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1.  Subacute Intranasal Administration of Tissue Plasminogen Activator Promotes Neuroplasticity and Improves Functional Recovery following Traumatic Brain Injury in Rats 
PLoS ONE  2014;9(9):e106238.
Traumatic brain injury (TBI) is a major cause of death and long-term disability worldwide. To date, there are no effective pharmacological treatments for TBI. Recombinant human tissue plasminogen activator (tPA) is the effective drug for the treatment of acute ischemic stroke. In addition to its thrombolytic effect, tPA is also involved in neuroplasticity in the central nervous system. However, tPA has potential adverse side effects when administered intravenously including brain edema and hemorrhage. Here we report that tPA, administered by intranasal delivery during the subacute phase after TBI, provides therapeutic benefit. Animals with TBI were treated intranasally with saline or tPA initiated 7 days after TBI. Compared with saline treatment, subacute intranasal tPA treatment significantly 1) improved cognitive (Morris water maze test) and sensorimotor (footfault and modified neurological severity score) functional recovery in rats after TBI, 2) reduced the cortical stimulation threshold evoking ipsilateral forelimb movement, 3) enhanced neurogenesis in the dentate gyrus and axonal sprouting of the corticospinal tract originating from the contralesional cortex into the denervated side of the cervical gray matter, and 4) increased the level of mature brain-derived neurotrophic factor. Our data suggest that subacute intranasal tPA treatment improves functional recovery and promotes brain neurogenesis and spinal cord axonal sprouting after TBI, which may be mediated, at least in part, by tPA/plasmin-dependent maturation of brain-derived neurotrophic factor.
doi:10.1371/journal.pone.0106238
PMCID: PMC4153585  PMID: 25184365
2.  A Multicenter prospective study of poor-grade aneurysmal subarachnoid hemorrhage (AMPAS): observational registry study 
BMC Neurology  2014;14:86.
Background
Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) is associated with very high mortality and morbidity. Our limited knowledge on predictors of long-term outcome in poor-grade patients with aSAH definitively managed comes from retrospective and prospective studies of small case series of patients in single center. The purpose of the AMPAS is to determine the long-term outcomes in poor-grade patients with different managements within different time after aSAH, and identify the independent predictors of the outcome that help guide the decision on definitive management.
Methods/design
The AMPAS study is a prospective, multicenter, observational registry of consecutive hospitalized patients with poor grade aSAH (WFNS grade IV and V). The aim is to enroll at least 226 poor-grade patients in 11 high-volume medical centers (eg, >150 aSAH cases per year) affiliated to different universities in China. This study will describe poor grade patients and aneurysm characteristics, treatment strategies (modality and time of definitive management), hospitalization complications and outcomes evolve over time. The definitive management is ruptured aneurysm treatment. Outcomes at 3, 6, 12 months after the management were measured using the Glasgow Outcome Scale and the Modified Rankin Scale.
Discussion
The AMPAS is the first prospective, multicenter, observational registry of poor grade aSAH with any management. This study will contribute to a better understanding of significant predictors of outcome in poor grade patients and help guide future treatment of the worst patients after aSAH.
Trial registration
Chinese Clinical Trial Registry: ChiCTR-TNRC-10001041.
doi:10.1186/1471-2377-14-86
PMCID: PMC3997185  PMID: 24742248
Aneurysmal subarachnoid hemorrhage; Poor-grade; Definitive management; Outcome; Predicators
3.  Effects of Erythropoietin on Reducing Brain Damage and Improving Functional Outcome after traumatic brain injury in mice 
Journal of neurosurgery  2008;109(3):510-521.
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) saline group (TBI + saline, n = 13); 2) EPO group (TBI + rhEPO, n = 12); and 3) sham group (sham + rhEPO, n = 8). TBI 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. rhEPO 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 sacrificed 35 days after injury and brain sections stained for immunohistochemistry.
Results
TBI caused both tissue loss in the cortex and cell loss in the dentate gyrus (DG) and impaired sensorimotor function (footfaults) and spatial learning (Morris Water Maze). TBI alone stimulated cell proliferation and angiogenesis. As compared to saline treatment, rhEPO significantly reduced lesion volume in the cortex and cell loss in the DG after TBI and substantially improved sensorimotor function recovery and spatial learning performance. rhEPO enhanced neurogenesis in the injured cortex and the DG.
