Search Results

You are looking at 1 - 10 of 26 items for

  • Author or Editor: Ye Xiong x
Clear All Modify Search
Restricted access

Asim Mahmood, Hongtao Wu, Changsheng Qu, Ye Xiong and Michael Chopp

Object

This study was designed to investigate how transplantation into injured brain of human bone marrow stromal cells (hMSCs) impregnated in collagen scaffolds affects axonal sprouting in the spinal cord after traumatic brain injury (TBI) in rats. Also investigated was the relationship of axonal sprouting to sensorimotor functional recovery after treatment.

Methods

Adult male Wistar rats (n = 24) underwent a controlled cortical impact injury and were divided into three equal groups (8 rats/group). The two treatment groups received either hMSCs (3 × 106) alone or hMSC (3 × 106)–impregnated collagen scaffolds transplanted into the lesion cavity. In the control group, saline was injected into the lesion cavity. All treatments were performed 7 days after TBI. On Day 21 after TBI, a 10% solution of biotinylated dextran amine (10,000 MW) was stereotactically injected into the contralateral motor cortex to label the corticospinal tract (CST) originating from this area. Sensorimotor function was tested using the modified neurological severity score (mNSS) and foot-fault tests performed on Days 1, 7, 14, 21, 28, and 35 after TBI. Spatial learning was tested with Morris water maze test on Days 31–35 after TBI. All rats were sacrificed on Day 35 after TBI, and brain and spinal cord (cervical and lumbar) sections were stained immunohistochemically for histological analysis.

Results

Few biotinylated dextran amine–labeled CST fibers crossing over the midline were found in the contralateral spinal cord transverse sections at both cervical and lumbar levels in saline-treated (control) rats. However, hMSC-alone treatment significantly increased axonal sprouting from the intact CST into the denervated side of the gray matter of both cervical and lumbar levels of the spinal cord (p < 0.05). Also, this axonal sprouting was significantly more in the scaffold+hMSC group compared with the hMSC-alone group (p < 0.05). Sensorimotor functional analysis showed significant improvement of mNSS (p < 0.05) and foot-fault tests (p < 0.05) in hMSC-alone and scaffold+hMSC-treated rats compared with controls (p < 0.05). Functional improvement, however, was significantly greater in the scaffold+hMSC group compared with the hMSC-alone group (p < 0.05). Morris water maze testing also showed significant improvement in spatial learning in scaffold+hMSC and hMSC-alone groups compared with the control group (p < 0.05), with rats in the scaffold+hMSC group performing significantly better than those in the hMSC-alone group (p < 0.05). Pearson correlation data showed significant correlation between the number of crossing CST fibers detected and sensorimotor recovery (p < 0.05).

Conclusions

Axonal plasticity plays an important role in neurorestoration after TBI. Transplanting hMSCs with scaffolds enhances the effect of hMSCs on axonal sprouting of CST fibers from the contralateral intact cortex into the denervated side of spinal cord after TBI. This enhanced axonal regeneration may at least partially contribute to the therapeutic benefits of treating TBI with hMSCs.

Full access

Yanlu Zhang, Michael Chopp, Yuling Meng, Mark Katakowski, Hongqi Xin, Asim Mahmood and Ye Xiong

OBJECT

Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). In this study the authors tested a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI.

METHODS

Two groups of 8 Wistar rats were subjected to TBI, followed 24 hours later by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle (phosphate-buffered saline). A third group of 8 rats was used as sham-injured, sham-treated controls. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, modified Neurological Severity Score, and foot-fault tests were performed. Animals were killed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation.

RESULTS

Compared with the saline-treated group, exosome-treated rats with TBI showed significant improvement in spatial learning at 34–35 days as measured by the modified Morris water maze test (p < 0.05), and sensorimotor functional recovery (i.e., reduced neurological deficits and foot-fault frequency) was observed at 14–35 days postinjury (p < 0.05). Exosome treatment significantly increased the number of newly generated endothelial cells in the lesion boundary zone and dentate gyrus and significantly increased the number of newly formed immature and mature neurons in the dentate gyrus as well as reducing neuroinflammation.

CONCLUSIONS

The authors demonstrate for the first time that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and by reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly for other neurological diseases.

Restricted access

Yanlu Zhang, Zheng Gang Zhang, Michael Chopp, Yuling Meng, Li Zhang, Asim Mahmood and Ye Xiong

OBJECTIVE

The authors' previous studies have suggested that thymosin beta 4 (Tβ4), a major actin-sequestering protein, improves functional recovery after neural injury. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an active peptide fragment of Tβ4. Its effect as a treatment of traumatic brain injury (TBI) has not been investigated. Thus, this study was designed to determine whether AcSDKP treatment improves functional recovery in rats after TBI.

