Eriodictyol-7-O- glucoside activates Nrf2 and protects against

cerebral ischemic injury

Xu Jing^{a, *}, Dongmei Ren^{b, *}, Xinbing Wei^a, Huanying Shi^a, Xiumei Zhang^a, Ruth G. Perez^c, Haiyan Lou^{a, &}, Hongxiang Lou^b

^&Corresponding author:

Haiyan Lou, Ph.D, Department of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhua Xi Road, Jinan, Shandong Province, 250012, PR China, Tel.: +86 531 88382605, Fax: +86 531 88383146, Email: louhaiyan@sdu.edu.cn

Abstract

Stroke is a complex disease that may involve oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and thus has been considered a potential target for neuroprotection in stroke. The aim of the present study was to determine whether eriodictyol-7-O-glucoside (E7G), a novel Nrf2 activator, can protect against cerebral ischemic injury and to understand the role of the Nrf2/ARE pathway in neuroprotection. In primary cultured astrocytes, E7G increased the nuclear localization of Nrf2 and induced the expression of the Nrf2/ARE-dependent genes. Exposure of astrocytes to E7G provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. The protective effect of E7G was abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo administration of E7G in a rat model of focal cerebral ischemia significantly reduced the amount of brain damage and ameliorated neurological deficits. These data demonstrate that activation of Nrf2/ARE signaling by E7G is directly associated with its neuroprotection against oxidative stress-induced ischemic injury and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in stroke.

Key words: eriodictyol-7-O-glucoside; Nrf2; astrocyte; cerebral ischemia