Edaravone attenuates oxidative stress induced by chronic cerebral hypoperfusion injury: role of ERK/Nrf2/HO-1 signaling pathway

Abstract

Objectives The potential protective effects and mechanisms of edaravone have not been well elucidated in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH). The aim of this study was to investigate whether edaravone could improve cognitive damage in rats induced by CCH, and whether the effects of edaravone were associated with ERK/Nrf2/HO-1 signaling pathway. Methods CCH was induced by bilateral common carotid arteries occlusion (BCCAO). Sprague-Dawley (SD) rats were randomly divided into four groups: sham (sham-operated) group, vehicle (BCCAO + normal saline) group, edaravone3.0 group and edaravone6.0 group. The edaravone3.0 and edaravone6.0 group rats were provided 3.0 mg/kg and 6.0 mg/kg of edaravone, respectively, intraperitoneal (i.p.) injection twice daily following the first day after BCCAO. In this experiment, the spatial learning and memory were assessed using the Morris water maze. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities in the hippocampus were measured biochemically. And, the levels of total ERK1/2 (t-ERK1/2), Phospho-ERK1/2 (p-ERK1/2), total Nrf2 (t-Nrf2), nuclear Nrf2 (n-Nrf2), and HO-1 were assessed by western blot. Results The results showed that the treatment with edaravone significantly improved CCH-induced cognitive damage, and boosted endogenous antioxidants SOD activity and HO-1 level, decreased MDA contents in the hippocampus by activating Nrf2 signaling pathway which was related to ERK1/2. We also found that the neuronal morphology of the hippocampal CA1 area significantly improved and the number of Nrf2 positive cells markedly increased in the edaravone treatment groups. Conclusion Our results demonstrated a neuroprotective effect of edaravone on hippocampus against oxidative stress and cognitive deficit induced by CCH. The mechanism may be related to the enhancement of antioxidant defense system by activating ERK/Nrf2/HO-1 signaling pathway.

Keywords: Chronic cerebral hypoperfusion; cognitive damage; edaravone; nuclear factor erythroid 2-related factor 2; oxidative stress; vascular dementia.