METHODS

Young adult male Wistar rats were randomly divided into the following groups: 1) sham group (no injury); 2) TBI + vehicle group (0.01 N acetic acid); and 3) TBI + AcSDKP (0.8 mg/kg/day). TBI was induced by controlled cortical impact over the left parietal cortex. AcSDKP or vehicle was administered subcutaneously starting 1 hour postinjury and continuously for 3 days using an osmotic minipump. Sensorimotor function and spatial learning were assessed using a modified Neurological Severity Score and Morris water maze tests, respectively. Some of the animals were euthanized 1 day after injury, and their brains were processed for measurement of fibrin accumulation and neuroinflammation signaling pathways. The remaining animals were euthanized 35 days after injury, and brain sections were processed for measurement of lesion volume, hippocampal cell loss, angiogenesis, neurogenesis, and dendritic spine remodeling.

RESULTS

Compared with vehicle treatment, AcSDKP treatment initiated 1 hour postinjury significantly improved sensorimotor functional recovery (Days 7–35, p < 0.05) and spatial learning (Days 33–35, p < 0.05), reduced cortical lesion volume, and hippocampal neuronal cell loss, reduced fibrin accumulation and activation of microglia/macrophages, enhanced angiogenesis and neurogenesis, and increased the number of dendritic spines in the injured brain (p < 0.05). AcSDKP treatment also significantly inhibited the transforming growth factor–β1/nuclear factor–κB signaling pathway.

CONCLUSIONS

AcSDKP treatment initiated 1 hour postinjury provides neuroprotection and neurorestoration after TBI, indicating that this small tetrapeptide has promising therapeutic potential for treatment of TBI. Further investigation of the optimal dose and therapeutic window of AcSDKP treatment for TBI and the associated underlying mechanisms is therefore warranted.

Restricted access

Ye Xiong, Dunyue Lu, Changsheng Qu, Anton Goussev, Timothy Schallert, Asim Mahmood and Michael Chopp

Object

This study was designed to investigate the beneficial effects of recombinant human erythropoietin (rhEPO) treatment of traumatic brain injury (TBI) in mice.

Methods

Adult male C57BL/6 mice were divided into 3 groups: 1) the saline group (TBI and saline [13 mice]); 2) EPO group (TBI and rhEPO [12]); and 3) sham group (sham and rhEPO [8]). Traumatic brain injury was induced by controlled cortical impact. Bromodeoxyuridine (100 mg/kg) was injected daily for 10 days, starting 1 day after injury, for labeling proliferating cells. Recombinant human erythropoietin was administered intraperitoneally at 6 hours and at 3 and 7 days post-TBI (5000 U/kg body weight, total dosage 15,000 U/kg). Neurological function was assessed using the Morris water maze and footfault tests. Animals were killed 35 days after injury, and brain sections were stained for immunohistochemical evaluation.

Results

Traumatic brain injury caused tissue loss in the cortex and cell loss in the dentate gyrus (DG) as well as impairment of sensorimotor function (footfault testing) and spatial learning (Morris water maze). Traumatic brain injury alone stimulated cell proliferation and angiogenesis. Compared with saline treatment, rhEPO significantly reduced lesion volume in the cortex and cell loss in the DG after TBI and substantially improved recovery of sensorimotor function and spatial learning performance. It enhanced neurogenesis in the injured cortex and the DG.

Conclusions

Recombinant human erythropoietin initiated 6 hours post-TBI provided neuroprotection by decreasing lesion volume and cell loss as well as neurorestoration by enhancing neurogenesis, subsequently improving sensorimotor and spatial learning function. It is a promising neuroprotective and neurorestorative agent for TBI and warrants further investigation.

Restricted access

Bon H. Verweij, J. Paul Muizelaar, Federico C. Vinas, Patti L. Peterson, Ye Xiong and Chuan P. Lee

Object. Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose—response curves in preclinical drug testing. This idea was tested in a model of TBI in rats.

Methods. Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose.

Conclusions. The authors established these time-window profiles and dose—response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose—response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.

Restricted access

Bing Zhao, Hua Yang, Kuang Zheng, Zequn Li, Ye Xiong, Xianxi Tan, Ming Zhong and the AMPAS Study Group

OBJECTIVE

An increasing number of patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) have received endovascular treatment. Endovascular treatment of poor-grade aSAH, however, is based on single-center retrospective studies, and predictors of long-term outcome have not been well defined. Using results from a multicenter prospective registry, the authors aimed to develop preoperative and postoperative prognostic models to predict poor outcome after endovascular treatment of poor-grade aSAH.