Conclusions
rhEPO initiated 6 hours post-TBI provides neuroprotection by decreasing lesion volume and cell loss as well as neurorestoration by enhancing neurogenesis, subsequently improving sensorimotor and spatial learning function. rhEPO is a promising neuroprotective and neurorestorative agent for TBI and warrants further investigation.
doi:10.3171/JNS/2008/109/9/0510
PMCID: PMC3977174  PMID: 18759585
erythropoietin; mouse; sensorimotor; spatial learning; traumatic brain injury
4.  Animal models of traumatic brain injury 
Nature reviews. Neuroscience  2013;14(2):128-142.
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity in both civilian life and the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs, which were identified to be effective in animal TBI models, have all failed in phase II or phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies.
doi:10.1038/nrn3407
PMCID: PMC3951995  PMID: 23329160
5.  Simvastatin Attenuates Axonal Injury after Experimental Traumatic Brain Injury and Promotes Neurite Outgrowth of Primary Cortical Neurons 
Brain research  2012;1486C:121-130.
The beneficial effects of simvastatin on experimental traumatic brain injury (TBI) have been demonstrated in previous studies. In this study, we investigated the effects of simvastatin on axonal injury and neurite outgrowth after experimental TBI and explored the underlying mechanisms. Wistar rats were subjected to controlled cortical impact or sham surgery. Saline or simvastatin was administered for 14 days. A modified neurological severity score (mNSS) test was performed to evaluate functional recovery. Immunohistochemistry studies using synaptophysin, neurofilament H (NF-H) and amyloid-β precursor protein (APP) were performed to examine synaptogenesis and axonal injury. Primary cortical neurons (PCNs) were subjected to oxygen glucose deprivation (OGD) followed by various treatments. Western blot analysis was utilized to assess the activation of phosphatidylinositol-3 kinase (PI-3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK- 3β)/adenomatous polyposis coli (APC) pathways. Simvastatin decreased the density of APP-positive profiles and increased the density of NF-H -positive profiles. Simvastatin reduced mNSS, which was correlated with the increase of axonal density. Simvastatin treatment stimulated the neurite outgrowth of PCNs after OGD, which was attenuated by LY294002 and enhanced by lithium chloride (LiCl). Simvastatin activated Akt and mTOR, inactivated GSK-3β and dephosphorylated APC in the injured PCNs. Our data suggest that simvastatin reduces axonal injury, enhances neurite outgrowth and promotes neurological functional recovery after experimental TBI. The beneficial effects of simvastatin on neurite outgrowth may be mediated through manipulation of the PI-3K/Akt/mTOR and PI-3K/GSK-3β/APC pathways.
doi:10.1016/j.brainres.2012.09.039
PMCID: PMC3496081  PMID: 23026078
axonal injury; glycogen synthase kinase 3β; neurite outgrowth; simvastatin; traumatic brain injury
6.  Treatment of neurological injury with thymosin β4 
Neurorestorative therapy targets multiple types of parenchymal cells in the intact tissue of the injured brain tissue to increase neurogenesis, angiogenesis, oligodendrogenesis, and axonal remodeling during recovery from neurological injury. In our laboratory, we tested thymosin β4 (Tβ4) as a neurorestorative agent to treat models of neurological injury. This review discusses our results demonstrating that Tβ4 improves neurological functional outcome in a rat model of embolic stroke, a mouse model of multiple sclerosis, and a rat model of traumatic brain injury. Tβ4 is a pleiotropic peptide exhibiting many actions in several different types of tissues. One mechanism associated with improvement of neurological improvement from Tβ4 treatment is oligodendrogenesis involving the differentiation of oligodendrocyte progenitor cells to mature myelin-secreting oligodendrocytes. Moreover, our preclinical data provide a basis for movement of Tβ4 into clinical trials for treatment of these devastating neurological diseases and injuries.
doi:10.1111/j.1749-6632.2012.06651.x
PMCID: PMC3471669  PMID: 23045978
thymosin β4; stroke; multiple sclerosis; traumatic brain injury; rat
7.  Neuroprotective and neurorestorative effects of Thymosin beta 4 treatment following experimental traumatic brain injury 
Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity worldwide. No effective pharmacological treatments are available for TBI because all Phase II/III TBI clinical trials have failed. This highlights a compelling need to develop effective treatments for TBI. Endogenous neurorestoration occurs in the brain after TBI, including angiogenesis, neurogenesis, synaptogenesis, oligodendrogenesis and axonal remodeling, which may be associated with spontaneous functional recovery after TBI. However, the endogenous neurorestoration following TBI is limited. Treatments amplifying these neurorestorative processes may promote functional recovery after TBI. Thymosin beta4 (Tβ4) is the major G-actin-sequestering molecule in eukaryotic cells. In addition, Tβ4 has other properties including anti-apoptosis and anti-inflammation, promotion of angiogenesis, wound healing, stem/progenitor cell differentiation, and cell migration and survival, which provide the scientific foundation for the corneal, dermal, and cardiac wound repair multicenter clinical trials. Here, we describe Tβ4 as a neuroprotective and neurorestorative candidate for treatment of TBI.
doi:10.1111/j.1749-6632.2012.06683.x
PMCID: PMC3547647  PMID: 23050817
thymosin beta4; traumatic brain injury; rat; neuroprotection; neurorestoration
8.  Effect of Simvastatin on Glioma Cell Proliferation, Migration and Apoptosis 
Neurosurgery  2009;65(6):1087-1097.
