Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin

2007 ◽  
Vol 107 (2) ◽  
pp. 392-397 ◽  
Author(s):  
Asim Mahmood ◽  
Dunyue Lu ◽  
Changsheng Qu ◽  
Anton Goussev ◽  
Zheng Gang Zhang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Spatial Learning ◽  
Neural Plasticity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Recombinant Erythropoietin ◽  
Proliferating Cells ◽  
Bdnf Expression ◽  
Male Wistar Rats ◽  
Carbamylated Erythropoietin

Object This study was designed to investigate the neuroprotective properties of recombinant erythropoietin (EPO) and carbamylated erythropoietin (CEPO) administered following traumatic brain injury (TBI) in rats. Methods Sixty adult male Wistar rats were injured with controlled cortical impact, and then EPO, CEPO, or a placebo (phosphate-buffered saline) was injected intraperitoneally. These injections were performed either 6 or 24 hours after TBI. To label newly regenerating cells, bromodeoxyuridine was injected intraperitoneally for 14 days after TBI. Blood samples were obtained on Days 1, 2, 3, 7, 14, and 35 to measure hematocrit. Spatial learning was tested using the Morris water maze. All rats were killed 35 days after TBI. Brain sections were immunostained as well as processed for the enzyme-linked immunosorbent assay to measure brain-derived neurotrophic factor (BDNF). Results A statistically significant improvement in spatial learning was seen in rats treated with either EPO or CEPO 6 or 24 hours after TBI (p < 0.05); there was no difference in the effects of EPO and CEPO. Also, these drugs were equally effective in increasing the number of newly proliferating cells within the dentate gyrus at both time points. A statistically significant increase in BDNF expression was seen in animals treated with both EPO derivatives at 6 or 24 hours after TBI. Systemic hematocrit was significantly increased at 48 hours and 1 and 2 weeks after treatment with EPO but not with CEPO. Conclusions These data demonstrate that at the doses used, EPO and CEPO are equally effective in enhancing spatial learning and promoting neural plasticity after TBI.

scholarly journals Freshly Thawed Cryobanked Human Neural Stem Cells Engraft within Endogenous Neurogenic Niches and Restore Cognitive Function Following Chronic Traumatic Brain Injury

2020 ◽  
Author(s):  
Anna Badner ◽  
Emily K. Reinhardt ◽  
Theodore V. Nguyen ◽  
Nicole Midani ◽  
Andrew T. Marshall ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Spatial Learning ◽  
Risk Taking ◽  
Mechanisms Of Action ◽  
Human Neural Stem Cells ◽  
Risk Taking Behavior

AbstractHuman neural stem cells (hNSCs) have potential as a cell therapy following traumatic brain injury (TBI). While various studies have demonstrated the efficacy of NSCs from on-going culture, there is a significant gap in our understanding of freshly thawed cells from cryobanked stocks – a more clinically-relevant source. To address these shortfalls, the therapeutic potential of our previously validated Shef-6.0 human embryonic stem cell (hESC)-derived hNSC line was tested following long-term cryostorage and thawing prior to transplant. Immunodeficient athymic nude rats received a moderate unilateral controlled cortical impact (CCI) injury. At 4-weeks post-injury, 6×105 freshly thawed hNSCs were transplanted into six injection sites (2 ipsi- and 4 contra-lateral) with 53.4% of cells surviving three months post-transplant. Interestingly, most hNSCs were engrafted in the meninges and the lining of lateral ventricles, associated with high CXCR4 expression and a chemotactic response to SDF1alpha (CXCL12). While some expressed markers of neuron, astrocyte, and oligodendrocyte lineages, the majority remained progenitors, identified through doublecortin expression (78.1%). Importantly, transplantation resulted in improved spatial learning and memory in Morris water maze navigation and reduced risk-taking behavior in an elevated plus maze. Investigating potential mechanisms of action, we identified an increase in ipsilateral host hippocampus cornu ammonis (CA) neuron survival, contralateral dentate gyrus (DG) volume and DG neural progenitor morphology as well as a reduction in neuroinflammation. Together, these findings validate the potential of hNSCs to restore function after TBI and demonstrate that long-term bio-banking of cells and thawing aliquots prior to use may be suitable for clinical deployment.Significance StatementThere is no cure for chronic traumatic brain injury (TBI). While human neural stem cells (hNSCs) offer a potential treatment, no one has demonstrated efficacy of thawed hNSCs from long-term cryobanked stocks. Frozen aliquots are critical for multisite clinical trials, as this omission impacted the use of MSCs for graft versus host disease. This is the first study to demonstrate the efficacy of thawed hNSCs, while also providing support for novel mechanisms of action – linking meningeal and ventricular engraftment to reduced neuroinflammation and improved hippocampal neurogenesis. Importantly, these changes also led to clinically relevant effects on spatial learning/memory and risk-taking behavior. Together, this new understanding of hNSCs lays a foundation for future work and improved opportunities for patient care.

