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, 28 (6), 671-683

Effects of Xiaoshuan Enteric-Coated Capsule on White and Gray Matter Injury Evaluated by Diffusion Tensor Imaging in Ischemic Stroke

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Effects of Xiaoshuan Enteric-Coated Capsule on White and Gray Matter Injury Evaluated by Diffusion Tensor Imaging in Ischemic Stroke

Jian Zhang et al. Cell Transplant.

Abstract

Xiaoshuan enteric-coated capsule (XSECC) is a drug approved by the Chinese State Food and Drug Administration for the treatment of stroke. This study was to investigate the effects of XSECC on white and gray matter injury in a rat model of ischemic stroke by diffusion tensor imaging (DTI) and histopathological analyses. The ischemia was induced by middle cerebral artery occlusion (MCAO). The cerebral blood flow measured by arterial spin labeling was improved by treatment with XSECC on the 3rd, 7th, 14th and 30th days after MCAO. Spatiotemporal white and gray matter changes in MCAO rats were examined with DTI-derived parameters (fractional anisotropy, FA; apparent diffusion coefficient, ADC; axial diffusivity, λ//; radial diffusivity, λ). The increased FA was found in the XSECC treatment group in the corpus callosum, external capsule and internal capsule, linked with the decreased λ//, λ and ADC on the 3rd day and reduced ADC on the 30th day in the external capsule, suggesting XSECC reduced the axon and myelin damage in white matter after stroke. The relative FA in the striatum, cortex and thalamus in XSECC treatment group was significantly increased on the 3rd, 7th, 14th and 30th days accompanied by the increased λ// on the 3rd day and reduced relative ADC and λ on the 30th day, indicating that XSECC attenuated cell swelling and membrane damage in the early stage and tissue liquefaction necrosis in the late stage in gray matter after stroke. Additionally, XSECC-treated rats exhibited increased mean fiber length assessed by diffusion tensor tractography. Moreover, histopathological analyses provided evidence that XSECC relieved nerve cell and myelin damage in white and gray matter after stroke. Our research reveals that XSECC could alleviate white and gray matter injury, especially reducing nerve cell damage and promoting the repair of axon and myelin after ischemic stroke.

Keywords: enteric-coated capsule; diffusion tensor imaging; gray matter; stroke; white matter.