OBJECTIVE
In this study, we seek to investigate the effects of simvastatin on proliferation, migration and apoptosis in human U251 and U87 glioma cells and the underlying molecular mechanism.
METHODS
We used colony formation assay to test the cell proliferation, in vitro scratch assay to examine the cell migration, and caspase-3 activity assay, annexin V staining and cytochrome C release to evaluate the cell apoptosis. Lipid raft fractions were isolated from glioma cells. Total cholesterol content assay was used to test the change of cholesterol level in lipid raft fractions. Immunocytochemistry staining was performed to detect the changes of lipid rafts in cell membrane. Western blotting analysis was performed to examine the signal transduction both in cells and in lipid raft fractions.
RESULTS
Simvastatin inhibited proliferation and migration of U251 and U87 cells dose-dependently. Simvastatin induced an increase of caspase-3 activity, annexin V staining, and downregulated the PI3K/Akt pathway. Simvastatin also decreased cholesterol content in lipid raft fractions, suppressed caveolin-1 expression in the lipid rafts and induced Fas translocation into lipid rafts, suggesting that simvastatin may inhibit pro-survival PI3K/Akt pathway and trigger caspase-3-dependent apoptotic cell death through the modulation of lipid rafts.
CONCLUSION
These results suggest that modulation of lipid rafts, Fas translocation and PI3K/Akt/caspase-3 pathway are involved in the antitumor effect of simvastatin and it may have a potential role in cancer prevention and treatment.
doi:10.1227/01.NEU.0000360130.52812.1D
PMCID: PMC3711082  PMID: 19934968
apoptosis; glioma; lipid rafts; PI3K/Akt pathway; simvastatin
9.  Treatment of Traumatic Brain Injury in Mice with Marrow Stromal Cells 
Brain research  2008;1208:234-239.
Objective
This study was designed to investigate the potential beneficial effects of bone marrow stromal cell (MSC) treatment of traumatic brain injury (TBI) in mice.
Methods
Twelve female C57BL/6J mice (weight, 21–26 g) were injured with controlled cortical impact and divided into 2 groups (n = 6 each). The experimental group was injected with MSCs (0.3 × 106) intravenously one day after TBI, whereas the control group was injected with saline. MSCs were harvested from male mice, and male to female transplantation performed to identify male donor cells within female recipient animals. This was achieved by localizing Y chromosomes within the female mice. Neurological function was assessed using the Morris water maze and Foot Fault tests. All mice were sacrificed 35 days after TBI. Brain sections were stained using in situ hybridization and immunohistochemistry to identify MSCs as well as to analyze vascular density following MSC treatment.
Results
Both modalities of testing demonstrated significant improvement in neurological function in the MSC-treated group compared to the saline-treated control group (p < 0.05). Histologically, Y-chromosome labeled MSCs were easily identified in the injured brain, localized primarily around the lesion boundary zone. There was also significant increase in vascular density in the lesion boundary zone and hippocampus of MSC-treated mice compared to control mice.
Conclusion
This is the first study to show beneficial effects of MSC treatment after TBI in mice.
doi:10.1016/j.brainres.2008.02.042
PMCID: PMC3707111  PMID: 18384759
Traumatic brain injury (TBI); marrow stromal cells (MSCs); mice
10.  Impact of inhibition of erythropoietin treatment-mediated neurogenesis in the dentate gyrus of the hippocampus on restoration of spatial learning after traumatic brain injury 
Experimental Neurology  2012;235(1):336-344.
