Abstract
Shuxuening injection (SXNI), one of the pharmaceutical preparations of Ginkgo biloba extract, has significant effects on both ischemic stroke and heart diseases from bench to bedside. Its major active ingredients are ginkgo flavonol glycosides (GFGs) and ginkgolides (GGs). We have previously reported that SXNI as a whole protected ischemic brain and heart, but the active ingredients and their contribution to the therapeutic effects remain unclear. Therefore, we combined experimental and network analysis approach to further explore the specific effects and underlying mechanisms of GFGs and GGs of SXNI on ischemia–reperfusion injury in mouse brain and heart. In the myocardial ischemia–reperfusion injury (MIRI) model, pretreatment with GFGs at 2.5 ml/kg was superior to the same dose of GGs in improving cardiac function and coronary blood flow and reducing the levels of lactate dehydrogenase and aspartate aminotransferase in serum, with an effect similar to that achieved by SXNI. In contrast, pretreatment with GGs at 2.5 ml/kg reduced cerebral infarction area and cerebral edema similarly to that of SXNI but more significantly compared with GFGs in cerebral ischemia–reperfusion injury (CIRI) model. Network pharmacology analysis of GFGs and GGs revealed that tumor necrosis factor-related weak inducer of apoptosis (TWEAK)–fibroblast growth factor-inducible 14 (Fn14) signaling pathway as an important common mechanism but with differential targets in MIRI and CIRI. In addition, immunohistochemistry and enzyme linked immunosorbent assay (ELISA) assays were performed to evaluate the regulatory roles of GFGs and GGs on the common TWEAK–Fn14 signaling pathway to protect the heart and brain. Experimental results confirmed that TWEAK ligand and Fn14 receptor were downregulated by GFGs to mitigate MIRI in the heart while upregulated by GGs to improve CIRI in the brain. In conclusion, our study showed that GFGs and GGs of SXNI tend to differentially protect brain and heart from ischemia–reperfusion injuries at least in part by regulating a common TWEAK–Fn14 signaling pathway.
Highlights
Cardio-cerebral vascular diseases, including mainly ischemic myocardial infarction and ischemic stroke, are the most common causes of disability and death worldwide (Benjamin et al, 2018)
ginkgo flavonol glycosides (GFGs), GGs, or Shuxuening injection (SXNI) had no effect on LV posterior wall diastole (LVPWd) (Figure 1H), LV posterior wall systole (LVPWs) (Figure 1I), heart rate (Figure 1L), and left ventricular (LV) mass (Figure 1M) compared with the I/R group
The decline in aorta velocity–time integral mean velocity (AoV VTI) (Figure 2B), aortic valve (AV) peak velocity (Figure 2C), AV peak pressure (Figure 2D), left ventricular maximum upstroke velocity (+dp/dtmax) (Figure 2E), and left ventricular maximum descent velocity (−dp/dtmax) (Figure 2F) in the I/R group were outstanding compared with the sham group
Summary
Cardio-cerebral vascular diseases, including mainly ischemic myocardial infarction and ischemic stroke, are the most common causes of disability and death worldwide (Benjamin et al, 2018). It is well-established that ischemia–reperfusion (I/R) injury of both heart and brain shares certain common pathological mechanisms such as inflammation (Iadecola and Anrather, 2011; Goldfine and Shoelson, 2017), oxidative stress (Sanderson et al, 2013; Muntean et al, 2016), microvascular dysfunction (Gursoy-Ozdemir et al, 2012; Granger and Kvietys, 2017), and mitochondrial dysfunction (Ago et al, 2010; Yang et al, 2015). More attention has been drawn to studying the underlying active ingredients and molecular mechanisms of SXNI in preventing and treating ischemia stroke and coronary heart disease
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