METHODS

A Multicenter Poor-grade Aneurysm Study (AMPAS) was a prospective and observational registry of consecutive patients with poor-grade aSAH. From October 2010 to March 2012, 366 patients were enrolled in the registry, and 136 patients receiving endovascular treatment were included in this study. Outcome was assessed by modified Rankin Scale (mRS) score at 12 months, and poor outcome was defined as an mRS score of 4, 5, or 6. Prognostic models were developed in multivariate logistic regression models. The area under receiver operating characteristic curves (AUC) was used to assess the model's discriminatory ability, and Hosmer-Lemeshow goodness-of-fit tests were used to assess the calibration.

RESULTS

At 12 months, 64 patients (47.0%) had a poor outcome: 9 (6.6%) had an mRS score of 4, 6 (4.4%) had an mRS score of 5, and 49 (36.0%) had died. Univariate analyses showed that older age (p = 0.001), female sex (p = 0.044), lower Glasgow Coma Scale score (p < 0.001), a World Federation of Neurosurgical Societies (WFNS) grade of V (p < 0.001), higher Fisher grade (p < 0.001), modified Fisher grade (p < 0.001), and wider neck aneurysm (p = 0.026) were associated with a poor outcome. There was a trend toward a worse outcome in patients with anterior communicating artery aneurysms (p = 0.080) and in those with incompletely occluded aneurysms (p = 0.063). After endovascular treatment, the presence of cerebral infarction (p = 0.039), symptomatic vasospasm (p = 0.039), and pneumonia (p = 0.006) were associated with a poor outcome. Multivariate analyses showed that the preoperative prognostic model including age, a WFNS grade of V, modified Fisher grade, and aneurysm neck size had excellent discrimination with an AUC of 0.86 (95% CI 0.80–0.92, p < 0.001), and a postoperative model that included these predictors as well as postoperative pneumonia had excellent discrimination (AUC = 0.87, 95% CI 0.81–0.93, p < 0.001). Both models had good calibration (p = 0.941 and p = 0.653, respectively).

CONCLUSIONS

Older age, WFNS Grade V, higher modified Fisher grade, wider neck aneurysm, and postoperative pneumonia were independent predictors of poor outcome after endovascular treatment of poor-grade aSAH. The preoperative model had almost the same discrimination as the postoperative model. Endovascular treatment should be carefully considered in patients with poor-grade aSAH with ruptured wide-neck aneurysms.

▪ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort trial; evidence: Class I.

Restricted access

Changsheng Qu, Ye Xiong, Asim Mahmood, David L. Kaplan, Anton Goussev, Ruizhuo Ning and Michael Chopp

Object

This study was designed to investigate new ways of delivering human marrow stromal cells (hMSCs) to the injured brain by impregnating them into collagen scaffolds in a mouse model of traumatic brain injury (TBI).

Methods

Eight C57BL/6 J mice were injured with controlled cortical impact and received transplantation into the lesion cavity of 0.3 × 106 hMSCs impregnated into 3D porous collagen scaffolds. Additional experimental groups of 8 mice each received scaffolds implanted alone into the lesion cavity, hMSCs administered alone intracerebrally or intravenously, or saline injected into the lesion core. All treatments were performed 7 days after TBI. Spatial learning was measured using a modified Morris water maze test, and brain tissue samples were processed for histopathological analysis.

Results

The results showed that hMSC-impregnated scaffolds were more effective than hMSCs administered alone (either intravenously or intracerebrally) in improving spatial learning, reducing lesion volume, and increasing vascular density after TBI.

Conclusions

Collagen scaffolds populated with hMSCs may be a new way to reconstruct injured brain tissue and improve neurological function after TBI.

Restricted access

Ye Xiong, Yanlu Zhang, Asim Mahmood, Yuling Meng, Zheng Gang Zhang, Daniel C. Morris and Michael Chopp

Object

Thymosin β4 (Tβ4) is a regenerative multifunctional peptide. The aim of this study was to test the hypothesis that Tβ4 treatment initiated 6 hours postinjury reduces brain damage and improves functional recovery in rats subjected to traumatic brain injury (TBI).