Our previous study demonstrates that delayed (initiated 24 hours post injury) erythropoietin (EPO) therapy for traumatic brain injury (TBI) significantly improves spatial learning. In this study, we investigated the impact of inhibition of EPO treatment-mediated neurogenesis on spatial learning after experimental TBI. Young male Wistar rats (318±7g) were subjected to unilateral controlled cortical impact injury. TBI rats received delayed EPO treatment (5,000 U/kg in saline) administered intraperitoneally once daily at 1, 2, and 3 days post injury and intracerebroventricular (icv) infusion of either a mitotic inhibitor cytosine-b-D-arabinofuranoside or vehicle (saline) for 14 days. Another 2 groups of TBI rats were treated intraperitoneally with saline and infused icv with either a mitotic inhibitor Ara-C or saline for 14 days. Animals receiving sham operation were infused icv with either Ara-C infusion or saline. Bromodeoxyuridine (BrdU) was administered to label dividing cells. Spatial learning was assessed using a modified Morris water maze test. Animals were sacrificed at 35 days after injury and brain sections stained for immunohistochemical analyses. As compared to the saline treatment, immunohistochemical analysis revealed that delayed EPO treatment significantly increased the number of BrdU-positive cells and new neurons co-stained with BrdU and NeuN (mature neuron marker) in the dentate gyrus in TBI rats. EPO treatment improved spatial learning after TBI. Ara-C infusion significantly abolished neurogenesis and spatial learning recovery after TBI and EPO treatment. Both EPO and Ara-C reduced the number of astrocytes and microglia/macrophages in the dentate gyrus after TBI. Our findings are highly suggestive for an important role of EPO-amplified dentate gyrus neurogenesis as one of the mechanisms underlying EPO therapeutic treatments after TBI, strongly indicating that strategies promoting endogenous neurogenesis may hold an important therapeutic potential for treatment of TBI.
doi:10.1016/j.expneurol.2012.02.015
PMCID: PMC3334417  PMID: 22414310
astrocytes; erythropoietin; microglia; neurogenesis; spatial learning; traumatic brain injury
11.  Neuroprotective and neurorestorative effects of thymosin beta4 treatment initiated 6 hours post injury following traumatic brain injury in rats 
Journal of Neurosurgery  2012;116(5):1081-1092.
Object
Thymosin beta 4 (Tβ4) is a regenerative multifunctional peptide. This study will test the hypothesis that Tβ4 treatment initiated 6 hours post-injury reduces brain damage and improves functional recovery in rats after traumatic brain injury (TBI).
Methods
TBI was induced by controlled cortical impact over the left parietal cortex. Young adult male Wistar rats with TBI were randomly divided into the following groups: 1) Saline group (n=7); 2) Tβ4-6 mg/kg group (n=8), and 3) Tβ4-30 mg/kg group (n=8). Tβ4 or saline was administered intraperitoneally starting at 6 hours post-injury and then repeated daily at 24 and 48 hours. An additional group of sham animals underwent surgery without injury (n=6). Sensorimotor function and spatial learning were assessed using a modified neurological severity score and Morris water maze tests, respectively. Animals were sacrificed 35 days after injury and brain sections processed to assess lesion volume, hippocampal cell loss, cell proliferation and neurogenesis after Tβ4 treatment.
Results
Compared to saline, Tβ4 treatment initiated 6 hours post-injury 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 to the low-dose treatment.
Conclusions
Tβ4 treatment initiated 6 hours post-injury provides both neuroprotection and neurorestoration after TBI, indicating that Tβ4 has promising therapeutic potential in TBI patients. These data warrant further investigation of the optimal dose and therapeutic window of Tβ4 treatment for TBI and the associated underlying mechanisms.
doi:10.3171/2012.1.JNS111729
PMCID: PMC3392183  PMID: 22324420
neuroprotection; neurogenesis; rat; thymosin beta 4; traumatic brain injury
12.  Erythropoietin Mediates Neurobehavioral Recovery and Neurovascular Remodeling Following Traumatic Brain Injury in Rats by Increasing Expression of Vascular Endothelial Growth Factor 
Translational stroke research  2011;2(4):619-632.
Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). Here, we investigated the role of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) on EPO-induced therapeutic efficacy in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury and then infused intracerebroventricularly with either a potent selective VEGFR2 inhibitor SU5416 or vehicle dimethyl sulfoxide. Animals from both groups received delayed EPO treatment (5,000 U/kg in saline) administered intraperitoneally daily at 1, 2, and 3 days post injury. TBI rats treated with saline administered intraperitoneally daily at 1, 2, and 3 days post injury served as EPO treatment controls. 5-bromo-2-deoxyuridine was administered to label dividing cells. Spatial learning and sensorimotor function were assessed using a modified Morris water maze test and modified neurological severity score, respectively. Animals were sacrificed at 4 days post injury for measurement of VEGF and VEGFR2 or 35 days post injury for evaluation of cell proliferation, angiogenesis and neurogenesis. EPO treatment promoted sensorimotor and cognitive functional recovery after TBI. EPO treatment increased brain VEGF expression and phosphorylation of VEGFR2. EPO significantly increased cell proliferation, angiogenesis and neurogenesis in the dentate gyrus after TBI. Compared to the vehicle, SU5416 infusion significantly inhibited phosphorylation of VEGFR2, cell proliferation, angiogenesis, and neurogenesis as well as abolished functional recovery in EPO-treated TBI rats. These findings indicate the VEGF/VEGFR2 activation plays an important role in EPO-mediated neurobehavioral recovery and neurovascular remodeling after TBI.
doi:10.1007/s12975-011-0120-2
PMCID: PMC3374663  PMID: 22707988
angiogenesis; erythropoietin; neurogenesis; traumatic brain injury; vascular endothelial growth factor
13.  Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats 
Journal of neurosurgery  2011;115(3):550-560.
