Total Flavonoids in Caragana (TFC) Promotes Angiogenesis and Enhances Cerebral Perfusion in a Rat Model of Ischemic Stroke

Never mind, this is in a rat and will never be tested in humans with our non-existent stroke leadership.
Total Flavonoids in Caragana (TFC) Promotes Angiogenesis and Enhances Cerebral Perfusion in a Rat Model of Ischemic Stroke 

Qiansong He^1*†, Shirong Li^2†, Lailai Li^1†, Feiran Hu¹, Ning Weng¹, Xiaodi Fan³ and Shixiang Kuang¹

• ¹Guiyang College of Traditional Chinese Medicine, Guiyang, China
• ²Department of Neurology, Guizhou Provincial People’s Hospital, Guiyang, China
• ³Department of Experimental Research Center, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China

Previous studies have demonstrated that total flavonoid extracts from Caragana sinica (TFC) exert multiple therapeutic effects, promote blood flow, and exhibit anti-inflammatory and antioxidant properties. The present study aimed to investigate whether TFC promotes angiogenesis and exerts neuroprotective effects in a rat model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats were subjected to tMCAO for 1.5 h, followed by 24 h of reperfusion. TFC (15, 30, 60 mg/kg) was administered for 14 days. Evaluations of neurological function were performed following reperfusion, and infarct volumes were assessed in brain slices stained with 2,3,5-triphenyltetrazolium chloride (TTC). Our results indicated that TFC significantly attenuated cerebral infarct volume and neurological deficits following tMCAO. Laser Doppler, micro-PET/CT, and MRI analyses further demonstrated that TFC reduced infarct volume and enhanced cerebral blood flow in a dose-dependent manner, with the most significant effects occurring at a concentration of 60 mg/kg. Significant up-regulation of CD31, VEGF, Ang-1, HIF-1α, delta-like 4 (Dll4), and Notch1 expression was also observed in the experimental groups, relative to that in the vehicle group. In summary, the results of the present study indicate that TFC (15, 30, 60 mg/kg) attenuates neurological deficits, reduces infarct volume, and promotes angiogenesis following MCAO in a concentration-dependent manner, likely via increases in the expression of CD31, VEGF, Ang-1, HIF-1α, Dll4, and Notch1. Further studies are required to determine the clinical usefulness and potential mechanisms of TFC in patients with cerebral focal ischemic stroke.

Introduction

Stroke is the second leading cause of death worldwide. As most cases of stroke occur due to ischemia, the need for more effective treatment strategies for ischemic stroke remains urgent (Bacigaluppi et al., 2008). In the ischemic brain, blood supply is severely reduced in the affected areas, eventually leading to cell death/apoptosis due to a lack of oxygen and nutrients (Plate, 1999). Accumulating evidence demonstrates that ischemic brain injury can be attenuated by restoring cerebral blood flow and rescuing dying neurons (Matsumoto et al., 1990; Zhang et al., 2002; Hoang et al., 2009). Indeed, thrombolytic and neuroprotective therapies represent the two primary measures currently used to treat acute cerebral infarction. Recent research has focused on the development of agents that induce angiogenesis and exert neuroprotective effects in an effort to cure ischemic stroke. Natural compounds such as medicinal herbs, which are associated with fewer adverse effects than standard medications, may allow for safe and effective induction of angiogenesis and neuroprotection (Pierre et al., 1999).

Caragana sinica (Fabaceae), commonly known as Chinese peashrub, is widely distributed throughout China, particularly in Mongolia and Tibet. Since the 10th century, Caragana sinica has been used in the treatment of a variety of symptoms (e.g., colds, strains, fatigue, wheezing) (Jia et al., 1997). Accumulating evidence has demonstrated that Caragana sinica improves blood profiles, facilitates blood flow, clears lung-heat, promotes kidney and spleen function, and aids in the healing of bruises/contusions (Jiangsu New Medical College, 1986). In our previous chemical constituent analysis, we revealed that flavonoids contained within ethyl acetate extracts of the Caragana sinica root exhibit multifaceted bioactivity (He et al., 2017). Previous studies have reported that flavonoids—which are defined as polyphenols that exert cytoprotective effects—exhibit anti-inflammatory, anticancer, antioxidative, antiviral, and antibacterial properties (Wang et al., 2010, 2014; Al-Nakkash et al., 2012; Li et al., 2012; Lim et al., 2013; Lin et al., 2015; He et al., 2017). Recently, we have investigated the effects of flavonoids and several known compounds derived from Caragana sinica [total flavonoids in caragana (TFC)], including quercetin, 6,3′-dimethoxy-7,5′-dihydroxy isoflavone, caraphenol C, and (-)-ampelopsin F (Figure 1) on ischemic brain injury. In particular, we aimed to determine whether and how TFC enhances angiogenesis in rodent models of stroke.

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