Abstract

ObjectiveThe purpose of the study was to explore the effect of YangXue QingNao Wan (YXQNW), a compound Chinese medicine, on cerebrovascular hyperpermeability, neuronal injury, and related mechanisms in spontaneously hypertensive rat (SHR).MethodsFourteen-week-old male SHR were used, with Wistar Kyoto (WKY) rats as control. YXQNW (0.5 g/kg/day), enalapril (EN, 8 mg/kg/day), and nifedipine (NF, 7.1 mg/kg/day) were administrated orally for 4 weeks. To assess the effects of the YXQNW on blood pressure, the systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) were measured. After administering the drugs for 4 weeks, the cerebral blood flow (CBF), albumin leakage from microvessels in middle cerebral artery (MCA)-dominated area, and the number and morphology of microvessels were assessed in the hippocampus area and cortex. Neuronal damage and apoptosis were assessed by Nissl staining and TUNEL staining. To assess the mechanisms of cerebrovascular hyperpermeability, we performed immunofluorescence and Western blot to assess the expression and integrity of cerebral microvascular tight junction (TJ) and caveolin-1 (Cav-1) in cortex. Energy metabolism and Src-MLC-MLCK pathway in cortex were assessed then for elucidating the underlying mechanism of the observed effect of YXQNW.ResultsSpontaneously hypertensive rat exhibited higher blood pressure, Evans blue (EB) extravasation, albumin leakage, increased brain water content, decreased CBF, perivascular edema, and neuronal apoptosis in the hippocampus and cortex, all of which were attenuated by YXQNW treatment. YXQNW inhibited the downregulation of TJ proteins, mitochondrial Complex I, Complex II, and Complex V, and upregulation of caveolin-1, inhibiting Src/MLCK/MLC signaling in SHR. YXQNW combined with EN + NF revealed a better effect for some outcomes compared with either YXQNW or EN + NF alone.ConclusionThe overall result shows the potential of YXQNW to attenuate blood–brain barrier (BBB) breakdown in SHR, which involves regulation of energy metabolism and Src/MLCK/MLC signaling. This result provides evidence supporting the application of YXQNW as an adjuvant management for hypertensive patients to prevent hypertensive encephalopathy.

Highlights

  • MATERIALS AND METHODSHypertension affects approximately 1.0 billion people in the world, with an incidence close to 30% (Marwick et al, 2015), which is a major risk factor for vascular diseases including coronary artery disease, congestive heart failure, stroke, end-stage renal disease, and peripheral vascular disease (Go et al, 2014).The constriction or sclerosis of arteriole blood vessel can cause hypertension, and impairs the microvascular integrity leading to plasma albumin leakage from cerebral vessels (Fan et al, 2015; Wang et al, 2018)

  • Blood–brain barrier (BBB) disruption during acute and chronic hypertension has been noticed in animal models, which may contribute to hypertensive encephalopathy observed in human (Heistad, 1984)

  • The present study aimed to explore the effect of YangXue QingNao Wan (YXQNW) on BBB dysfunction during hypertension, and underlying mechanism in spontaneously hypertensive rats (SHRs)

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Summary

Introduction

The constriction or sclerosis of arteriole blood vessel can cause hypertension, and impairs the microvascular integrity leading to plasma albumin leakage from cerebral vessels (Fan et al, 2015; Wang et al, 2018). Blood–brain barrier (BBB) disruption during acute and chronic hypertension has been noticed in animal models, which may contribute to hypertensive encephalopathy observed in human (Heistad, 1984). Antihypertensive drugs can dilate arterioles and lower blood pressure (Chrysant, 2007), the effect of these drugs on BBB disruption during hypertension is largely unknown. At least some antihypertensive drugs have been reported as ineffective for prevention of BBB dysfunction (Mamo et al, 2017). It is appealing to search for a management that possesses the potential to protect BBB dysfunction during hypertension benefits patients at risk of hypertensive encephalopathy

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