Object
Delayed (24 hours post injury) treatment with erythropoietin (EPO) improves functional recovery following experimental traumatic brain injury (TBI). In this study, we 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 sacrificed 35 days after injury and brain sections stained for immunohistochemical analyses.
Results
Compared to the saline treatment, EPO treatment at doses from1000 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 medium dose at 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 post injury) 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.
doi:10.3171/2011.3.JNS101721
PMCID: PMC3166387  PMID: 21495821
angiogenesis; cell proliferation; erythropoietin; neurogenesis; rat; sensorimotor; spatial learning; traumatic brain injury
14.  Treatment of TBI with Collagen Scaffolds and Human Marrow Stromal Cells Increases the Expression of Tissue Plasminogen Activator 
Journal of Neurotrauma  2011;28(7):1199-1207.
Abstract
This study examines the effects of combination therapy of collagen scaffolds and human marrow stromal cells (hMSCs) on the expression of tissue plasminogen activator (tPA) after traumatic brain injury (TBI) in rats. Adult male Wistar rats (n=48) were injured with controlled cortical impact and treated either with scaffolds suffused with hMSCs (3×106) or hMSCs (3×106) alone transplanted into the lesion cavity 1 week after TBI. A control group was treated with saline. Neurological function was assessed using the Morris Water Maze test (MWM) and modified Neurological Severity Scores (mNSS). The rats were sacrificed 14 days after TBI and brain samples were processed for immunohistochemical analysis and quantitative Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) studies. Enhanced functional improvement was observed on both the mNSS and MWM tests in the scaffold+hMSC-treated group compared to the other two groups. Immunostaining with anti-human mitochondrial antibody (E5204) showed more hMSCs in the injury zone of the scaffold+hMSC group compared to the hMSC-alone group. Triple staining showed that more neurons were tPA-positive in the scaffold+hMSC group compared to the other two groups (p<0.05). Western blot analysis and qRT-PCR showed that scaffold+hMSC and hMSC-alone treatment enhanced the expression of tPA compared to controls (p<0.05), but tPA expression was significantly greater in the scaffold+hMSC group. The induction of tPA by hMSCs after TBI may be one of the mechanisms involved in promoting functional improvement after TBI.
doi:10.1089/neu.2010.1694
PMCID: PMC3283444  PMID: 21355820
collagen scaffolds; marrow stromal cells; tissue plasminogen activator; traumatic brain injury
15.  Induction of angiogenesis and modulation of VEGFR-2 by simvastatin after traumatic brain injury 
Neurosurgery  2011;68(5):1363-1371.
Background
Our previous studies demonstrated that simvastatin reduced neuronal death, increased neurogenesis, and promoted functional recovery after TBI. Objective: To investigate the effect of simvastatin on angiogenesis after TBI, and the related signaling pathways.
Methods
Saline or simvastatin (1 mg/kg) was administered orally to rats starting at day 1 after TBI or sham surgery and then daily for 14 days. Rats were sacrificed at 3 and 14 days after treatment. Brain sections and tissues were prepared for immunohistochemical staining, ELISA, and Western blot analysis, respectively. Cultured rat brain microvascular endothelial cells (RBMVECs) were subjected to oxygen-glucose deprivation (OGD) followed by immunocytochemical staining with phallotoxins and vascular endothelial growth factor receptor-2 (VEGFR-2). Western blot analysis was carried out to examine the simvastatin-induced activation of the v-akt murine thymoma viral oncogene homolog (Akt) signaling pathway. The expression of VEGFR-2 was detected by ELISA.
Results
Simvastatin significantly increased the length of vascular perimeter, promoted the proliferation of endothelial cells, and improved the sensorimotor function after TBI. Simvastatin stimulated endothelial cell tube formation after OGD in vitro. VEGFR-2 expression in both brain tissues and cultured RBMVECs was enhanced after simvastatin treatment, which may be modulated by activation of Akt. Akt-dependent endothelial nitric oxide synthase (eNOS) phosphorylation was also induced by simvastatin in vivo and in vitro.
