Sharma Hari Shanker, Muresanu Dafin Fior, Patnaik Ranjana, Stan Adina Dora, Vacaras Vitalie, Perju-Dumbrav Laura, Alexandru Badisor, Buzoianu Anca, Opincariu Iulian, Menon Preeti Kumaran, Sharma Aruna
Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden.
J Nanosci Nanotechnol. 2011 Sep;11(9):7549-69. doi: 10.1166/jnn.2011.5114.
The possibility that cerebrolysin, a mixture of several active fragments of neurotrophic factors and peptides induces neuroprotection following nanoparticles induced exacerbation of brain damage in heat stroke was examined in a rat model. For this purpose, the therapeutic efficacy of Cerebrolysin (2.5 or 5 ml/kg) recommended for stroke treatment was used in comparison with other drugs in standard doses recommended for such therapy in clinical situations e.g., levetiracetam (44 mg/kg), pregabalin (200 mg/kg), topiramate (40 mg/kg,i.p.) and valproate (400 mg/kg). Rats subjected to 4 h heat stress in a biological oxygen demand (BOD) incubator at 38 degrees C (Rel Humid 45-47%; Wind vel 22.4 to 25.6 cm/sec) developed profound behavioral symptoms of heat stroke e.g., hyperthermia, profuse salivation, prostration and gastric ulcerations in the stomach. These rats also exhibited marked brain pathology at this time. Thus, breakdown of the blood-brain barrier (BBB) to proteins associated with brain edema formation could be seen in these heat stressed rats as compared to control groups. The edematous brain areas showed profound neuronal damage and/or distortion in large areas of the neuropil. These pathological symptoms were further exacerbated in Cu or Ag nanoparticles treated group (50-60 nm particle size, 50 mg/kg, i.p./day for 7 days) after identical heat stress on the 8th day. Pretreatment with cerebrolysin (2.5 ml/kg, i.v.) daily for 3 days in normal rats before heat stress significantly reduced the behavioral stress symptoms and the breakdown of the BBB function, edema formation and neuronal injuries. However, the magnitude and intensity of these neuroprotective effects were much less intense in all other drug treated rats after similar heat stress. On the other hand, almost double dose of cerebrolysin (5 ml/kg) was needed to achieve comparable neuroprotection in nanoparticles treated animals after heat stress. Whereas, double dose of all other compounds was much less effective in inducing neuroprotection in nanoparticles treated heat-exposed animals. These observations are the first to show that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal and in nanoparticles treated group. Furthermore, cerebrolysin in double dose was the most effective in inducing neuroprotection in nanoparticles treated heat exposed rats on brain pathology as compared to double doses of other drugs. Taken together, our results show that cerebrolysin has the most superior neuroprotective effects on brain pathology in heat stroke in both normal and nanoparticles treated rats as compared to other contemporary neuroprotective agents, not reported earlier.
在大鼠模型中，研究了脑蛋白水解物（一种神经营养因子和肽的几种活性片段的混合物）在纳米颗粒诱导热中风脑损伤加重后是否具有神经保护作用。为此，将推荐用于中风治疗的脑蛋白水解物（2.5或5 ml/kg）的治疗效果与临床情况下推荐用于此类治疗的标准剂量的其他药物进行比较，例如左乙拉西坦（44 mg/kg）、普瑞巴林（200 mg/kg）、托吡酯（40 mg/kg，腹腔注射）和丙戊酸盐（400 mg/kg）。在38℃（相对湿度45 - 47%；风速22.4至25.6 cm/秒）的生物需氧量（BOD）培养箱中对大鼠进行4小时热应激，大鼠出现了严重的热中风行为症状，如体温过高、大量流涎、虚脱和胃内胃溃疡。此时这些大鼠还表现出明显的脑病理学变化。因此，与对照组相比，在这些热应激大鼠中可以看到血脑屏障（BBB）对与脑水肿形成相关的蛋白质的破坏。水肿的脑区在神经毡的大片区域显示出严重的神经元损伤和/或变形。在第8天进行相同热应激后，铜或银纳米颗粒处理组（粒径50 - 60 nm，50 mg/kg，腹腔注射/天，共7天）的这些病理症状进一步加重。在热应激前，正常大鼠每天静脉注射脑蛋白水解物（2.5 ml/kg），连续3天，可显著减轻行为应激症状以及血脑屏障功能的破坏、水肿形成和神经元损伤。然而，在类似热应激后，所有其他药物处理的大鼠中这些神经保护作用的程度和强度要小得多。另一方面，在热应激后的纳米颗粒处理动物中，几乎需要两倍剂量的脑蛋白水解物（5 ml/kg）才能实现相当的神经保护作用。而在纳米颗粒处理的热暴露动物中，所有其他化合物的两倍剂量在诱导神经保护方面效果要差得多。这些观察结果首次表明，与其他神经保护剂相比，脑蛋白水解物在热应激中对正常组和纳米颗粒处理组的脑病理学具有最优异的神经保护作用。此外，与其他药物的两倍剂量相比，两倍剂量的脑蛋白水解物在纳米颗粒处理的热暴露大鼠中对脑病理学诱导神经保护方面最有效。综上所述，我们的结果表明，与其他当代神经保护剂相比，脑蛋白水解物在正常大鼠和纳米颗粒处理大鼠的热中风中对脑病理学具有最优异的神经保护作用，此前未见报道。
