Effects of Xiaoshuan enteric-coated capsule on neurovascular functions assessed by quantitative multiparametric MRI in a rat model of permanent cerebral ischemia

Abstract

BackgroundBuyang Huanwu Decoction (BYHWD) is a Traditional Chinese Medicine (TCM) formula for treating stroke-induced disability. Xiaoshuan enteric-coated capsule (XSECC), derived from the formula BYHWD, is a drug approved by the China Food and Drug Administration (CFDA) for stroke management. To further investigate the potential protective effects of XSECC on neurovascular functions, we endeavour to monitor the neurovascular functions using multimodal magnetic resonance imaging (MRI) and evaluated histopathological changes of neurovascular unit (NVU) after stroke.MethodsIschemic stroke was induced by permanent middle cerebral artery occlusion (pMCAO). XSECC (420 mg/kg) was orally administered 2 h after stroke and daily thereafter. T2-weighted imaging (T2WI), T2 relaxometry mapping and diffusion tensor imaging (DTI) were used to measure cerebral infarct volume, edema and white matter fiber integrity, respectively. Neurochemical metabolite levels were monitored by 1H-magnetic resonance spectroscopy (1H-MRS). Arterial spin labeling (ASL) – cerebral blood flow (CBF) measurements and structural magnetic resonance angiography (MRA) images provided real-time and dynamic information about vascular hemodynamic dysfunction on the 3rd, 7th and 14th days after pMCAO. At the last imaging time point, immunohistochemistry, immunofluorescence as well as transmission electron microscopy (TEM) were used to test the microscopic and ultrastructural changes of NVU.ResultsT2WI, T2 relaxometry mapping and Fractional anisotropy (FA) in DTI showed that XSECC significantly reduced cerebral infarct volume, relieved edema and alleviated nerve fiber injuries, respectively. 1H-MRS provided information about improvement of neuronal/glial metabolism after XSECC treatment. Moreover, ASL – CBF measurements combined with MRA showed that XSECC significantly increased CBF and vascular signal strength and alleviated ischemia-induced morphological changes of arteries in ischemic hemisphere within 14 days after stroke. In addition, neuron specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), CD34 staining and TEM detection indicated that XSECC not only ameliorated neuronal injury, but also reduced endothelial damage and inhibited astrocyte proliferation.ConclusionsOur results suggested that XSECC has multi-target neurovascular protective effects on ischemic stroke, which may be closely correlated with the improvement of cerebral blood supply and neuronal/glial metabolism.

MRI Evaluation of Axonal Remodeling After Combination Treatment With Xiaoshuan Enteric-Coated Capsule and Enriched Environment in Rats After Ischemic Stroke

“…Although several lines of evidence have demonstrated that XSEC and EE may independently promote brain plasticity and neurological recovery after an ischemic stroke (Nygren et al, 2006;Chen et al, 2015Chen et al, , 2017Zhang et al, 2016), the efficacy of a combination of XSEC and EE on post-stroke axonal injury and remodeling still needed to be elucidated. Based on our MRI and histological methodologies, the present study demonstrated that the combined actions of XSEC and EE exerted synergistic effects on reducing cerebral atrophy, facilitating axonal remodeling, and improving spatial learning and memory in a permanent MCAO rat model accompanied with amplifying stroke-induced oligodendrogenesis and overcoming the intrinsic axonal growth inhibitory signals, which was beneficial to axonal outgrowth.…”

“…XSEC (batch no: 20170706) was supplied by Sanmenxia Sinoway Pharmaceutical, Co., Ltd. (Henan, China). The processing of XSEC followed a strict quality control, and the main ingredients of XSEC were subjected to standardization in our previous study (Zhang et al, 2016). XSEC was dissolved in physiological saline to a concentration of 28 mg/mL before use.…”

“…Diffusion tensor imaging (DTI) was performed with an axial single-shot spin echo-planar imaging sequence (Zhang et al, 2016). The directionally encoded color (DEC), fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) maps were reconstructed by Paravision version5.1 software (Bruker, Germany).…”

“…XSEC is a novel preparation of BYHWD approved by the China Food and Drug Administration for treating strokeinduced disabilities (drug permit document: Z20000025). Our previous study demonstrated that XSEC promotes neurovascular remodeling and improves neurological function after ischemic stroke in animal models (Zhang et al, 2016). However, the effects of XSEC on axonal remodeling after stroke have not been investigated.…”

Expression and Significance of MicroRNA155 in Serum of Patients with Cerebral Small Vessel Disease

“…BBB dysfunction is considered to be a biological marker of cerebral stroke, and increased cerebral vascular permeability and BBB leakage will lead to ischemic brain damage 1) . Zhang et al 34) pointed out that miR-155 can be used as a negative regulator of BBB function. This study found that the inhibition of endogenous miR-155 attenuated some of the high permeability induced by cytokines 2) .…”