Muramatsu Y, Kurosaki R, Kato H, Araki T
Department of Drug Metabolism and Therapeutics, Graduate school and Faculty of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan.
Acta Physiol Scand. 2004 Sep;182(1):95-107. doi: 10.1111/j.1365-201X.2004.01300.x.
We investigated the immunohistochemical alterations of S100beta-, S100-, glial fibrillary acidic protein (GFAP)- and isolectin B4-positive cells in the hippocampus after 5 min of transient cerebral ischaemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pitavastatin against neuronal damage in the hippocampal CA1 sector after ischaemia.
Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons from 5 days after ischaemia. GFAP-positive cells increased gradually in the hippocampus from 5 days after ischaemia. Five and 14 days after ischaemia, significant increases in the number of GFAP-positive cells and isolectin B4-positive cells were observed in the hippocampal CA1 and CA3 sector. Mild increases in the number of S100 and S100beta-positive cells were observed in the hippocampal CA1 sector from 1 h to 2 days after ischaemia. Thereafter, S100beta-positive cells increased in the hippocampal CA1 sector after ischaemia, whereas S100-positive cells decreased in this region. In our double-labelled immunostainings, S100 and S100beta immunoreactivity was found in GFAP-positive astrocytes, but not in isolectin B4-positive microglia. Pharmacological study showed that HMG-CoA reductase inhibitor, pitavastatin, can protect against the hippocampal CA1 neuronal damage after ischaemia. This drug also prevented increases in the number of GFAP-positive astrocytes, isolectin B4-positive microglia, S100-positive astrocytes and S100beta-positive astrocytes after ischaemia.
The present study demonstrates that pitavastatin can decrease the neuronal damage of hippocampal CA1 sector after ischaemia. This beneficial effect may be, at least in part, mediated by inhibiting the expression of astrocytic activation in the hippocampus at the acute phase after ischaemia. Thus the modulation of astrocytic activation may offer a novel therapeutic strategy of ischaemic brain damage.
我们研究了沙土鼠短暂性脑缺血5分钟后海马中S100β、S100、胶质纤维酸性蛋白（GFAP）和异凝集素B4阳性细胞的免疫组化变化。我们还研究了3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂匹伐他汀对缺血后海马CA1区神经元损伤的影响。
缺血后5天，在海马CA1锥体细胞中观察到严重的神经元损伤。缺血后5天起，海马中GFAP阳性细胞逐渐增多。缺血后5天和14天，海马CA1和CA3区GFAP阳性细胞和异凝集素B4阳性细胞数量显著增加。缺血后1小时至2天，海马CA1区S100和S100β阳性细胞数量轻度增加。此后，缺血后海马CA1区S100β阳性细胞增加，而该区域S100阳性细胞减少。在我们的双重免疫染色中，S100和S100β免疫反应性在GFAP阳性星形胶质细胞中发现，而在异凝集素B4阳性小胶质细胞中未发现。药理学研究表明，HMG-CoA还原酶抑制剂匹伐他汀可预防缺血后海马CA1区神经元损伤。该药物还可防止缺血后GFAP阳性星形胶质细胞、异凝集素B4阳性小胶质细胞、S100阳性星形胶质细胞和S100β阳性星形胶质细胞数量增加。
本研究表明，匹伐他汀可减少缺血后海马CA1区的神经元损伤。这种有益作用可能至少部分是通过抑制缺血急性期海马星形胶质细胞活化的表达介导的。因此，调节星形胶质细胞活化可能为缺血性脑损伤提供一种新的治疗策略。