scholarly journals LO86: Lack of association between four biomarkers and the presence of persistent post-concussion symptoms after a mild traumatic brain injury

CJEM ◽  
2020 ◽  
Vol 22 (S1) ◽  
pp. S38-S39
Author(s):  
N. Le Sage ◽  
N. Le Sage ◽  
J. Frenette ◽  
J. Chauny ◽  
S. Berthelot ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Clinical Data ◽  
Neuron Specific Enolase ◽  
Primary Outcome Measure ◽  
S100b Protein ◽  
Future Research ◽  
Enzyme Linked Immunosorbent Assay ◽  
Persistent Symptoms

Introduction: Mild Traumatic Brain Injury (mTBI) is a common problem: each year in Canada, its incidence is estimated at 500-600 cases per 100 000. Between 10 and 56% of mTBI patients develop persistent post-concussion symptoms (PPCS) that can last for more than 90 days. It is therefore important for clinicians to identify patients who are at risk of developing PPCS. We hypothesized that blood biomarkers drawn upon patient arrival to the Emergency Department (ED) could help predict PPCS. The main objective of this project was to measure the association between four biomarkers and the incidence of PPCS 90 days post mTBI. Methods: Patients were recruited in seven Canadian ED. Non-hospitalized patients, aged ≥14 years old with a documented mTBI that occurred ≤24 hrs of ED consultation, with a GCS ≥13 at arrival were included. Sociodemographic and clinical data as well as blood samples were collected in the ED. A standardized telephone questionnaire was administered at 90 days post ED visit. The following biomarkers were analyzed using enzyme-linked immunosorbent assay (ELISA): S100B protein, Neuron Specific Enolase (NSE), cleaved-Tau (c-Tau) and Glial fibrillary acidic protein (GFAP). The primary outcome measure was the presence of persistent symptoms at 90 days after mTBI, as assessed using the Rivermead Post-Concussion symptoms Questionnaire (RPQ). A ROC curve was constructed for each biomarker. Results: 1276 patients were included in the study. The median age for this cohort was 39 (IQR 23-57) years old, 61% were male and 15% suffered PPCS. The median values (IQR) for patients with PPCS compared to those without were: 43 pg/mL (26-67) versus 42 pg/mL (24-70) for S100B protein, 50 pg/mL (50-223) versus 50 pg/mL (50-199) for NSE, 2929 pg/mL (1733-4744) versus 3180 pg/mL (1835-4761) for c-Tau and 1644 pg/mL (650-3215) versus 1894 pg/mL (700-3498) for GFAP. For each of these biomarkers, Areas Under the Curve (AUC) were 0.495, 0.495, 0.51 and 0.54, respectively. Conclusion: Among mTBI patients, S100B protein, NSE, c-Tau or GFAP during the first 24 hours after trauma do not seem to be able to predict PPCS. Future research testing of other biomarkers is needed in order to determine their usefulness in predicting PPCS when combined with relevant clinical data.

scholarly journals Spatial learning deficits following traumatic brain injury in rats: Reversal by bFGF

