title: The synergetic effect of edaravone and borneol in the rat model of ischemic stroke.
abstract: Free radical production contributes to the early ischemic response and the neuroinflammatory response to injury initiates the second wave of cell death following ischemic stroke. Edaravone is a free radical scavenger, and borneol has shown anti-inflammatory effect. We investigated the synergistic effect of these two drugs in the rat model of transient cerebral ischemia. Edaravone scavenged OH, NO and ONOO─ concentration-dependently, and borneol inhibited ischemia/reperfusion-induced tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) expressions. In the rat model of transient cerebral ischemia and reperfusion, the combination of edaravone and borneol significantly ameliorated ischemic damage with an optimal proportion of 4:1. Emax (% inhibition) of edaravone, borneol and two drugs in combination was 55.7%, 65.8% and 74.3% respectively. ED50 of edaravone and borneol was 7.17 and 0.36 mg/kg respectively. When two drugs in combination, ED50 was 0.484 mg/kg, in which edaravone was 0.387 mg/kg (ineffective dose) and borneol was 0.097 mg/kg (ineffective dose). Combination index (CI)<1 among effects observed in experiments, suggesting a significant synergistic effect. Reduced levels of pro-inflammatory mediators and free radicals were probably associated with the synergistic effect of edaravone and borneol. The combination exhibited a therapeutic time window of 6h in ischemia/reperfusion model, and significantly ameliorated damages in permanent ischemia model. Moreover, two drugs in combination promoted long-term effect, including improved elemental vital signs, sensorimotor functions and spatial cognition. Our results suggest that the combination of edaravone and borneol have a synergistic effect for treating ischemic stroke.
authors: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China; Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
authors: Hai-Yin
authors: HY
authors: Wu
authors: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
authors: Ying
authors: Y
authors: Tang
authors: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
authors: Li-Yan
authors: LY
authors: Gao
authors: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
authors: Wei-Xiang
authors: WX
authors: Sun
authors: Simcere Pharmaceutical R&D, Nanjing, China.
authors: Yao
authors: Y
authors: Hua
authors: Simcere Pharmaceutical R&D, Nanjing, China.
authors: Shi-Bao
authors: SB
authors: Yang
authors: Simcere Pharmaceutical R&D, Nanjing, China.
authors: Zheng-Ping
authors: ZP
authors: Zhang
authors: Simcere Pharmaceutical R&D, Nanjing, China.
authors: Gao-Yong
authors: GY
authors: Liao
authors: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
authors: Qi-Gang
authors: QG
authors: Zhou
authors: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China; Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China. Electronic address: chunxialuo@njmu.edu.cn.
authors: Chun-Xia
authors: CX
authors: Luo
authors: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China; Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
authors: Dong-Ya
authors: DY
authors: Zhu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001892:Camphanes / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D009457:Neuroglia; D009474:Neurons / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001892:Camphanes; D016166:Free Radical Scavengers; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C022871:isoborneol; D000077553:Edaravone; D000983:Antipyrine
keywords: Anti-inflammation; Borneol; Cerebral ischemia/reperfusion; Edaravone; Free radical; Synergistic effect