Neuroprotective effects of a novel carnosine-hydrazide derivative on hippocampal CA1 damage after transient cerebral ischemia.
Neuroprotective effects of a novel carnosine-hydrazide derivative on hippocampal CA1 damage after transient cerebral ischemia.
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DOI：
10.1016/j.ejmech.2018.11.060
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发表时间：
2019-02
影响因子：
6.7
通讯作者：
K. Noguchi;T. Ali;Junko Miyoshi;K. Orito;Tetsuya Negoto;Tanima Biswas;Naomi Taira;Ryoko Koga;Yoshinari Okamoto;M. Fujita;M. Otsuka;M. Morioka
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文献类型：
--
作者：
K. Noguchi;T. Ali;Junko Miyoshi;K. Orito;Tetsuya Negoto;Tanima Biswas;Naomi Taira;Ryoko Koga;Yoshinari Okamoto;M. Fujita;M. Otsuka;M. Morioka
缺血-再灌注损伤产生活性氧物质，其促进过氧化物脂质氧化过程，导致内源性脂质过氧化物4-羟基-反式-2-壬烯醛（4-HNE）的产生，4-HNE是一种诱导细胞死亡的高细胞毒性醛。我们合成了一种新型的4-HNE清除剂--肌肽酰肼衍生物L-肌肽酰肼（CNN），并在短暂性脑缺血模型中检测了其神经保护作用。24小时后进行MTT测定以检查细胞存活。采用双侧颈总动脉阻断（BCCO）法建立蒙古沙土鼠短暂性脑缺血模型。将动物分配到假手术组（n= 6）、安慰剂治疗组（n= 12）、CNN预治疗组（20 mg/kg; n= 12）、CNN后治疗组（100 mg/kg; n= 11）和组氨酰肼（先前已知的4-HNE清除剂）后治疗组（100 mg/kg; n= 7）。热休克蛋白70在海马CA 1区的免疫反应性进行了评价24小时后，而迟发性神经元死亡使用4-HNE染色7天后进行了评价。用30 mmol/L CNN预孵育可完全抑制4-HNE诱导的细胞毒性。在预处理组中，CNN防止了> 60%的迟发性神经元死亡（p< 0.001）。
Ischemia-reperfusion injuries produce reactive oxygen species that promote the peroxide lipid oxidation process resulting in the production of an endogenic lipid peroxide, 4-hydroxy-trans-2-nonenal (4-HNE), a highly cytotoxic aldehyde that induces cell death. We synthesized a novel 4-HNE scavenger–a carnosine-hydrazide derivative, L-carnosine hydrazide (CNN)–and examined its neuroprotective effect in a model of transient ischemia.PC-12 cells were pre-incubated with various doses (0-50 mmol/L) of CNN for 30 min, followed by incubation with 4-HNE (250 μM). An MTT assay was performed 24 h later to examine cell survival. Transient ischemia was induced by bilateral common carotid artery occlusion (BCCO) in the Mongolian gerbil. Animals were assigned to sham-operated (n= 6), placebo-treated (n= 12), CNN pre-treated (20 mg/kg; n= 12), CNN post-treated (100 mg/kg; n= 11), and histidyl hydrazide (a previously known 4-HNE scavenger) post-treated (100 mg/kg; n= 7) groups. Heat shock protein 70 immunoreactivity in the hippocampal CA1 region was evaluated 24 h later, while delayed neuronal death using 4-HNE staining was evaluated 7 days later. Pre-incubation with 30 mmol/L CNN completely inhibited 4-HNE-induced cell toxicity. CNN prevented delayed neuronal death by> 60% in the pre-treated group (p< 0.001)