1998 ◽  
Vol 76 ◽  
pp. 193
Author(s):  
Hiroshi Uramoto ◽  
Shizuo Nakamura ◽  
Kyoshi Saitoh ◽  
Tomochika Ohno
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Spatial Learning ◽  
Learning Deficits

scholarly journals Treatment of traumatic brain injury with thymosin β4 in rats

2011 ◽  
Vol 114 (1) ◽  
pp. 102-115 ◽  
Author(s):  
Ye Xiong ◽  
Asim Mahmood ◽  
Yuling Meng ◽  
Yanlu Zhang ◽  
Zheng Gang Zhang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Sham Group ◽  
Therapeutic Potential ◽  
Cell Loss ◽  
Saline Group ◽  
Lesion Volume ◽  
Male Wistar Rats ◽  
Left Parietal Cortex ◽  
First Time

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.

scholarly journals Effect of Intermediate-Frequency Repetitive Transcranial Magnetic Stimulation on Recovery following Traumatic Brain Injury in Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Leticia Verdugo-Diaz ◽  
Francisco Estrada-Rojo ◽  
Aron Garcia-Espinoza ◽  
Eduardo Hernandez-Lopez ◽  
Alejandro Hernandez-Chavez ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Repetitive Transcranial Magnetic Stimulation ◽  
Intermediate Frequency ◽  
Health Concern ◽  
Sufficient Evidence ◽  
Movement Restriction ◽  
Male Wistar Rats

Traumatic brain injury (TBI) represents a significant public health concern and has been associated with high rates of morbidity and mortality. Although several research groups have proposed the use of repetitive transcranial magnetic stimulation (rTMS) to enhance neuroprotection and recovery in patients with TBI, few studies have obtained sufficient evidence regarding its effects in this population. Therefore, we aimed to analyze the effect of intermediate-frequency rTMS (2 Hz) on behavioral and histological recovery following TBI in rats. Male Wistar rats were divided into six groups: three groups without TBI (no manipulation, movement restriction plus sham rTMS, and movement restriction plus rTMS) and three groups subjected to TBI (TBI only, TBI plus movement restriction and sham rTMS, and TBI plus movement restriction and rTMS). The movement restriction groups were included so that rTMS could be applied without anesthesia. Our results indicate that the restriction of movement and sham rTMS per se promotes recovery, as measured using a neurobehavioral scale, although rTMS was associated with faster and superior recovery. We also observed that TBI caused alterations in the CA1 and CA3 subregions of the hippocampus, which are partly restored by movement restriction and rTMS. Our findings indicated that movement restriction prevents damage caused by TBI and that intermediate-frequency rTMS promotes behavioral and histologic recovery after TBI.

scholarly journals Vascular Endothelial Growth Factor Increases Neurogenesis after Traumatic Brain Injury

2010 ◽  
Vol 30 (5) ◽  
pp. 1008-1016 ◽  
Author(s):  
Orli Thau-Zuchman ◽  
Esther Shohami ◽  
Alexander G Alexandrovich ◽  
Ronen R Leker
Keyword(s):  
Traumatic Brain Injury ◽  
Vascular Endothelial Growth Factor ◽  
Brain Injury ◽  
Growth Factor ◽  
Functional Outcome ◽  
Vascular Endothelial ◽  
Proliferating Cells ◽  
Neuroprotective Effects ◽  
Neurologic Disorders ◽  
Endothelial Growth Factor

Activation of endogenous stem cells has been proposed as a novel form of therapy in a variety of neurologic disorders including traumatic brain injury (TBI). Vascular endothelial growth factor (VEGF) is expressed in the brain after TBI and serves as a potent activator of angiogenesis and neurogenesis. In this study, we infused exogenous VEGF into the lateral ventricles of mice for 7 days after TBI using mini-osmotic pumps to evaluate the effects on recovery and functional outcome. The results of our study show that VEGF significantly increases the number of proliferating cells in the subventricular zone and in the perilesion cortex. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia and only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF compared with vehicle-treated animals after TBI. Injury size was significantly smaller at 90 days after TBI in VEGF-treated animals, suggesting additional neuroprotective effects of VEGF. In conclusion, VEGF significantly augments neurogenesis and angiogenesis and reduces lesion volumes after TBI. These changes are associated with significant improvement in recovery rates and functional outcome.

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