Conclusion
Simvastatin augments TBI-induced angiogenesis in the lesion boundary zone and hippocampus and improves functional recovery. Simvastatin also promotes angiogenesis in vitro. These beneficial effects on angiogenesis may be related to simvastatin-induced activation of the VEGFR-2/Akt/eNOS signaling pathway.
doi:10.1227/NEU.0b013e31820c06b9
PMCID: PMC3119744  PMID: 21307798
Angiogenesis; Simvastatin; Traumatic brain injury; VEGFR-2
16.  Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury 
Brain research  2011;1384:140-150.
Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). This study was designed to investigate long-term (3 mo) effects of EPO on brain remodeling and functional recovery in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury. TBI rats were divided into the following groups: 1) Saline group (n = 7); 2) EPO-6h group (n = 8); and 3) EPO-24h group (n = 8). EPO (5,000 U/kg in saline) was administered intraperitoneally at 6 h, and 1 and 2 days (EPO-6h group) or at 1, 2, and 3 days (EPO-24h group) post injury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed at 3 mos after injury and brain sections stained for immunohistochemical analyses. Compared to the saline, EPO-6h treatment significantly reduced cortical lesion volume, while EPO-24h therapy did not affect the lesion volume (P<0.05). Both the EPO-6h and EPO-24h treatments significantly reduced hippocampal cell loss (P<0.05), promoted angiogenesis (P<0.05) and increased endogenous cellular proliferation (BrdU-positive cells) in the injury boundary zone and hippocampus (P<0.05) compared to saline controls. Significantly enhanced neurogenesis (BrdU/NeuN-positive cells) was seen in the dentate gyrus of both EPO groups compared to the saline group. Both EPO treatments significantly improved long-term sensorimotor and cognitive functional recovery after TBI. In conclusion, the beneficial effects of posttraumatic EPO treatment on injured brain persisted for at least 3 months. The long-term improvement in functional outcome may in part be related to the neurovascular remodeling induced by EPO.
doi:10.1016/j.brainres.2011.01.099
PMCID: PMC3065541  PMID: 21295557
angiogenesis; cell proliferation; erythropoietin; neurogenesis; functional recovery; traumatic brain injury
18.  Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome in rats following traumatic brain injury 
Journal of neurosurgery  2010;114(2):549-559.
Object
Carbamylated erythropoietin (CEPO) is a modified erythropoietin molecule that does not affect hematocrit. In this study, we compared the efficacy of a single dose with triple dose of CEPO treatment of traumatic brain injury (TBI) in rats.
Methods
TBI was induced by controlled cortical impact over the left parietal cortex. CEPO (50 μg/kg) was administered intraperitoneally in rats with TBI at 6 hours (CEPO x 1 group) or 6, 24 and 48 hours (CEPO x 3 group) post injury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed 35 days after injury and brain sections stained for immunohistochemistry to assess lesion volume, cell loss, cell proliferation, angiogenesis and neurogenesis after CEPO treatment.
Results
Compared to 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 to the CEPO x 1 group.
Conclusions
Our results indicate that CEPO has considerable therapeutic potential in TBI and related pathologies and furthermore that repeated dosing in the sub-acute phase might have important pharmacological relevance.
doi:10.3171/2010.10.JNS10925
PMCID: PMC3057520  PMID: 21073254
angiogenesis; carbamylated erythropoietin; functional recovery; neurogenesis; traumatic brain injury
19.  The Treatment of TBI with Human Marrow Stromal Cells Impregnated into Collagen Scaffold: Functional Outcome and Gene Expression Profile 
Brain research  2010;1371:129-139.
We have previously demonstrated that human marrow stromal cells (hMSCs) embedded in collagen I scaffolds significantly enhance the restorative therapeutic effect of hMSCs after traumatic brain injury (TBI). In this study, we test the hypothesis that the collagen scaffold alters gene expression in hMSCs and that hMSCs impregnated into scaffolds increase the astrocytic expression of vascular endothelial growth factor (VEGF) in the injured brain. Following TBI induced by controlled cortical impact injury, scaffold with hMSCs (3.0 × 106), hMSCs-only and saline were implanted into the lesion cavity one week after brain injury (n = 8/each group). Morris water Maze and modified neurological severity scores were performed to evaluate the spatial learning and sensorimotor functions, respectively. Lesion volume and expression of VEGF were measured one week after different treatments. In vitro, total RNA from hMSCs was extracted one week after culture with or without collagen I scaffold for evaluation of gene microarrays. Furthermore, an RT-PCR study on a select subgroup of genes was performed to identify the changes of expression between the culturing hMSCs with collagen scaffolds and hMSCs only. The treatment of TBI with collagen scaffold impregnated with hMSCs significantly decreases the functional deficits from TBI within 7 days after treatment, and significantly enhances the VEGF expression of astrocytes in the injured brain compared to the hMSCs-only group. In vitro data indicate that collagen scaffolds stimulate hMSCs to express multiple factors which may contribute to hMSC survival, tissue repair and functional recovery after TBI.
