Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy.
Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy.
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DOI：
10.3892/ijmm.2015.2219
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发表时间：
2015-07
影响因子：
5.4
通讯作者：
Lee W
中科院分区：
文献类型：
--
作者：
Rong Z;Pan R;Chang L;Lee W
新生儿缺氧缺血性脑损伤对新生儿造成严重的脑损伤。缺氧损伤后，快速积累的氧化剂损伤神经元，中断正在进行的发育过程。抗氧化剂丙酮酸钠已被证明可以减轻缺氧缺糖(OGD)和缺氧损伤条件下新生大鼠的神经元损伤。在这项研究中，我们评估了丙酮酸乙酯(EP)和胰岛素样生长因子-I(IGF-I)单独或在类似环境下联合使用的效果。为此，我们采用了原代新生大鼠皮质神经元缺氧2.5h的体外模型和出生后7d单侧颈动脉结扎2.5h的在体模型，并对培养的神经元进行乳酸脱氢酶(LDH)和细胞存活率的检测。对于活体实验，在康复4周时，通过足部错误测试来评估行为发育。2，3，5-三苯基四氮唑一水合物染色和甲酚紫染色评价缺氧缺血损伤。损伤神经元用荧光素B标记，新的神经前体用溴脱氧尿嘧啶核苷(BrdU)和双皮质酸双标记，新的成熟神经元用BrdU标记，神经元核用免疫荧光标记。在OGD条件下，LDH水平升高，神经元存活率下降。0.5 mM EP或25 ng/mlIGF-I对神经元有保护作用(P<；0.05)，具有相加效应。同样，无论是早期使用EP还是延迟使用IGF-I治疗，都可以保护新生大鼠的大脑免受HI损伤，并改善神经功能，这些效果也是相加的。这种效应可能是神经元损伤减少，神经发生和成熟增强的结果。总体而言，我们的研究结果表明，早期给予EP和延迟给予IGF-I治疗相结合，对新生大鼠脑缺血再灌注损伤具有神经保护作用。
Neonatal hypoxic-ischemic (HI) brain injury causes severe brain damage in newborns. Following HI injury, rapidly accumulating oxidants injure neurons and interrupt ongoing developmental processes. The antioxidant, sodium pyruvate, has been shown to reduce neuronal injury in neonatal rats under conditions of oxygen glucose deprivation (OGD) and HI injury. In this study, we evaluated the effects of ethyl pyruvate (EP) and insulin-like growth factor-I (IGF-I) alone or in combination in a similar setting. For this purpose, we used an in vitro model involving primary neonatal rat cortical neurons subjected to OGD for 2.5 h and an in vivo model involving unilateral carotid ligation in rats on post-natal day 7 with exposure to 8% hypoxia for 2.5 h. The cultured neurons were examined by lactate dehydrogenase (LDH) and cell viability assays. For the in vivo experiments, behavioral development was evaluated by the foot fault test at 4 weeks of recovery. 2,3,5-Triphenyltetrazolium chloride monohydrate and cresyl violet staining were used to evaluate HI injury. The injured neurons were Fluoro-Jade B-labeled, new neuroprecursors were double labeled with bromodeoxyuridine (BrdU) and doublecortin, new mature neurons were BrdU-labeled and neuronal nuclei were labeled by immunofluorescence. Under conditions of OGD, the LDH levels increased and neuronal viability decreased. Treatment with 0.5 mM EP or 25 ng/ml IGF-I protected the neurons (P<0.05), exerting additive effects. Similarly, either the early administration of EP or delayed treatment with IGF-I protected the neonatal rat brains against HI injury and improved neurological performance and these effects were also additive. This effect may be the result of reduced neuronal injury, and enhanced neurogenesis and maturation. On the whole, our findings demonstrate that the combination of the early administration of EP with delayed treatment with IGF-I exerts neuroprotective effects against HI injury in neonatal rat brains.
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