Artesunate restores spatial learning of rats with hepatic encephalopathy by inhibiting ammonia-induced oxidative damage in neurons and dysfunction of glutamate signaling in astroglial cells

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• 作者：Yuan-Bo Wu^a ; ¹ ; Li Zhang^a ; ¹ ; Wen-ting Li^b ; Yi Yang^a ; Jiang-ming Zhao^a ; ^{zhaojm_ah@163.com}
• 关键词：Hepatic encephalopathy ; Artesunate ; Ammonia toxicity ; Cerebellar granule neurons ; Astroglial cells
• 刊名：Biomedicine & Pharmacotherapy
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：84
• 期：Complete
• 页码：972-978
• 全文大小：1154 K
• 卷排序：84

文摘

Artesunate (ART) is an antimalarial drug with potential anti-inflammatory effect. This study aimed to explore the potential protective role of ART in hepatic encephalopathy (HE), involving its function against ammonia toxicity.MethodsHE rats were induced by the administration of thioacetamide (TAA, 300 mg/kg/day). Spatial learning ability was tested in both Morris water and eight-arm radial maze. Rat cerebellar granule neurons (CGNs) were prepared for ammonia treatment in vitro, in line with SH-SY5Y and C6 cells. ART was administrated at 50 or 100 mg/kg/day in vivo or added at 50 or 100 μM in vitro. Oxidative damages were evaluated by the changes of cell viability, reactive oxygen species (ROS) levels and glutathione (GSH) content, while glutamate uptake and release, and the activities of glutamine synthetase (GS) and Na+K+-ATPase were measured to indicate the dysfunction of glutamate signaling.ResultsDecreased escape latency and increased numbers of working errors were observed in TAA-induced HE rats, which could be significantly restored by ART at a dosage-dependent manner. Decreased cell viability and GSH content and increased ROS accumulation were detected in ammonia-treated SH-SY5Y and CGNs, while ammonia-treated C6 cells showed reduced glutamate uptake, increased glutamate release, and decrease of GSH content, GS and Na+K+-ATPase activity. In contrast, ART, especially at 100 μM, strongly reversed all changes induced by ammonia, showing a similar dosage-dependent manner in vitro.ConclusionThis study revealed a new neuroprotective role of ART in the pathogenesis of HE, by protecting neurons and astroglial cells from ammonia-induced damages and dysfunctions.