Oxidative Stress and Antioxidant: What We Should Do for Brain Damage and Brain Repair and Its Implication in Stroke Treatment

抄録

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. Last decade, we made great efforts to explore the molecular targets in mediating the BBB disruption and brain damage. Our studies indicate that RNS mediated loss of caveolin-1 (Cav-1) activates nitric oxide synthase (NOS) for amplifying RNS production and matrix metalloproteinase (MMP) activation. The feedback interaction of RNS/Cav-1/MMPs provides an amplifying mechanism for aggravating ischemic brain damage.

Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. We found that medicinal plant compounds, such as calycosin-7-O-β-D-glucoside, baicalin, targeted the RNS/Cav-1/MMP signaling cascades and attenuated cerebral ischemia-reperfusion injury. Moreover, targeting RNS reduce hemorrhagic transformation in ischemic stroke animal model with delayed thrombolytic treatment. Notably, 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. In conclusion, antioxidant therapy at early phage of ischemic brain injury might be benefit for reducing brain damage but the efficacy of antioxidant therapy for brain repair remain to be further investigated. The detrimental or benefit effects of RNS in brain damage or brain repair could depend on their concentrations and microenvironment.

Acknowledgement: This study are supported by Hong Kong RGC AoE/P-705/16, RGC GRF grants (No. 17102915, 17118717)