Anti-platelet aggregation of Panax notoginseng triol saponins by regulating GP1BA for ischemic stroke therapy

Abstract

Background Panax notoginseng triol saponins (PTS) has been used clinically for ischemic stroke therapy (IST) in China for more than 17 years due to its anti-platelet aggregation and neuro-protective effects, but its mechanism of action is not fully understand. In this study, anti-platelet aggregation-related protein analysis and computer simulations of drug-protein binding interactions were performed to explore the mechanism of the effects of PTS against ischemic stroke in an ischemia reperfusion model. Methods Three oral doses of PTS were administered in a model of middle cerebral artery occlusion (MCAO) in rats. Panax notoginseng total saponins (PNS) and a combination of PTS and aspirin were chosen for comparison. To evaluate therapeutic effects and explore possible mechanisms of anti-platelet aggregation, we measured cerebral infarct size and water content in brain tissue, histomorphological changes, expression of related factors (such as arachidonic acid metabolites) and platelet receptors in serum, as well as the binding affinity of PTS for platelet adhesion receptors. Results Compared with PNS, PTS showed a stronger and more potent anti-platelet aggregation effect in MCAO model rats. The combination of PTS and aspirin could reduce adverse gastrointestinal effects by regulating the TXA2/PGI2 ratio. We demonstrated for the first time that PTS was able to regulate Glycoprotein Ib-α (GP1BA) in a model animal. The binding of ginsenoside Rg1 and GP1BA could form a stable structure. Moreover, PTS could reduce von Willebrand factor (VWF)-mediated platelet adhesion to damaged vascular endothelium, and thus enhance the probability of anti-platelet aggregation and anti-thrombosis under pathological conditions. Conclusions Our results showed that GP1BA was closely related to the anti-platelet aggregation action of PTS, which provided new scientific and molecular evidence for its clinical application.

Challenges and Improvements of Novel Therapies for Ischemic Stroke

“…Compared with the control group, PNS reduced the infarction area and increased Nissl bodies markedly; besides, the TXA 2 (platelet activator)/PGI 2 (platelet inhibitor) ratio, the indictor for vascular tension, and gastrointestinal bleeding were reduced. Meanwhile, PNS led to fewer calcium ions influx and more cAMP by binding to Glycoprotein 1b platelet subunit alpha (GP1BA), which prevented the formation and exacerbation of platelet aggregation ( Xu et al, 2021 ). In addition, PNS had effects on neuron protection through inhibiting apoptosis and neural plasticity–related protein and promoting cell viability, NSCs proliferation and differentiation, and neurotrophic factors secretion ( Wu et al, 2020 ).…”

Mechanism and Potential Target of Blood-Activating Chinese Botanical Drugs Combined With Anti-Platelet Drugs: Prevention and Treatment of Atherosclerotic Cardiovascular Diseases

“…Panax notoginseng triol saponins mainly contained Ginsenoside Rg 1 , ginsenoside Re and notoginsenoside R 1 . The treatment of Panax notoginseng triol saponins (50 mg/kg) combined with aspirin (21 mg/kg) in middle cerebral artery occlusion model rats by gavage can reduce adverse gastrointestinal reactions by regulating the TXA2/PGI2 ratio, and enhance the anti-platelet aggregation and anti-thrombotic ability by reducing the adhesion between platelets and damaged vascular endothelial cells mediated by vWF (Xu et al, 2021) (Han et al, 2019). Ginkgolide B can inhibit the adhesion of platelets to monocytes and reduce VCAM-1 and Cx43 in tumour necrosis factor.…”

Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

“…F.H. Chen, PNS has antiarrhythmia, antiplatelet [ 37 ], antishock [ 38 ], antioxidation [ 39 ], sedative [ 40 ], and antitumor [ 41 ] effects. Panax notoginseng saponins have been approved in the treatment of central retinal vein occlusion, sequelae of cerebrovascular disease, enophthalmos, and anterior chamber hemorrhage in China.…”