Jiangang Shen
The University of Hong Kong, Hong Kong
Title: Oxidative Stress and Antioxidant: What We Should Do for Preventing Brain Damage and Improving Brain Repair in Stroke Treatment
Biography
Biography: Jiangang Shen
Abstract
Free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), play important roles in ischemic brin injury. However, both ROS and RNS at low concentration could be redox signaling to maintain biological functions. Although antioxidant therapy revealed neuroprotective effects in stroke animal models, no promising neuroprotective effect has been reported in clinical trials on stroke patients. Thus, the efficacy of antioxidant therapy for stroke treatment is still a puzzle. Peroxynitrite, a representative RNS, is produced from the rapid reaction of NO and O2-. , but it has higher cytotoxic effects than its parent free radicals. Peroxynitrite could increase blood brain barrier (BBB) disruption and aggravate ischemic brain damage. We have explored the molecular targets of RNS in mediating the BBB disruption and brain damage in experimental rat models of cerebral ischemia-reperfusion injury. We found that RNS down-regulated caveolin-1 (Cav-1) in the ischemic brains. Importantly, the loss of Cav-1 activated nitric oxide synthase (NOS), amplified RNS production and activated matrix metalloproteinases (MMP), subsequently inducing the BBB disruption and aggravating cerebral ischemia-reperfusion injury. The feedback interaction of RNS/Cav-1/MMPs provides an amplifying mechanism for aggravating ischemic brain damage. Furthermore, we tested the potentials of targeting the RNS/Cav-1/MMP pathway for drug discovery and found that that medicinal plant compounds, such as glycyrrhizin and baicalin, could regulate the RNS/Cav-1/MMP signaling cascades and attenuate cerebral ischemia-reperfusion injury. Moreover, glycyrrhizin and baicalin revealed to scavenge RNS, inhibit MMPs activation and reduced the BBB damages and hemorrhagic transformation in ischemic stroke animal model with delayed thrombolytic treatment. Therefore, targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. On the other hand, peroxynitrite at low concentration could be a cellular redox signaling for promoting neural stem cell (NSCs) proliferation, self-renewal and neuronal differentiation in ischemic/hypoxic NSCs. Therefore, antioxidant therapy at early phage of ischemic brain injury might be benefit for reducing RNS-mediated brain damage. Whether the antioxidant therapy could be benefit for brain repair without affecting the redox regulations remain to be further investigated. The detrimental or benefit effects of RNS in brain damage or brain repair could depend on their concentrations and their microenvironments in the ischemic brain