Himeda Toshiki, Hayakawa Natsumi, Tounai Hiroko, Sakuma Mio, Kato Hiroyuki, Araki Tsutomu
Department of Drug Metabolism and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan.
Neuropsychopharmacology. 2005 Nov;30(11):2014-25. doi: 10.1038/sj.npp.1300798.
We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can prevent the damage of interneurons in the hippocampus after cerebral ischemia. Thus, our study provides valuable information for the pathogenesis after cerebral ischemia.
我们研究了沙土鼠短暂性脑缺血后海马中表达小白蛋白（PV）的中间神经元的免疫组化变化，并与表达神经元型一氧化氮合酶（nNOS）的中间神经元进行了比较。我们还研究了3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂匹伐他汀对脑缺血后海马神经元和中间神经元损伤的影响。缺血后5天和14天，在海马CA1锥体神经元中观察到严重的神经元损伤。缺血后2天内，PV免疫反应性无变化。相比之下，缺血后5天和14天，在海马CA1区的中间神经元中观察到PV免疫反应性明显降低。此外，在海马CA3区的中间神经元中发现PV免疫反应性显著降低。在缺血后1天内，沙土鼠海马中未检测到nNOS免疫阳性中间神经元的损伤。此后，在缺血后14天内，海马CA1区nNOS免疫反应性中间神经元减少。匹伐他汀显著预防了缺血后5天海马CA1区的神经元细胞丢失。我们的免疫组化研究还表明，匹伐他汀可预防缺血后海马中PV和nNOS阳性中间神经元的显著减少。双重免疫染色显示，在脑的nNOS免疫阳性中间神经元中未发现PV免疫反应性。本研究表明，脑缺血可导致海马CA1区PV和nNOS免疫反应性中间神经元的丢失。我们的研究结果还表明，缺血后海马CA1区nNOS免疫阳性中间神经元的损伤可能先于神经元细胞丢失，且nNOS阳性中间神经元可能在脑缺血性疾病的发病机制中起一定作用。此外，我们目前的研究表明，匹伐他汀可预防脑缺血后海马中间神经元的损伤。因此，我们的研究为脑缺血后的发病机制提供了有价值的信息。
