The protective effect of harpagoside on angiotensin II (Ang II)‐induced blood–brain barrier leakage in vitro

Hypertension and its associated dysfunction of the blood–brain barrier (BBB) contribute to cerebral small vessel disease (cSVD). Angiotensin II (Ang II), a vasoactive peptide of the renin–angiotensin system (RAS), is not only a pivotal molecular signal in hypertension but also causes BBB leakage, cSVD, and cognitive impair. Harpagoside, the major bioactive constituent of Scrophulariae Radix, has been commonly used for the treatment of multiple diseases including hypertension in China. The effect of harpagoside on Ang II‐induced BBB damage is unclear. We employed an immortalized endothelial cell line (bEnd.3) to mimic a BBB monolayer model in vitro and investigated the effect of harpagoside on BBB and found that harpagoside alleviated Ang II‐induced BBB destruction, inhibited Ang II–associated cytotoxicity in a concentration‐dependent manner and attenuated Ang II‐induced reactive oxygen species (ROS) impair by downregulation of Nox2, Nox4, and COX‐2. Harpagoside prevented Ang II–induced apoptosis via keeping Bax/Bcl‐2 balance, decreasing cytochrome c release, and inactivation of caspase‐8, caspase‐9, and caspase‐3 (the mitochondria‐dependent and death receptor–mediated apoptosis pathways). Moreover, harpagoside can alleviate Ang II–induced BBB damage through upregulation of tight junction proteins and decrease of caveolae‐mediated endocytosis. Thus, harpagoside might be a potential drug to treat Ang II–induced cSVD.