doi:10.1016/j.brainres.2010.10.088
PMCID: PMC3022100  PMID: 21062621
endothelial vascular growth factor (VEGF); traumatic brain injury (TBI); marrow stromal cell; collagen scaffold; restorative therapy
20.  Treatment of traumatic brain injury with thymosin β4 in rats 
Journal of neurosurgery  2010;114(1):102-115.
Object
This study was designed to investigate the efficacy of delayed thymosin β4 (TB4) 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). TBI 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), footfault and Morris water maze tests. Animals were killed 35 days after injury, and brain sections stained for immunohistochemistry to assess angiogenesis, neurogenesis, and oligodendrogenesis after Tβ4 treatment.
Results
Compared to 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.
doi:10.3171/2010.4.JNS10118
PMCID: PMC2962722  PMID: 20486893
angiogenesis; neurogenesis; oligodendrogenesis; rat; thymosin beta4; traumatic brain injury
21.  Neurorestorative Treatments for Traumatic Brain Injury 
Discovery medicine  2010;10(54):434-442.
Traumatic brain injury (TBI) remains a major cause of death and permanent disability worldwide, especially in children and young adults. A total of 1.5 million people experience head trauma each year in the United States, with an annual economic cost exceeding $56 billion. Unfortunately, almost all Phase III TBI clinical trials have yet to yield a safe and effective neuroprotective treatment, raising questions regarding the use of neuroprotective strategies as the primary therapy for acute brain injuries. Recent preclinical data suggest that neurorestorative strategies that promote angiogenesis (formation of new blood vessels from pre-existing endothelial cells), axonal remodeling (axonal sprouting and pruning), neurogenesis (generation of new neurons) and synaptogenesis (formation of new synapses) provide promising opportunities for the treatment of TBI. This review discusses select cell-based and pharmacological therapies that activate and amplify these endogenous restorative brain plasticity processes to promote both repair and regeneration of injured brain tissue and functional recovery after TBI.
PMCID: PMC3122155  PMID: 21122475
angiogenesis; functional recovery; neurogenesis; plasticity; synaptogenesis; traumatic brain injury
22.  Antiobesity and Antihyperglycemic Effects of Ginsenoside Rb1 in Rats 
Diabetes  2010;59(10):2505-2512.
OBJECTIVE
Obesity and type 2 diabetes are national and worldwide epidemics. Because currently available antiobesity and antidiabetic drugs have limited efficacy and/or safety concerns, identifying new medicinal agents, such as ginsenoside Rb1 (Rb1) as reported here, offers exciting possibilities for future development of successful antiobesity and antidiabetic therapies.
RESEARCH DESIGN AND METHODS
Changes in feeding behavior after acute intraperitoneal administration of Rb1 and the effects of intraperitoneal Rb1 for 4 weeks on body weight, energy expenditure, and glucose tolerance in high-fat diet (HFD)-induced obese rats were assessed. We also examined the effects of Rb1 on signaling pathways and neuropeptides in the hypothalamus.
RESULTS
Acute intraperitoneal Rb1 dose-dependently suppressed food intake without eliciting signs of toxicity. This inhibitory effect on feeding may be mediated by central mechanisms because Rb1 stimulated c-Fos expression in brain areas involved in energy homeostasis. Consistent with this, Rb1 activated the phosphatidylinositol 3-kinase/Akt signaling pathway and inhibited NPY gene expression in the hypothalamus. Four-week administration of Rb1 significantly reduced food intake, body weight gain, and body fat content and increased energy expenditure in HFD-induced obese rats. Rb1 also significantly decreased fasting blood glucose and improved glucose tolerance, and these effects were greater than those observed in pair-fed rats, suggesting that although Rb1's antihyperglycemic effect is partially attributable to reduced food intake and body weight; there may be additional effects of Rb1 on glucose homeostasis.
CONCLUSIONS
These results identify Rb1 as an antiobesity and antihyperglycemic agent.
doi:10.2337/db10-0315
PMCID: PMC3279544  PMID: 20682695
23.  Sprouting of corticospinal tract axons from the contralateral hemisphere into the denervated side of the spinal cord is associated with functional recovery in adult rat after traumatic brain injury and erythropoietin treatment 
Brain research  2010;1353:249-257.