Methods

Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex in young adult male Wistar rats. The rats were randomly divided into the following groups: 1) saline group (n = 7); 2) 6 mg/kg Tβ4 group (n = 8); and 3) 30 mg/kg Tβ4 group (n = 8). Thymosin β4 or saline was administered intraperitoneally starting at 6 hours postinjury and again at 24 and 48 hours. An additional group of 6 animals underwent surgery without TBI (sham-injury group). Sensorimotor function and spatial learning were assessed using the modified Neurological Severity Score and the Morris water maze test, respectively. Animals were euthanized 35 days after injury, and brain sections were processed to assess lesion volume, hippocampal cell loss, cell proliferation, and neurogenesis after Tβ4 treatment.

Results

Compared with saline administration, Tβ4 treatment initiated 6 hours postinjury significantly improved sensorimotor functional recovery and spatial learning, reduced cortical lesion volume and hippocampal cell loss, and enhanced cell proliferation and neurogenesis in the injured hippocampus. The high dose of Tβ4 showed better beneficial effects compared with the low-dose treatment.

Conclusions

Thymosin β4 treatment initiated 6 hours postinjury provides both neuroprotection and neurorestoration after TBI, indicating that Tβ4 has promising therapeutic potential in patients with TBI. These data warrant further investigation of the optimal dose and therapeutic window of Tβ4 treatment for TBI and the associated underlying mechanisms.

Full access

Asim Mahmood, Hongtao Wu, Changsheng Qu, Selina Mahmood, Ye Xiong, David L. Kaplan and Michael Chopp

Object

Neurocan is a major form of growth-inhibitory molecule (growth-IM) that suppresses axonal regeneration after neural injury. Bone marrow stromal cells (MSCs) have been shown to inhibit neurocan expression in vitro and in animal models of cerebral ischemia. Therefore, the present study was designed to investigate the effects of treatment of MSCs impregnated with collagen scaffolds on neurocan expression after traumatic brain injury (TBI).

Methods

Adult male Wistar rats were injured with controlled cortical impact and treated with saline, human MSCs (hMSCs) (3 × 106) alone, or hMSCs (3 × 106) impregnated into collagen scaffolds (scaffold + hMSCs) transplanted into the lesion cavity 7 days after TBI (20 rats per group). Rats were sacrificed 14 days after TBI, and brain tissues were harvested for immunohistochemical studies, Western blot analyses, laser capture microdissections, and quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) to evaluate neurocan protein and gene expressions after various treatments.

Results

Animals treated with scaffold + hMSCs after TBI showed increased axonal and synaptic densities compared with the other groups. Scaffold + hMSC treatment was associated with reduced TBI-induced neurocan protein expression and upregulated growth-associated protein 43 (GAP-43) and synaptophysin expression in the lesion boundary zone. In addition, animals in the scaffold + hMSC group had decreased neurocan transcription in reactive astrocytes after TBI. Reduction of neurocan expression was significantly greater in the scaffold + hMSC group than in the group treated with hMSCs alone.

Conclusions

The results of this study show that transplanting hMSCs with scaffolds enhances the effect of hMSCs on axonal plasticity in TBI rats. This enhanced axonal plasticity may partially be attributed to the downregulation of neurocan expression by hMSC treatment after injury.

Restricted access

Yuling Meng, Ye Xiong, Asim Mahmood, Yanlu Zhang, Changsheng Qu and Michael Chopp

Object

Delayed (24 hours postinjury) treatment with erythropoietin (EPO) improves functional recovery following experimental traumatic brain injury (TBI). In this study, the authors tested whether therapeutic effects of delayed EPO treatment for TBI are dose dependent in an attempt to establish an optimal dose paradigm for the delayed EPO treatment.

Methods

Experimental TBI was performed in anesthetized young adult male Wistar rats using a controlled cortical impact device. Sham animals underwent the same surgical procedure without injury. The animals (8 rats/group) received 3 intraperitoneal injections of EPO (0, 1000, 3000, 5000, or 7000 U/kg body weight, at 24, 48, and 72 hours) after TBI. Sensorimotor and cognitive functions were assessed using a modified neurological severity score and foot fault test, and Morris water maze tests, respectively. Animals were killed 35 days after injury, and the brain sections were stained for immunohistochemical analyses.

Results

Compared with the saline treatment, EPO treatment at doses from 1000 to 7000 U/kg did not alter lesion volume but significantly reduced hippocampal neuron loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved sensorimotor function and spatial learning. The animals receiving the medium dose of 5000 U/kg exhibited a significant improvement in histological and functional outcomes compared with the lower or higher EPO dose groups.

Conclusions

These data demonstrate that delayed (24 hours postinjury) treatment with EPO provides dose-dependent neurorestoration, which may contribute to improved functional recovery after TBI, implying that application of an optimal dose of EPO is likely to increase successful preclinical and clinical trials for treatment of TBI.