Research Papers:

Neuroprotective effect of a novel gastrodin derivative against ischemic brain injury: involvement of peroxiredoxin and TLR4 signaling inhibition

Xiao-Na Mao, Hong-Jing Zhou, Xiao-Jia Yang, Li-Xue Zhao, Xi Kuang, Chu Chen, Dong-Ling Liu and Jun-Rong Du _

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Oncotarget. 2017; 8:90979-90995. https://doi.org/10.18632/oncotarget.18773

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Xiao-Na Mao1,*, Hong-Jing Zhou1,*, Xiao-Jia Yang1, Li-Xue Zhao1, Xi Kuang1, Chu Chen2, Dong-Ling Liu1 and Jun-Rong Du1

1Department of Pharmacology, Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

2Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China

*These authors contributed equally to this work

Correspondence to:

Jun-Rong Du, email: [email protected]

Keywords: ischemic stroke, neuroinflammation, peroxiredoxins, therapeutic window, gastrodin derivative

Received: March 10, 2017     Accepted: June 11, 2017     Published: June 28, 2017


The inhibition of extracellular inflammatory peroxiredoxin (Prx) signaling appears to be a potential therapeutic strategy for neuroinflammatory injury after acute ischemic stroke. Gastrodin (Gas) is a phenolic glycoside that is used for the treatment of cerebral ischemia, accompanied by regulation of the autoimmune inflammatory response. The present study investigated the neuroprotective effects of Gas and its derivative, Gas-D, with a focus on the potential mechanism associated with inflammatory Prx–Toll-like receptor 4 (TLR4) signaling. Gas-D significantly inhibited Prx1-, Prx2-, and Prx4-induced inflammatory responses in RAW264.7 macrophages and H2O2-mediated oxidative injury in SH-SY5Y nerve cells. In rats, intraperitoneal Gas-D administration 10 h after reperfusion following 2-h middle cerebral artery occlusion (MCAO) ameliorated neurological deficits, brain infarction, and neuropathological alterations, including neuron loss, astrocyte and microglia/macrophage activation, T-lymphocyte invasion, and lipid peroxidation. Delayed Gas-D treatment significantly inhibited postischemic Prx1/2/4 expression and spillage, TLR4 signaling activation, and inflammatory mediator production. In contrast, Gas had no significant effects in either cell model or in MCAO rats under the same conditions. These results indicate that Gas-D may be a drug candidate with an extended therapeutic time window that blocks inflammatory responses and attenuates the expression and secretome of inflammatory Prxs in acute ischemic stroke.

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