Conflict of interest statement

Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Fig 1.
Fig 1.
The effects of XSECC on rCBF in the cortex, striatum and thalamus on the 3rd, 7th, 14th and 30th days after stroke. n=4, 7, 7 in the sham, model and XSECC groups respectively on the 3rd day; n=4, 6, 6 in the sham, model and XSECC groups respectively on the 7th day; n=4, 3, 5 in the sham, model and XSECC groups respectively on the 14th day; n=4, 2, 4 in the sham, model and XSECC groups respectively on the 30th day. Values are means ± SD. Asterisks indicates significant differences. *P < 0.05, **P < 0.01 versus the model group. rCBF: relative cerebral blood flow; SD: standard deviation; XSECC: Xiaoshuan enteric-coated capsule.
Fig 2.
Fig 2.
The representative images of FA and ADC of the rat brains at the level of bregma −1.4 mm on the 3rd, 7th, 14th and 30th days. Serious damage occurred in the ischemic hemisphere in the model group evidenced by the obvious abnormal signals pointed with dotted lines on FA and ADC maps. The damage signals were weakened by XSECC treatment on the 3rd, 7th, 14th and 30th days. ADC: apparent diffusion coefficient; FA: fractional anisotropy; XSECC: Xiaoshuan enteric-coated capsule.
Fig 3.
Fig 3.
The effects of XSECC on white matter on the 3rd, 7th, 14th and 30th days after stroke. (A) The regions of interest drawn on white matter (corpus callosum, external capsule and internal capsule). (B, C, D) The statistical analysis of FA, ADC, λ// and λ in the corpus callosum, external capsule and internal capsule on the 3rd, 7th, 14th and 30th days after stroke. n=4, 7, 7 in the sham, model and XSECC groups respectively on the 3rd day; n=4, 6, 6 in the sham, model and XSECC groups respectively on the 7th day; n=4, 3, 5 in the sham, model and XSECC groups respectively on the 14th day; n=4, 2, 4 in the sham, model and XSECC groups respectively on the 30th day. Values are means ± SD. Asterisks indicates significant differences. *P < 0.05, **P < 0.01 versus the model group. λ//: axial diffusivity; λ⊥: radial diffusivity; ADC: apparent diffusion coefficient; FA: fractional anisotropy; SD: standard deviation; XSECC: Xiaoshuan enteric-coated capsule.
Fig 4.
Fig 4.
The effects of XSECC on gray matter on the 3rd, 7th, 14th and 30th days after stroke. (A) The regions of interest drawn on gray matter (cortex, striatum and thalamus). (B, C, D) The statistical analysis of FA, rADC, λ// and λ in the cortex, striatum, and thalamus on the 3rd, 7th, 14th and 30th days after stroke. n=4, 7, 7 in the sham, model and XSECC groups respectively on the 3rd day; n=4, 6, 6 in the sham, model and XSECC groups respectively on the 7th day; n=4, 3, 5 in the sham, model and XSECC groups respectively on the 14th day; n=4, 2, 4 in the sham, model and XSECC groups respectively on the 30th day. Values are means ± SD. Asterisks indicates significant differences. *P < 0.05, **P < 0.01 versus the model group. λ//: axial diffusivity; λ: radial diffusivity; rADC: relative apparent diffusion coefficient; rFA: relative fractional anisotropy; SD: standard deviation; XSECC: Xiaoshuan enteric-coated capsule.
Fig 5.
Fig 5.
The effects of XSECC on nerve fiber injury on the 3rd, 7th, 14th and 30th days after stroke. (A) The representative images of fiber reconstruction of the rat brains at the level of bregma −1.4 mm on the 3rd, 7th, 14th and 30th days. White matter fibers in the ischemic hemisphere were sparser than that in the contralateral hemisphere with abnormal morphology, partial curl, and even were missing in the rats of the model group on the 3rd, 7th, 14th and 30th days. (B) The statistical analysis of mean tract length (% of contralateral hemisphere) on the 3rd, 7th, 14th and 30th days after stroke. n=4, 7, 7 in the sham, model and XSECC groups respectively on the 3rd day; n=4, 6, 6 in the sham, model and XSECC groups respectively on the 7th day; n=4, 3, 5 in the sham, model and XSECC groups respectively on the 14th day; n=4, 2, 4 in the sham, model and XSECC groups respectively on the 30th day. Values are means ± SD. Asterisks indicates significant differences. *P < 0.05, **P < 0.01 versus the model group. XSECC: Xiaoshuan enteric-coated capsule; SD: standard deviation.
Fig 6.
Fig 6.
The effects of XSECC on the histopathological changes in white matter (corpus callosum, external capsule and internal capsule) on the 30th day after stroke. (A) Representative HE and LFB staining images in the corpus callosum, external capsule and internal capsule from the sham, model and XSECC group rats. The well-defined white matter structures, including corpus callosum, external capsule and internal capsule, were seen in the sham group on HE and LFB staining images. However, the loss of white matter integrity in the external capsule and internal capsule were observed in the model group on both HE and LFB staining images. HE staining showed that rats in the model group had vacuolation indicated by arrows in the external capsule and internal capsule. LFB staining displayed severe myelin disruptions indicated by arrows in the external capsule and internal capsule in the model group. By contrast, vacuolation and myelin damage were alleviated in external capsule and internal capsule by XSECC treatment. Images were visualized under an optical microscope at 400× magnification. (B) The statistical analysis of the myelin damage grade on the 30th day after stroke. n=4, 2, 4 in the sham, model and XSECC groups respectively. Values are means ± SD. Asterisks indicates significant differences. *P < 0.05, **P < 0.01 versus the model group. (C) Pearson correlational analysis of the myelin damage grade and DTI parameter FA. A negative correlation was found between myelin damage grade and FA in the corpus callosum, external capsule and internal capsule. HE: hematoxylin-eosin; LFB: luxol Fast Blue; MCAO: middle cerebral artery occlusion; XSECC: Xiaoshuan enteric-coated capsule.
Fig 7.
Fig 7.
The effects of XSECC on the histopathological changes in gray matter (cortex, striatum and thalamus) on the 30th day after stroke. (A) Representative HE staining images in the cortex, striatum and thalamus from the sham, model and XSECC group rats. The tissues and cells with normal histomorphology were observed in the cortex, striatum and thalamus in the sham group. By contrast, the brain tissues in the model group exhibited obvious pathological abnormalities with loosed arranged neurons, pyknotic nucleus and loss or dark color staining as indicated by arrows in the cortex, striatum and thalamus. However, these histopathological alterations were reversed following treatment with XSECC. Images were visualized under an optical microscope at 400× magnification. (B) The statistical analysis of the number of surviving neurons in the cortex, striatum and thalamus. n=4, 2, 4 in the sham, model and XSECC groups respectively. Values are means ± SD. Asterisks indicates significant differences. *P < 0.05, **P < 0.01 versus the model group. (C) Pearson correlational analysis of the number of surviving neurons and DTI parameter FA. A positive correlation was found between the number of surviving neurons and FA in the cortex, striatum and thalamus. DTI: diffusion tensor imaging; FA: fractional anisotropy; HE: hematoxylin-eosin; SD: standard deviation; XSECC: Xiaoshuan enteric-coated capsule.

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