Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation
Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation
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DOI：
10.1161/01.str.0000252091.36912.65
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发表时间：
2007-01-01
期刊：
影响因子：
8.3
通讯作者：
Roh, Jae-Kyu
中科院分区：
文献类型：
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作者：
Chu, Kon;Lee, Soon-Tae;Roh, Jae-Kyu
背景和目的-星形细胞谷氨酸转运蛋白 GLT-1 (EAAT2) 可回收细胞外谷氨酸并确保神经元免受过度刺激。最近，据报道，头孢曲松 (CTX) 等 β-内酰胺类抗生素可诱导 GLT-1 上调。在这里，我们在局灶性脑缺血的实验模型中研究了 CTX 诱导的缺血耐受性。方法 - 在短暂性局灶性缺血之前连续 5 天注射 CTX（每天 200 mg/kg，IP），短暂性局灶性缺血是通过管腔内线闭塞大脑中动脉 90 分钟或永久诱导的。结果 - 重复 CTX 注射分别在治疗 3 天和 5 天后增强 GLT-1 mRNA 和蛋白表达。缺血后 24 小时，与媒介物预处理的动物相比，CTX 预处理的动物梗塞体积减少了 58%（再灌注）和 39%（永久性）（P < 0.01）。较低剂量的 CTX（每天 20 毫克/公斤和每天 100 毫克/公斤）可将梗塞体积减少到较小程度。缺血前30分钟注射GLT-1抑制剂（二氢红藻氨酸）可改善CTX预处理的效果。然而，缺血后 30 分钟给予 CTX 并没有显着减少梗塞体积。 CTX 降低促炎细胞因子（肿瘤坏死因子-a，FasL）、基质金属蛋白酶（MMP）-9 和活化的 caspase-9 的水平（P < 0.01）。此外，CTX预处理的动物在缺血后第1天至第5周表现出更好的功能恢复（P<0.05）。结论-这项研究提供了证据，表明CTX在局灶性脑缺血中诱导缺血耐受，并且这是由GLT-1上调介导的。
Background and Purpose-Astrocytic glutamate transporter protein, GLT-1 (EAAT2), recovers extracellular glutamate and ensures that neurons are protected from excess stimulation. Recently, beta-lactam antibiotics, like ceftriaxone (CTX), were reported to induce the upregulation of GLT-1. Here, we investigated ischemic tolerance induction by CTX in an experimental model of focal cerebral ischemia.Methods-CTX (200 mg/kg per day, IP) was administered for 5 consecutive days before transient focal ischemia, which was induced by intraluminal thread occlusion of the middle cerebral artery for 90 minutes or permanently.Results-Repeated CTX injections enhanced GLT-1 mRNA and protein expressions after 3 and 5 days of treatment, respectively. CTX-pretreated animals showed a reduction in infarct volume by 58% (reperfusion) and 39% (permanent), compared with the vehicle-pretreated animals at 24 hours postischemia (P < 0.01). Lower doses of CTX (20 mg/kg per day and 100 mg/kg per day) reduced infarct volumes to a lesser degree. The injection of GLT-1 inhibitor (dihydrokainate) at 30 minutes before ischemia ameliorated the effect of CTX pretreatment. However, CTX administration at 30 minutes after ischemia produced no significant reduction in infarct volume. CTX reduced the levels of proinflammatory cytokines (tumor necrosis factor-a, FasL), matrix metalloproteinase (MMP)-9, and activated caspase-9 (P < 0.01). In addition, CTX-pretreated animals showed better functional recovery at day I to week 5 after ischemia (P < 0.05).Conclusions-This study presents evidence that CTX induces ischemic tolerance in focal cerebral ischemia and that this is mediated by GLT-1 upregulation.