title: Edaravone attenuates hippocampal damage in an infant mouse model of pneumococcal meningitis by reducing HMGB1 and iNOS expression via the Nrf2/HO-1 pathway.
abstract: OBJECTIVE
  Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger that has shown potent antioxidant, anti-inflammatory and neuroprotective effects in variety of disease models. In this study, we investigated whether edaravone produced neuroprotective actions in an infant mouse model of pneumococcal meningitis.
  
  
  METHODS
  C57BL/6 mice were infected on postnatal d 11 by intracisternal injection of a certain inoculum of Streptococcus pneumoniae. The mice received intracisternal injection of 10 μL of saline containing edaravone (3 mg/kg) once a day for 7 d. The severity of pneumococcal meningitis was assessed with a clinical score. In mice with severe meningitis, the survival rate from the time of infection to d 8 after infection was analyzed using Kaplan-Meier curves. In mice with mild meningitis, the CSF inflammation and cytokine levels in the hippocampus were analyzed d 7 after infection, and the clinical neurological deficit score was evaluated using a neurological scoring system d 14 after infection. The nuclear factor (erythroid-derived 2)-like 2 knockout (Nrf2 KO) mice and heme oxygenase-1 knockout (HO-1 KO) mice were used to confirm the involvement of Nrf2/HO-1 pathway in the neuroprotective actions of edaravone.
  
  
  RESULTS
  In mice with severe meningitis, edaravone treatment significantly increased the survival rate (76.4%) compared with the meningitis model group (32.2%). In mice with mild meningitis, edaravone treatment significantly decreased the number of leukocytes and TNF- levels in CSF, as well as the neuronal apoptosis and protein levels of HMGB1 and iNOS in the hippocampus, but did not affect the high levels of IL-10 and IL-6 in the hippocampus. Moreover, edaravone treatment significantly improved the neurological function of mice with mild meningitis. In Nrf2 KO or HO-1 KO mice with the meningitis, edaravone treatment was no longer effective in improving the survival rate of the mice with severe meningitis (20.2% and 53.6%, respectively), nor it affected the protein levels of HMGB1 and iNOS in the hippocampus of the mice with mild meningitis.
  
  
  CONCLUSIONS
  Edaravone produces neuroprotective actions in a mouse model of pneumococcal meningitis by reducing neuronal apoptosis and HMGB1 and iNOS expression in the hippocampus via the Nrf2/HO-1 pathway. Thus, edaravone may be a promising agent for the treatment of bacterial meningitis.
authors: Department of Pediatrics, BaYi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital of Southern Medical University, Beijing 100700, China.
authors: Zheng
authors: Z
authors: Li
authors: Department of Pediatrics, BaYi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital of Southern Medical University, Beijing 100700, China.
authors: Qian-Qian
authors: QQ
authors: Ma
authors: Department of Pediatrics, BaYi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital of Southern Medical University, Beijing 100700, China.
authors: Yan
authors: Y
authors: Yan
authors: Department of Pediatrics, BaYi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital of Southern Medical University, Beijing 100700, China.
authors: Feng-Dan
authors: FD
authors: Xu
authors: Department of Pediatrics, BaYi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital of Southern Medical University, Beijing 100700, China.
authors: Xiao-Ying
authors: XY
authors: Zhang
authors: Department of Pediatrics, BaYi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital of Southern Medical University, Beijing 100700, China.
authors: Wei-Qin
authors: WQ
authors: Zhou
authors: Department of Pediatrics, BaYi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital of Southern Medical University, Beijing 100700, China.
authors: Zhi-Chun
authors: ZC
authors: Feng
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077553:Edaravone; D024243:HMGB1 Protein / Q000378:metabolism*; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000077553:Edaravone; D000983:Antipyrine