Abstract
Xiaoshuan enteric-coated capsule (XSEC) is a compound Chinese medicine widely used for the treatment of ischemic stroke. Enriched environment (EE) is a rehabilitative intervention designed to facilitate physical, cognitive, and social activity after brain injury. This study aimed to assess whether the XSEC and EE combination could provide synergistic efficacy in axonal remodeling compared to that with a single treatment after ischemic stroke using magnetic resonance imaging (MRI) followed by histological analysis. Rats were subjected to permanent middle cerebral artery occlusion and treated with XSEC and EE alone or in combination for 30 days. T2-weighted imaging and diffusion tensor imaging (DTI) were performed to examine the infarct volume and axonal remodeling, respectively. The co-localization of Ki67 with NG2 or CNPase was examined by immunofluorescence staining to assess oligodendrogenesis. The expressions of growth associated protein-43 (GAP-43) and growth inhibitors NogoA/Nogo receptor (NgR)/RhoA/Rho-associated kinase2 (ROCK2) were measured using western blot and qRT-PCR. The Morris water maze (MWM) was performed to evaluate the cognitive function. MRI and histological measurements indicated XSEC and EE individually benefited axonal reorganization after stroke. Notably, XSEC + EE decreased infarct volume compared with XSEC or EE monotherapy and increased ipsilateral residual volume compared with vehicle group. DTI showed XSEC + EE robustly increased fractional anisotropy while decreased axial diffusivity and radial diffusivity in the injured cortex, striatum, and external capsule. Meanwhile, diffusion tensor tractography revealed XSEC + EE elevated fiber density in the cortex and external capsule and increased fiber length in the striatum and external capsule compared with the monotherapies. These MRI measurements, confirmed by histology, showed that XSEC + EE promoted axonal restoration. Additionally, XSEC + EE amplified oligodendrogenesis, decreased the expressions of NogoA/NgR/RhoA/ROCK2, and increased the expression of GAP-43 in the peri-infarct tissues. In parallel to these findings, rats treated with XSEC + EE exhibited higher cognitive recovery than those treated with XSEC or EE monotherapy, as evidenced by MWM test. Taken together, our data implicated that XSEC + EE exerted synergistic effects on alleviating atrophy and encouraging axonal reorganization partially by promoting oligodendrogenesis and overcoming intrinsic growth-inhibitory signaling, thereby facilitating higher cognitive recovery.
Highlights
Ischemic stroke is one of the most common causes of morbidity and mortality worldwide (Chen et al, 2014)
When compared with the vehicle group, Xiaoshuan enteric-coated capsule (XSEC) + EE robustly elevated the ratio of residual volume (P < 0.05), while XSEC or EE monotherapy showed no statistic differences on the ratio of residual volume (Vehicle, 0.4094 ± 0.0482; XSEC, 0.5615 ± 0.0478; EE, 0.4983 ± 0.0386; XSEC + EE, 0.7922 ± 0.0436, Figure 1D), indicating that the combined actions of XSEC and EE significantly alleviated atrophy of the ipsilateral hemisphere
Based on our Magnetic resonance imaging (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
Summary
Ischemic stroke is one of the most common causes of morbidity and mortality worldwide (Chen et al, 2014). Stroke mortality has been declining with effective thrombolysis, a large proportion of stroke patients exhibit long-term disability (Zhang and Chopp, 2009). Additional attention should be paid to protect the white matter and boost axonal remodeling that may provide long-term neurological benefits after an ischemic stroke. BYHWD has shown a convincing effect on neuroprotection and neuroregeneration in stroke patients and experimental stroke animal models (Hao et al, 2012; Zhao et al, 2012; Wei et al, 2013). 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). The effects of XSEC on axonal remodeling after stroke have not been investigated
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call