title: Rhinacanthin-C, A Fat-Soluble Extract from Rhinacanthus nasutus, Modulates High-Mobility Group Box 1-Related Neuro-Inflammation and Subarachnoid Hemorrhage-Induced Brain Apoptosis in a Rat Model.
abstract: OBJECTIVE
  High-mobility group box 1 (HMGB1) was shown to be a major extracellular mediator involved in relayed neuro-inflammation in animals after subarachnoid hemorrhage (SAH). It is of interest to examine the effect of rhinacanthin-C (RCT-C, C25H30O5) on pro-inflammatory cytokines/HMGB1 in an SAH-related early brain injury model.
  
  
  METHODS
  A rodent double SAH model was used. RCT-C was administered orally at 100, 200, and 400 μmol/kg/day. Cerebral spinal fluid samples were obtained to assess interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor α using a real-time polymerase chain reaction. Basilar arteries were harvested and cerebral cortex was examined for HMGB1 mRNA and protein expression (western blot) and caspases (real-time polymerase chain reaction). An intrathecal injection of 1 ng of HMGB-1 recombinant protein was given in the 400 μmol/kg/day RCT-C plus SAH groups.
  
  
  RESULTS
  The levels of IL-1β, IL-6, and tumor necrosis factor α mRNA were significantly increased in animals subject to SAH, compared with the healthy controls, but were absent in the RCT-C groups. Cleaved caspase-9a as well as HMGB-1 mRNA and protein were significantly reduced in the 400 μmol/kg/day RCT-C treatment groups. Similarly, administration of RCT-C reduced HMGB-1 mRNA and protein expression (P <0.01).
  
  
  CONCLUSIONS
  RCT-C exerts a neuroprotective effect by reducing cleaved caspase-3- and caspase-9a-related apoptosis. Decreased HMGB-1 mRNA and protein expression in the RCT-C groups corresponds to its anti-inflammatory effect. HMGB-1 recombinant protein administration impaired the neuroprotective and immunosuppressive effect of RCT-C. This finding lends credence that RCT-C modulates the HMGB-1-related pathway and attenuates brain apoptosis in the pathogenesis of SAH.
authors.affiliation: Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Municipal Ta Tung Hospital, Kaohsiung, Taiwan. Electronic address: changchihzen2002@yahoo.com.tw.
authors.forename: Chih-Zen
authors.initials: CZ
authors.lastname: Chang
authors.affiliation: Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Aij-Lie
authors.initials: AL
authors.lastname: Kwan
authors.affiliation: Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Chih-Lung
authors.initials: CL
authors.lastname: Lin
mesh_terms: D027901:Acanthaceae / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001488:Basilar Artery / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024243:HMGB1 Protein / Q000235:genetics* / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D009285:Naphthoquinones / Q000627:therapeutic use*; D009443:Neuritis / Q000473:pathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010936:Plant Extracts / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013345:Subarachnoid Hemorrhage / Q000473:pathology*
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D009285:Naphthoquinones; D018696:Neuroprotective Agents; D010936:Plant Extracts; D011994:Recombinant Proteins; C515073:rhinacanthin-C
keywords: Caspase-3; Caspase-9a; Early brain injury; High-mobility group box-1; Neuro-inflammation; Rhinacanthin-C; Subarachnoid hemorrhage