title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  HE rats were induced by the administration of thioacetamide (TAA, 300mg/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 100mg/kg/day in vivo or added at 50 or 100μM 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.
  
  
  RESULTS
  Decreased 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 100μM, strongly reversed all changes induced by ammonia, showing a similar dosage-dependent manner in vitro.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Anhui Medical University, HeFei 230001, Anhui Province, China.
authors.forename: Yuan-Bo
authors.initials: YB
authors.lastname: Wu
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Anhui Medical University, HeFei 230001, Anhui Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Infectious Disease, Provincial Hospital Affiliated to Anhui Medical University, HeFei 230001, Anhui Province, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Li
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Anhui Medical University, HeFei 230001, Anhui Province, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Anhui Medical University, HeFei 230001, Anhui Province, China. Electronic address: zhaojm_ah@163.com.
authors.forename: Jiang-Ming
authors.initials: JM
authors.lastname: Zhao
mesh_terms: D000641:Ammonia; D000818:Animals; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use*; D000077332:Artesunate; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018698:Glutamic Acid / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000066829:Neuroprotection / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D065853:Spatial Learning / Q000187:drug effects*
chemical_list: D037621:Artemisinins; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D000077332:Artesunate; D000641:Ammonia
keywords: Ammonia toxicity; Artesunate; Astroglial cells; Cerebellar granule neurons; Hepatic encephalopathy