ORALS

Stroke is a major disease burden worldwide and over 85% incidences are ischemic stroke. Tissue plasminogen activator (t-PA) is the only FDA approved drug for acute ischemic stroke, but its use is limited with the restrictive time window within 4.5 hours and the complications of the blood brain barrier (BBB) disruption and hemorrhagic transformation (HT). Exploring molecular targets to reducing the BBB permeability and HT incidence is timely important to develop novel therapeutic approaches for reducing the complications and increasing outcome in ischemic stroke.Oxidative/nitrosative stress and neuroinflammation are two crucial pathological processes in ischemic stroke. Reactive nitrogen species (RNS) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. Peroxynitrite (ONOO-) is a representative RNS but its roles in mediating inflammation signaling in the blood-brain barrier (BBB) damage and hemorrhagic transformation (HT) in ischemic brain injury remain unclear. In basic study, our group has tested the hypothesis that ONOO- could directly mediate HMGB1 signaling in ischemic brains with delayed t-PA treatment [1,2]. In clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Plasma levels of nitrotyrosine and HMGB1 were increased in t-PA-treated ischemic stroke patients with hemorrhagic transformation [2]. Furthermore, animal experiments revealed that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly inhibited the activations of HMGB1/TLR2/MMP-9 signaling cascades, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced HMGB1/TLR2/MMP-9 signaling cascades in naive rat brains in vivo and brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling, contributing to the BBB disruption and HT in ischemic brain injury [1-2]. We also demonstrate that ONOO- mediated MMPs and NLRP3 inflammasome could aggravate the BBB damage and HT and induce poor outcome in ischemic stroke with hyperglycemia [3]. Thus, the interactions of ONOO- and inflammation factors play crucial roles in the BBB disruption and HT. For drug discovery, we found that medicinal plant compounds, such as baicalin and glycyrrhizin, and a classic Chinese medicinal formula named Angong Niuhuang Pill regulated the RNS/Cav-1/MMP signaling cascades, decreased the mortality rate, attenuated the BBB disruption, HT, brain swelling, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment [1-4]. In conclusion, targeting peroxynitrite-mediated inflammation signaling cascades could be a potential adjuvant therapy to prevent hemorrhagic transformation and improve outcome in ischemic stroke with delayed t-PA treatment, potentially extending the therapeutic window for thrombolysis. 

References:
[1] Chen HS, Guan BH, Chen X, Chen XM, Li CM, Qiu JH, Yang D, Liu KJ, Q SH, Shen JG. Baicalin attenuates blood-brain barrier disruption and hemorrhagic transformation and improves neurological outcome in ischemic stroke rats with delayed t-PA treatment: Involvement of ONOO--MMP-9 pathway. Translational Stroke Research 2019; 9(5): 515-529.
[2] Chen H, Guan B, Wang B, Pu H, Bai X, Chen X, Liu J, Li C, Qiu J, Yang D, Liu K, Wang Q, Qi S, Shen J. Glycyrrhizin prevents hemorrhagic transformation and improves neurological outcome in ischemic stroke with delayed thrombolysis through targeting peroxynitrite-mediated HMGB1 signaling. Translational Stroke Research 2020;11(5):967-982
[3] Chen H, Guan B, Chen S, Yang D, Shen J. Peroxynitrite activates NLRP3 inflammasome and contributes to hemorrhagic transformation and poor outcome in ischemic stroke with hyperglycemia. Free Radical Biology and Medicine 2021; 165, 171-183
[4] Chen H, Luo Y, Tsoi B, Qi S, Shen J. Angong Niuhuang Wan reduces hemorrhagic transformation and mortality in ischemic stroke rats with delayed thrombolysis: involvement of peroxynitrite-mediated MMP-9 activation. Chinese Medicine 2022; 17(1):51