Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia.
Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia.
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DOI：
10.1371/journal.pone.0186243
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Pera J
中科院分区：
文献类型：
--
作者：
Krzyżanowska W;Pomierny B;Bystrowska B;Pomierny-Chamioło L;Filip M;Budziszewska B;Pera J
脑缺血的病理生理学中的主要参与者之一是谷氨酸能神经传递的稳态被破坏，导致细胞外谷氨酸（Glu）浓度升高和兴奋性毒性相关的细胞死亡。在大脑中，Glu浓度受Glu转运蛋白调节，包括Glu转运蛋白-1（GLT-1）和胱氨酸/Glu反向转运蛋白（系统xc-）。通过施用头孢曲松（CEF，200 mg/kg，i. p.）或N-乙酰半胱氨酸（NAC，150 mg/kg，i. p.）在局灶性脑缺血前5天，可通过显著限制中风相关损伤和使Glu浓度正常化来诱导脑对缺血的耐受。本研究采用大脑中动脉阻塞（MCAO）90分钟造成局灶性脑缺血。我们比较了CEF和NAC预处理对细胞外液中Glu浓度以及GLT-1和xCT细胞特异性表达的影响，并与两种参考预处理方法（即缺血预处理和化学预处理）的影响进行了比较。CEF和NAC均显著降低局灶性脑缺血期间额叶皮质和海马中的Glu水平，并且这种降低与参考预处理策略所实现的Glu水平相当。星形胶质细胞、神经元和小胶质细胞上GLT-1和xCT的免疫荧光染色结果在一定程度上解释了观察到的细胞外Glu水平的变化。简言之，MCAO后，星形胶质细胞上GLT-1的表达下降，但CEF预处理似乎阻止了这种下调。此外，本研究中使用的每种干预似乎都减少了星形胶质细胞和神经元上的xCT表达。这项研究的结果表明，谷氨酸转运蛋白的表达的调制可能会恢复谷氨酸稳态。此外，我们的研究结果表明，CEF和NAC可能通过影响GLT-1和系统xc-表达水平诱导脑缺血耐受。这些转运蛋白可能是开发脑缺血新疗法的良好靶点。
One of the major players in the pathophysiology of cerebral ischemia is disrupted homeostasis of glutamatergic neurotransmission, resulting in elevated extracellular glutamate (Glu) concentrations and excitotoxicity-related cell death. In the brain, Glu concentrations are regulated by Glu transporters, including Glu transporter-1 (GLT-1) and cystine/Glu antiporter (system xc-). Modulation of these transporters by administration of ceftriaxone (CEF, 200 mg/kg, i.p.) or N-acetylcysteine (NAC, 150 mg/kg, i.p.) for 5 days before focal cerebral ischemia may induce brain tolerance to ischemia by significantly limiting stroke-related damage and normalizing Glu concentrations. In the present study, focal cerebral ischemia was induced by 90-minute middle cerebral artery occlusion (MCAO). We compared the effects of CEF and NAC pretreatment on Glu concentrations in extracellular fluid and cellular-specific expression of GLT-1 and xCT with the effects of two reference preconditioning methods, namely, ischemic preconditioning and chemical preconditioning in rats. Both CEF and NAC significantly reduced Glu levels in the frontal cortex and hippocampus during focal cerebral ischemia, and this decrease was comparable with the Glu level achieved with the reference preconditioning strategies. The results of immunofluorescence staining of GLT-1 and xCT on astrocytes, neurons and microglia accounted for the observed changes in extracellular Glu levels to a certain extent. Briefly, after MCAO, the expression of GLT-1 on astrocytes decreased, but pretreatment with CEF seemed to prevent this downregulation. In addition, every intervention used in this study seemed to reduce xCT expression on astrocytes and neurons. The results of this study indicate that modulation of Glu transporter expression may restore Glu homeostasis. Moreover, our results suggest that CEF and NAC may induce brain tolerance to ischemia by influencing GLT-1 and system xc- expression levels. These transporters are presumably good targets for the development of novel therapies for brain ischemia.
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影响因子：
4.2
作者：
Khan, M;Sekhon, B;Singh, AK
通讯作者：
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