Targeting ONOO^-/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment

Abstract

Stroke is the leading cause of death and disability worldwide, and ischemic stroke accounts for more than 85% of the stroke incidence. Tissue plasminogen activator (t-PA) is the only FDA-approved drug for ischemic stroke treatment with a narrow treatment time window of 4.5 h. Hemorrhagic transformation (HT) is a severe complication of delayed t-PA treatment in ischemic stroke. Thus, it is critically important to develop combination therapies to reduce HT and extend the therapeutic time window of t-PA. Current progress suggests that peroxynitrite (ONOO^-)/high-mobility group box 1 protein (HMGB1)/matrix metalloproteinase-9 (MMP-9) signaling cascades could be important for attenuating HT during thrombolytic treatment for acute ischemic stroke. Recently, important progress has been made in seeking for natural compounds from Chinese medicine for reducing ischemic stroke injury, with some of them targeting ONOO^-/HMGB1/MMP-9 signaling cascades. Herein, we analyze the roles and interactions of these three targets in mediating HT; subsequently, we summarize the potential compounds from Chinese herbal medicine for attenuating HT and analyze the related targets. Finally, we raise the potential issues to be addressed in further development of these compounds as combination therapy.

Targeting Myeloperoxidase (MPO) Mediated Oxidative Stress and Inflammation for Reducing Brain Ischemia Injury: Potential Application of Natural Compounds

“…Treatment of peroxynitrite scavengers attenuated the BBB damage, neuronal cell death and hemorrhagic transformation in different experimental ischemic stroke models (Xu et al, 2013;Chen et al, 2019). In our recent review articles, we highlight peroxynitrite as a therapeutic target for ischemic stroke (Chen et al, 2013(Chen et al, , 2016Chen H.S. et al, 2018).…”

The Development of Integrative Medicine

“…It is helpful to evaluate the efficacy of a drug with an objective recording instrument, such as an actigraph [11,12], to establish quantitative parameters from body activity recordings for neurological deficits or use advanced testing technology to assess limb blood flow, etc. These methods refer to the combination of branches of medicine in the methodology, and this approach is also called GIM [13]. …”