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Eur J Pharmacol. 2014 Oct 5;740:522-31. doi: 10.1016/j.ejphar.2014.06.035. Epub 2014 Jun 27.

The synergetic effect of edaravone and borneol in the rat model of ischemic stroke.

Author information

1
Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China; Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
2
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
3
Simcere Pharmaceutical R&D, Nanjing, China.
4
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.

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.

KEYWORDS:

Anti-inflammation; Borneol; Cerebral ischemia/reperfusion; Edaravone; Free radical; Synergistic effect

PMID:
24975100
DOI:
10.1016/j.ejphar.2014.06.035
[Indexed for MEDLINE]

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