Hoshi Akihiko, Nakahara Toshiki, Kayama Hisae, Yamamoto Teiji
Department of Neurology, Fukushima Medical University, Fukushima, Japan.
J Neurosci Res. 2006 Jul;84(1):130-41. doi: 10.1002/jnr.20869.
Glutamine synthetase (GS), localized to astrocyte is a key enzyme in the glutamate-glutamine pathway in the brain. 3-Nitropropionic acid (3-NPA) is an irreversible inhibitor of succinate dehydrogenase in the tricarboxylic-acid cycle, and provides ischemic tolerance to the brain. So far, there have been no reports on the relationship of astrocytic GS and ischemic tolerance by chemical preconditioning. In order to test the hypothesis that astrocytes serve a pivotal role in 3-NPA-induced chemical preconditioning, we have investigated the temporal profile of GS expression in astrocyte parallel with those of glial fibrillary acidic protein and heat-shock protein 70 (HSP70). In our rat model of permanent focal ischemia, preconditioning with 3-NPA singnificantly reduced the subsequent neurological deficits and infarct volume within 24-72 hours after treatment. Immunohistochemically, protoplasmic astrocytes in the cortex and striatum were activated in terms of upregulation of GS and more abundant protoplasmic processes with 3-NPA preconditioning, however, HSP70 expression could not be induced. Thus, the activation of astrocytes and upregulation of GS play an important role in 3-NPA-induced preconditioning but HSP70 does not. In view of glutamate being imposed on the cerebral ischemic damage, the astrocytic GS may contribute to 3-NPA-induced ischemic tolerance.
谷氨酰胺合成酶（GS）定位于星形胶质细胞，是大脑中谷氨酸 - 谷氨酰胺途径的关键酶。3 - 硝基丙酸（3 - NPA）是三羧酸循环中琥珀酸脱氢酶的不可逆抑制剂，可赋予大脑缺血耐受性。迄今为止，尚无关于化学预处理诱导的星形胶质细胞GS与缺血耐受性之间关系的报道。为了验证星形胶质细胞在3 - NPA诱导的化学预处理中起关键作用这一假设，我们研究了星形胶质细胞中GS表达与胶质纤维酸性蛋白和热休克蛋白70（HSP70）表达的时间变化情况。在我们的大鼠永久性局灶性缺血模型中，3 - NPA预处理在治疗后24 - 72小时内显著减轻了随后的神经功能缺损和梗死体积。免疫组织化学结果显示，3 - NPA预处理使皮质和纹状体中的原浆性星形胶质细胞在GS上调和原浆性突起更丰富方面被激活，然而，HSP70表达未被诱导。因此，星形胶质细胞的激活和GS的上调在3 - NPA诱导的预处理中起重要作用，但HSP70不起作用。鉴于谷氨酸会加重脑缺血损伤，星形胶质细胞的GS可能有助于3 - NPA诱导的缺血耐受性。
