Zhang Yanlu, Chopp Michael, Zhang Yi, Gang Zhang Zheng, Lu Mei, Zhang Talan, Wu Kuan-Han H, Zhang Li, Mahmood Asim, Xiong Ye
Departments of1Neurosurgery.
2Neurology, and.
J Neurosurg. 2019 Sep 6;133(4):1072-1082. doi: 10.3171/2019.6.JNS191027. Print 2020 Oct 1.
The authors previously demonstrated that Cerebrolysin is effective for treatment of mild closed head injury (CHI) when administered 4 hours after injury. The aim of this study was to determine Cerebrolysin's effects on functional and histological outcomes in rats subjected to moderate CHI.
In this randomized, blinded, and vehicle-controlled preclinical trial, male adult Wistar rats subjected to moderate CHI received either Cerebrolysin treatment at a dose of 2.5 ml/kg (n = 13) or vehicle (saline, n = 13) intraperitoneally administered daily for 10 days, starting at 4 hours after injury. Animals were subjected to cognitive and sensorimotor functional tests at multiple time points, and they were killed 3 months after injury. The brains were processed for analyses of neuronal cell loss, amyloid precursor protein, axonal damage, and neurogenesis.
Compared with rats treated with vehicle (saline), rats treated with Cerebrolysin had significantly increased numbers of neuroblasts and newborn mature neurons in the dentate gyrus (DG) and attenuated amyloid precursor protein accumulation and axonal damage in various brain regions, as well as decreased neuronal loss in the DG and cornu ammonis 3 (CA3) region of the hippocampus (p < 0.05). Global testing using generalized estimating equations showed a significant beneficial effect of Cerebrolysin treatment on sensorimotor functional outcomes from 1 day to 3 months after injury compared to that of saline treatment (p < 0.05). Compared with vehicle-treated rats, Cerebrolysin-treated rats showed significantly and robustly improved long-term (up to 3 months) cognitive functional recovery, as measured by social interaction, Morris water maze, novel object recognition, and odor recognition tests. In the Cerebrolysin-treated rats there were significant correlations between multiple histological outcomes and functional recovery evident 3 months after moderate CHI, as indicated by Pearson partial correlation analyses.
The authors' findings demonstrate that Cerebrolysin treatment significantly improves long-term functional and histological outcomes in rats with moderate CHI, with functional outcomes significantly correlated with histological indices of neuroplasticity and neuroprotection. These data indicate that Cerebrolysin may be useful for the treatment of moderate CHI.
作者先前证明，脑蛋白水解物在损伤后4小时给药时对轻度闭合性颅脑损伤（CHI）有效。本研究的目的是确定脑蛋白水解物对中度CHI大鼠功能和组织学结果的影响。
在这项随机、双盲、以赋形剂为对照的临床前试验中，中度CHI的成年雄性Wistar大鼠在损伤后4小时开始，每天腹腔注射2.5 ml/kg剂量的脑蛋白水解物（n = 13）或赋形剂（生理盐水，n = 13），持续10天。在多个时间点对动物进行认知和感觉运动功能测试，并在损伤后3个月处死。对大脑进行处理，以分析神经元细胞丢失、淀粉样前体蛋白、轴突损伤和神经发生情况。
与用赋形剂（生理盐水）治疗的大鼠相比，用脑蛋白水解物治疗的大鼠齿状回（DG）中的神经母细胞和新生成熟神经元数量显著增加，不同脑区的淀粉样前体蛋白积累和轴突损伤减轻，海马齿状回和海马角3（CA3）区的神经元丢失减少（p < 0.05）。使用广义估计方程进行的整体测试显示，与生理盐水治疗相比，脑蛋白水解物治疗对损伤后1天至3个月的感觉运动功能结果有显著的有益影响（p < 0.05）。通过社交互动、莫里斯水迷宫、新物体识别和气味识别测试测量，与用赋形剂治疗的大鼠相比，用脑蛋白水解物治疗的大鼠显示出显著且强劲的长期（长达3个月）认知功能恢复改善。在中度CHI后3个月，脑蛋白水解物治疗的大鼠多项组织学结果与功能恢复之间存在显著相关性，皮尔逊偏相关分析表明了这一点。
作者的研究结果表明，脑蛋白水解物治疗可显著改善中度CHI大鼠的长期功能和组织学结果，功能结果与神经可塑性和神经保护的组织学指标显著相关。这些数据表明，脑蛋白水解物可能对中度CHI的治疗有用。
