Review article

Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery

Authors: Han-sen CHEN1,2, Xi CHEN3, Wen-ting LI1, Jian-gang SHEN1,2
1 School of Chinese Medicine, The University of Hong Kong, Hong Kong SAR, China
2 The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China
3 Department of Core Facility, The People’s Hospital of Bao-an; The 8th People’s Hospital of Shenzhen, The Affiliated Bao-an Hospital of Southern Medical University, Shenzhen 518000, China
Corresponding to: Jian-gang SHEN:,
DOI: 10.1038/aps.2018.27
Received: 30 November 2017
Accepted: 26 January 2018
Advance online: 29 March 2018


Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO-), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/ MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemiareperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment. Keywords: Ischemic
Keywords: Ischemic stroke; caveolin-1; reactive nitrogen species (RNS); MMPs; natural compound