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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.

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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.

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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.

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

Object

This study was designed to investigate the efficacy of delayed thymosin β4 (Tβ4) treatment of traumatic brain injury (TBI) in rats.

Methods

Young adult male Wistar rats were divided into the following groups: 1) sham group (6 rats); 2) TBI + saline group (9 rats); 3) and TBI + Tβ4 group (10 rats). Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex. Thymosin β4 (6 mg/kg) or saline was administered intraperitoneally starting at Day 1 and then every 3 days for an additional 4 doses. Neurological function was assessed using a modified neurological severity score (mNSS), foot fault, and Morris water maze tests. Animals were killed 35 days after injury, and brain sections were stained for immunohistochemistry to assess angiogenesis, neurogenesis, and oligodendrogenesis after Tβ4 treatment.

Results

Compared with the saline treatment, delayed Tβ4 treatment did not affect lesion volume but significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, increased oligodendrogenesis in the CA3 region, and significantly improved sensorimotor functional recovery and spatial learning.

Conclusions

These data for the first time demonstrate that delayed administration of Tβ4 significantly improves histological and functional outcomes in rats with TBI, indicating that Tβ4 has considerable therapeutic potential for patients with TBI.

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

Object

This efficacy study was designed to investigate traumatic brain injury (TBI) in rats treated with delayed erythropoietin (EPO) administered in a single dose compared with a triple dose.

Methods

Young adult male Wistar rats were randomly divided into the following groups: 1) sham group (6 animals); 2) TBI/saline group (6 animals); 3) TBI/EPO×1 group (6 animals); and 4) TBI/EPO×3 group (7 animals). Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex. Erythropoietin (5000 U/kg) or saline was administered intraperitoneally on Day 1 (EPO×1 group) or on Days 1, 2, and 3 (EPO×3 group) postinjury. Neurological function was assessed using a modified neurological severity score, foot-fault, and Morris water maze tests. Animals were killed 35 days after injury and brain sections were stained for immunohistochemistry.

Results

Compared with the saline treatment, EPO treatment in both the EPO×1 and EPO×3 groups significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved neurological functional outcome. The EPO×3 group exhibited significantly improved functional and histological outcomes compared with the EPO×1 group.

Conclusions

These data demonstrate that delayed posttraumatic administration of EPO significantly improved histological and long-term functional outcomes in rats after TBI. The triple doses of delayed EPO treatment produced better histological and functional outcomes in rats, although a single dose provided substantial benefits compared with saline treatment.

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

Object

Cerebrolysin is a unique peptide preparation that mimics the action of neurotrophic factors. This study was designed to investigate the effects of acute treatment of experimental closed head injury (CHI) in rats with Cerebrolysin on neurological function.

Methods

Adult male Wistar rats (n = 60) were subjected to impact acceleration–induced CHI. Closed head injured rats received intraperitoneal injection of saline (n = 30) or Cerebrolysin (2.5 ml/kg, n = 30) starting 1 hour postinjury and administered once daily until they were killed (2 or 14 days after CHI). To evaluate functional outcome, the modified neurological severity score (mNSS), foot fault, adhesive removal, and Morris water maze (MWM) tests were performed. Animals were killed on Day 14 (n = 20) after injury, and their brains were removed and processed for measurement of neuronal cells, axonal damage, apoptosis, and neuroblasts. The remaining rats (n = 40) were killed 2 days postinjury to evaluate cerebral microvascular patency by fluorescein isothiocyanate (FITC)–dextran perfusion (n = 16) and to measure the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase–9 (MMP-9) by using real-time reverse transcriptase-polymerase chain reaction (RT-PCR, n = 8) and by immunohistochemical analysis (n = 16).

Results

At 14 days post-CHI, the Cerebrolysin treatment group exhibited significant improvements in functional outcomes (the adhesive removal, mNSS, foot-fault, and MWM tests), and significantly more neurons and neuroblasts were present in the dentate gyrus (DG) (p < 0.05) compared with the saline-treated group (p < 0.05). At 2 days post-CHI, the Cerebrolysin group exhibited a significantly higher percentage of phosphorylated neurofilament H (pNF-H)–positive staining area in the striatum (p < 0.05), a significant increase in the percentage of FITC-dextran perfused vessels in the brain cortex (p < 0.05), a significant increase in the number of VEGF-positive cells (p < 0.05), and a significant reduction in the MMP-9 staining area (p < 0.05) compared with the saline-treated group. There was no significant difference in mRNA levels of MMP-9 and VEGF in the hippocampus and cortex 48 hours postinjury between Cerebrolysin- and saline-treated rats that sustained CHI.

Conclusions

Acute Cerebrolysin treatment improves functional recovery in rats after CHI. Cerebrolysin is neuroprotective for CHI (increased neurons in the dentate gyrus and the CA3 regions of the hippocampus and increased neuroblasts in the dentate gyrus) and may preserve axonal integrity in the striatum (significantly increased percentage of pNF-H–positive tissue in the striatum). Reduction of MMP-9 and elevation of VEGF likely contribute to enhancement of vascular patency and integrity as well as neuronal survival induced by Cerebrolysin. These promising results suggest that Cerebrolysin may be a useful treatment in improving the recovery of patients with CHI.

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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.