Erythropoietin (EPO) promotes functional recovery after traumatic brain injury (TBI). This study was designed to investigate whether EPO treatment promotes contralateral corticospinal tract (CST) plasticity in the spinal cord in rats after TBI. Biotinylated dextran amine (BDA) was injected into the right sensorimotor cortex to anterogradely label the CST. TBI was induced by controlled cortical impact over the left parietal cortex immediately after BDA injections. EPO (5,000 U/kg) or saline was administered intraperitoneally at Days 1, 2, and 3 post injury. Neurological function was assessed using a modified neurological severity score (mNSS) and footfault tests. Animals were sacrificed 35 days after injury and brain sections stained for histological analysis. Compared to the saline treatment, EPO treatment significantly improved sensorimotor functional outcome (lower mNSS and reduced footfaults) from Days 7 to 35 post injury. TBI alone significantly stimulated contralateral CST axon sprouting toward the denervated gray matter of the cervical and lumbar spinal cord; however, EPO treatment further significantly increased the axon sprouting in TBI rats although EPO treatment did not significantly affect axon sprouting in sham animals. The contralesional CST sprouting was highly and positively correlated with sensorimotor recovery after TBI. These data demonstrate that CST fibers originating from the contralesional intact cerebral hemisphere are capable of sprouting into the denervated spinal cord after TBI and EPO treatment, which may at least partially contribute to functional recovery.
doi:10.1016/j.brainres.2010.07.046
PMCID: PMC2933297  PMID: 20654589
axonal plasticity; erythropoietin; functional recovery; rats; traumatic brain injury
24.  Delayed administration of erythropoietin reduces hippocampal cell loss, enhances angiogenesis and neurogenesis, and improves functional outcome following traumatic brain injury in rats: comparison of treatment with single dose and triple dose 
Journal of neurosurgery  2010;113(3):598-608.
Object
This study was designed to investigate delayed erythropoietin (EPO) treatment for traumatic brain injury (TBI) in rats comparing efficacy of a single dose with triple doses.
Methods
Young adult male Wistar rats were randomly divided into the following groups: 1) Sham group (n = 6); 2) TBI + Saline group (n = 6); 3) TBI + EPOx1 group (n = 6); and 4) TBI + EPOx3 group (n = 7). TBI was induced by controlled cortical impact over the left parietal cortex. EPO (5,000 U/kg) or saline was administered intraperitoneally at 1 day (EPOx1 group) or at days 1, 2, and 3 (EPOx3 group) post injury. Neurological function was assessed using a modified neurological severity score (mNSS), footfault and Morris water maze tests. Animals were sacrificed 35 days after injury and brain sections stained for immunohistochemistry.
Results
Compared to the saline treatment, EPO treatment in both the EPOx1 and EPOx3 groups significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved neurological functional outcome. The EPOx3 group exhibited significantly improved functional and histological outcomes compared with the EPOx1 group.
Conclusions
These data demonstrate that delayed posttraumatic administration of EPO significantly improves histological and long-term functional outcomes in rats after TBI. The triple doses of delayed EPO treatment exhibit better histological and functional outcomes in rats although a single dose of EPO provides substantial benefits compared to saline treatment.
doi:10.3171/2009.9.JNS09844
PMCID: PMC2898921  PMID: 19817538
angiogenesis; cell proliferation; erythropoietin; neurogenesis; rat; sensorimotor; spatial learning; traumatic brain injury
25.  The Treatment of Traumatic Brain Injury with Velcade 
Journal of Neurotrauma  2010;27(9):1625-1634.
Abstract
Traumatic brain injury (TBI) elicits a strong inflammatory response that contributes to the acute pathological processes seen following TBI, including cerebral edema and disruption of the blood–brain barrier (BBB), in addition to longer-term neurological damage and cognitive impairment. Proteasome inhibitors reduce vascular thrombotic and inflammatory events and consequently protect vascular function. In the present study we evaluated the neuroprotective effect of Velcade® (bortezomib), a potent and selective inhibitor of proteasomes, which is in clinical use for the treatment of multiple myeloma. When administered within 2 h after TBI onset, Velcade reduced inflammatory responses, lesion volume, and neurological functional deficits, and enhanced neuronal survival. Western blot and ELISA showed that Velcade decreased the expression of NF-κB. These results suggest that in the experimental setting, Velcade is an effective neuroprotective agent for the treatment of TBI.
doi:10.1089/neu.2010.1359
PMCID: PMC2966855  PMID: 20649468
neuroprotection; rats; traumatic brain injury; Velcade

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