氨酸脑蛋白水解物Ⅱ饮品给药28d后体重、脏器系数、血生化毒性指标和组织病理均无显著差异。新生鼠感染性脑损伤实验显示，造模后脑皮层炎症因子明显升高，而不同剂量给药组可显著降低皮层炎症因子的表达，并改善造模引起的长期神经缺陷。新生鼠缺氧缺血性脑病实验表明，不同剂量药物对造模后大鼠体重的降低有所改善，神经行为明显改善，脑皮层炎症因子表达减少；药物也能拮抗造模引起的SOD活性下降及MDA含量的升高，并改善长期神经行为学功能。结论：N-乙酰神经氨酸脑蛋白水解物Ⅱ饮品安全无毒且对新生鼠感染性脑损伤和新生鼠缺氧缺血性脑病具有明显的保护作用。

关键词: font-size:medium, ">N-乙酰神经氨酸脑蛋白水解物Ⅱ饮品；早期安全性；新生鼠缺氧缺血性脑病；炎症因子

Abstract: Objective： To observe the early safety of N-acetylneuraminic acid cerebroprotein hydrolysate Ⅱ beverage， and to explore its therapeutic effect on neonatal rats with infectious brain injury and neonatal rats with hypoxic-ischemic brain injury. Methods： In the early safety experiment， different doses of N-acetylneuraminic acid cerebroprotein hydrolysate Ⅱ beverages were given intragastrically for 28 days and its early safety was studied by mouse body weight， organ coefficient， blood biochemical toxicity index and histopathological sections. Construct a neonatal rat model with infectious brain injury and detect the expression of inflammatory factors in the cerebral cortex， and depression-like behaviors 4 weeks after modeling. Establish a neonatal rat hypoxic-ischemic encephalopathy model， and the rats were sacrificed 3 days after modeling. Body weight， short-term behavior and cortical inflammatory factor levels were performed. Long-term neurobehavioral testing was performed 4 weeks after modeling. Results： Early safety test showed that there were no significant differences in body weight， organ coefficient， blood biochemical toxicity indexes and histopathology after 28 days of administration of different doses of N-acetylneuraminic cerebroprotein hydrolysate Ⅱ beverage. The experiment of the neonatal rat infectious brain injury showed that the inflammatory factors in the cerebral cortex were significantly increased in model， but the expression of inflammatory factors was significantly reduced after administration. The experiment of the neonatal rat hypoxic-ischemic encephalopathy showed that different doses of drugs improved the body weight， neurobehavior， and decreased expression of inflammatory factors in the cerebral cortex； drugs can also antagonize the decrease in SOD activity and the increase in MDA content of model， and improve long-term neurobehavioral function. Conclusion： N-Acetylneuraminic acid cerebroprotein hydrolysate Ⅱ beverage is safe， and has a protective effect on neonatal rat infectious brain injury and neonatal rat hypoxic-ischemic encephalopathy.

Key words: font-size:medium, ">N-acetylneuraminic acid cerebroprotein hydrolysate Ⅱ beverage； Early safety； Neonatal rat hypoxic-ischemic encephalopathy； Inflammatory factor

中图分类号:

宋锦乾, 姜其慧, 余芳, 余炳胜, 杭伟锋, 庞涛. N-乙酰神经氨酸脑蛋白水解物II饮品对新生鼠脑损伤的保护作用及早期安全性研究[J]. 中国药物评价, 2021, 38(5): 391-397.

SONG Jin-qian, JIANG Qi-hui, YU Fang, YU Bing-shen, HANG Wei-feng, PANG Tao. The Protective Effect of N-acetylneuraminic Acid Cerebroprotein Hydrolysate Ⅱ Beverage on Neonatal Rats with Brain Injury and Early Safety Study[J]. CHINESE JOURNAL OF DRUG EVALUATION, 2021, 38(5): 391-397.

参考文献

[1]Dixon BJ， Reis C， Ho WM， et al. Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy[J]. Int J Mol Sci， 2015， 16(9)： 22368-22401.
     [2]Isabel Benavente-Fernandez， Juan J Ramos-Rodriguez，Carmen Infante-Garcia， et al. Altered plasma-type gelsolin and amyloid-β in neonates with hypoxic-ischaemic encephalopathy under therapeutic hypothermia[J]. Cereb Blood Flow Metab， 2019， 39(7)： 1349-1354.
     [3]Qin Xingping，Cheng Jing，Zhong Yi, et al. Mechanism and Treatment Related to Oxidative Stress in Neonatal Hypoxic-Ischemic Encephalopathy[J] .Front Mol Neurosci， 2019， 12： 88.
     [4]Savran M， Aslankoc R， Ozmen O， et al. Agomelatine could prevent brain and cerebellum injury against LPS-induced neuroinflammation in rats[J]. Cytokine，2020，127：154957.
     [5]Martinello KA， Meehan C， Avdic-Belltheus A， et al. Acute LPS sensitization and continuous infusion exacerbates hypoxic brain injury in a piglet model of neonatal encephalopathy[J]. Sci Rep， 2019，9(1)：10184.
     [6]Davies A， Wassink G， Bennet L， et al. Can we further optimize therapeutic hypothermia for hypoxic-ischemic encephalopathy?[J]. Neural Regen Res， 2019， 14(10)： 1678-83.
     [7]Nanetti L， Vignini A， Raffaelli F， et al. Sialic acid and sialidase activity in acute stroke[J]. Dis Markers， 2008， 25(3)： 167-173.
     [8]Brainin M. Cerebrolysin： a multi-target drug for recovery after stroke[J]. Expert Rev Neurother， 2018， 18(8)： 681-687.
     [9]刘玲，邱相君，和素娜，等.芍药苷对LPS脑损伤模型小鼠氧化应激和能量代谢的影响[J]. 中国中药杂志，2015，40(14)：2871-2875.
     [10]Gao C-L， Hou G-G， Liu J， et al. Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti-Neuroinflammatory Agents for Ischemic Stroke[J]. Angew Chem Int Ed Engl， 2020， 59(6)： 2429-2439.
     [11]李芸达，颜祖弟，黄涛，等.羌活不同提取物对小鼠脑缺血缺氧的保护作用[J]. 中国医院药学杂志，2015，35(4)：296-299.
     [12]邓俊超，罗冲，朱小石，等.佛司可林通过TLR4/STAT3通路对新生大鼠缺血缺氧性脑损伤氧自由基水平和炎症反应的调节作用[J]. 免疫学杂志，2019，35(10)：829-837.
     [13]Xu J， Feng Z， Wang X， et al. hUC-MSCs Exert a Neuroprotective Effect via Anti-apoptotic Mechanisms in a Neonatal HIE Rat Model[J]. Cell Transplant， 2019， 28(12)： 1552-1559.
     [14]尹利顺，吕莉莉，龚彦胜，等.吴茱萸挥发油对大鼠长期毒性实验研究[J]. 中国药物警戒，2015，12(1)：20-25，29.
     [15]Liu Zehui，Wang Wanyan，Huang Tingyu，et al. CH(Ⅱ)， a cerebroprotein hydrolysate， exhibits potential neuro-protective effect on Alzheimer′s disease[J]. PLoS One， 2019， 14(9)： e0222757.
     [16]曹悦悦，万玉骁，李阳，等.关于新生儿缺血缺氧性脑病的研究进展[J]. 现代生物医学进展，2018，18(3)：585-587，600.