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Yuxia Han, Don Seyfried, Yuling Meng, Dongmei Yang, Lonni Schultz, Michael Chopp and Donald Seyfried

OBJECTIVE

Previous studies have demonstrated that transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after experimental intracerebral hemorrhage (ICH). In this study the authors tested the hypothesis that administration of multipotent MSC-derived exosomes promotes functional recovery, neurovascular remodeling, and neurogenesis in a rat model of ICH.

METHODS

Sixteen adult male Wistar rats were subjected to ICH via blood injection into the striatum, followed 24 hours later by tail vein injection of 100 μg protein of MSC-derived exosomes (treatment group, 8 rats) or an equal volume of vehicle (control group, 8 rats); an additional 8 rats that had identical surgery without blood infusion were used as a sham group. The modified Morris water maze (mMWM), modified Neurological Severity Score (mNSS), and social odor–based novelty recognition tests were performed to evaluate cognitive and sensorimotor functional recovery after ICH. All 24 animals were killed 28 days after ICH or sham procedure. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume and neurovascular and white matter remodeling.

RESULTS

Compared with the saline-treated controls, exosome-treated ICH rats showed significant improvement in the neurological function of spatial learning and motor recovery measured at 26–28 days by mMWM and starting at day 14 by mNSS (p < 0.05). Senorimotor functional improvement was measured by a social odor–based novelty recognition test (p < 0.05). Exosome treatment significantly increased newly generated endothelial cells in the hemorrhagic boundary zone, neuroblasts and mature neurons in the subventricular zone, and myelin in the striatum without altering the lesion volume.

CONCLUSIONS

MSC-derived exosomes effectively improve functional recovery after ICH, possibly by promoting endogenous angiogenesis and neurogenesis in rats after ICH. Thus, cell-free, MSC-derived exosomes may be a novel therapy for ICH.

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Yanlu Zhang, Michael Chopp, Yuling Meng, Zheng Gang Zhang, Edith Doppler, Stefan Winter, Timothy Schallert, Asim Mahmood and Ye Xiong

OBJECT

Long-term memory deficits occur after mild traumatic brain injuries (mTBIs), and effective treatment modalities are currently unavailable. Cerebrolysin, a peptide preparation mimicking the action of neurotrophic factors, has beneficial effects on neurodegenerative diseases and brain injuries. The present study investigated the long-term effects of Cerebrolysin treatment on cognitive function in rats after mTBI.

METHODS

Rats subjected to closed-head mTBI were treated with saline (n = 11) or Cerebrolysin (2.5 ml/kg, n = 11) starting 24 hours after injury and then daily for 28 days. Sham animals underwent surgery without injury (n = 8). To evaluate cognitive function, the modified Morris water maze (MWM) test and a social odor–based novelty recognition task were performed after mTBI. All rats were killed on Day 90 after mTBI, and brain sections were immunostained for histological analyses of amyloid precursor protein (APP), astrogliosis, neuroblasts, and neurogenesis.

RESULTS

Mild TBI caused long-lasting cognitive memory deficits in the MWM and social odor recognition tests up to 90 days after injury. Compared with saline treatment, Cerebrolysin treatment significantly improved both long-term spatial learning and memory in the MWM test and nonspatial recognition memory in the social odor recognition task up to 90 days after mTBI (p < 0.05). Cerebrolysin significantly increased the number of neuroblasts and promoted neurogenesis in the dentate gyrus, and it reduced APP levels and astrogliosis in the corpus callosum, cortex, dentate gyrus, CA1, and CA3 regions (p < 0.05).

CONCLUSIONS

These results indicate that Cerebrolysin treatment of mTBI improves long-term cognitive function, and this improvement may be partially related to decreased brain APP accumulation and astrogliosis as well as increased neuroblasts and neurogenesis.

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Ye Xiong, Asim Mahmood, Yanlu Zhang, Yuling Meng, Zheng Gang Zhang, Changsheng Qu, Thomas N. Sager and Michael Chopp

Object

Carbamylated erythropoietin (CEPO) is a modified erythropoietin molecule that does not affect hematocrit. In this study, the authors compared the efficacy of a single dose with a triple dose of CEPO treatment for traumatic brain injury (TBI) in rats.

Methods

Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex. Carbamylated erythropoietin (50 μg/kg) was administered intraperitoneally in rats with TBI at 6 hours (CEPO × 1) or at 6, 24, and 48 hours (CEPO × 3) postinjury. Neurological function was assessed using a modified neurological severity score and foot fault and Morris water maze tests. Animals were killed 35 days after injury, and brain sections were stained for immunohistochemical analysis to assess lesion volume, cell loss, cell proliferation, angiogenesis, and neurogenesis after CEPO treatment.

Results

Compared with the vehicle treatment, single treatment of CEPO (6 hours) significantly reduced lesion volume and hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved sensorimotor functional recovery and spatial learning in rats after TBI. Importantly, triple dosing of CEPO (6, 24, and 48 hours) further reduced lesion volume and improved functional recovery and neurogenesis compared with the CEPO × 1 group.

Conclusions

The authors' results indicate that CEPO has considerable therapeutic potential in TBI and related pathologies and furthermore that repeated dosing in the subacute phase might have important pharmacological relevance.