Tounai Hiroko, Hayakawa Natsumi, Kato Hiroyuki, Araki Tsutomu
Department of Drug Metabolism and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan.
Metab Brain Dis. 2007 Mar;22(1):89-104. doi: 10.1007/s11011-006-9040-3. Epub 2007 Jan 17.
We investigated the immunohistochemical alterations of the transcription nuclear factor kappa-B (NF-kappaB) and transcription factor p53 in the hippocampus after transient cerebral ischemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the alterations of NF-kappaB, p53 and neuronal nuclei in the hippocampus after ischemia. Severe neuronal damage was observed in the hippocampal CA1 neurons 5 and 14 days after ischemia. In the present study, the increase of NF-kappaB immunoreactivity in glial cells and p53 immunoreactivity in neurons preceded neuronal damage in the hippocampal CA1 sector after ischemia. Thereafter, NF-kappaB immunoreactivity was induced highly in reactive astrocytes and microglia of the hippocampal CA1 sector where severe neuronal damage was observed. Our immunohistochemical study showed that pitavastatin prevented the alterations of NF-kappaB and p53 in the hippocampal CA1 sector 5 days after transient ischemia. Furthermore, our results with neuronal nuclei immunostaining indicate that pitavastatin dose-dependently prevented the neuronal cell death in the hippocampal CA1 sector 5 days after transient cerebral ischemia. These results suggest that the up-regulations of NF-kappaB in glia and p53 in neurons can cause neuronal cell death after ischemia. Our findings also support the hypothesis that NF-kappaB- and/or p53-mediated neuronal cell death is prevented through decreasing oxidative stress by pitavastatin. Thus, NF-kappaB and p53 may provide an attractive target for the development of novel therapeutic approaches for brain stroke.
我们研究了沙土鼠短暂性脑缺血后海马中转录核因子κB（NF-κB）和转录因子p53的免疫组化改变。我们还检测了3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂匹伐他汀对缺血后海马中NF-κB、p53和神经元细胞核改变的影响。缺血后5天和14天，海马CA1神经元中观察到严重的神经元损伤。在本研究中，缺血后海马CA1区神经元损伤之前，胶质细胞中NF-κB免疫反应性增加，神经元中p53免疫反应性增加。此后，在观察到严重神经元损伤的海马CA1区的反应性星形胶质细胞和小胶质细胞中，NF-κB免疫反应性被高度诱导。我们的免疫组化研究表明，匹伐他汀可预防短暂性缺血后5天海马CA1区NF-κB和p53的改变。此外，我们神经元细胞核免疫染色的结果表明，匹伐他汀剂量依赖性地预防了短暂性脑缺血后5天海马CA1区的神经元细胞死亡。这些结果表明，胶质细胞中NF-κB和神经元中p53的上调可导致缺血后神经元细胞死亡。我们的研究结果还支持以下假设：匹伐他汀通过降低氧化应激来预防NF-κB和/或p53介导的神经元细胞死亡。因此，NF-κB和p53可能为开发新型脑卒治疗方法提供有吸引力的靶点。
