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Asim Mahmood, Dunyue Lu, Changsheng Qu, Anton Goussev, and Michael Chopp

Object

This study was designed to follow the effects of bone marrow stromal cell (BMSC) administration in rats after traumatic brain injury (TBI) for a 3-month period.

Methods

Forty adult female Wistar rats were injured by a controlled cortical impact and, 1 week later, were injected intravenously with one of three different doses of BMSCs (2 × 106, 4 × 106, or 8 × 106 cells per animal) obtained in male rats. Control rats received phosphate-buffered saline (PBS). Neurological function in these rats was studied using a neurological severity scale (NSS). The rats were killed 3 months after injury, and immunohistochemical stains were applied to brain samples to study the distribution of the BMSCs. Additional brain samples were analyzed by quantitative enzyme-linked immunosorbent assays to measure the expression of the growth factors brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).

Three months after injury, BMSCs were present in the injured brain and their number was significantly greater in animals that received 4 × 106 or 8 × 106 BMSCs than in animals that received 2 × 106 BMSCs. The cells were primarily distributed around the lesion boundary zone. Functional outcome was significantly better in rats that received 4 × 106 or 8 × 106 BMSCs, compared with control animals, although no improvement was seen in animals that received 2 × 106 BMSCs. All doses of BMSCs significantly increased the expression of BDNF but not that of NGF; however, this increase was significantly larger in animals that received 4 × 106 or 8 × 106 BMSCs than in controls or animals that received 2 × 106 BMSCs.

Conclusions

In summary, when injected in rats after TBI, BMSCs are present in the brain 3 months later and significantly improve functional outcome.

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Dunyue Lu, Asim Mahmood, Changsheng Qu, Anton Goussev, Mei Lu, and Michael Chopp

Object. Atorvastatin, a β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor, has pleiotropic effects such as improving thrombogenic profile, promoting angiogenesis, and reducing inflammatory responses and has shown promise in enhancing neurological functional improvement and promoting neuroplasticity in animal models of traumatic brain injury (TBI), stroke, and intracranial hemorrhage. The authors tested the effect of atorvastatin on intracranial hematoma after TBI.

Methods. Male Wistar rats were subjected to controlled cortical impact, and atorvastatin (1 mg/kg) was orally administered 1 day after TBI and daily for 7 days thereafter. Rats were killed at 1, 8, and 15 days post-TBI. The temporal profile of intraparenchymal hematoma was measured on brain tissue sections by using a MicroComputer Imaging Device and light microscopy.

Conclusions. Data in this study showed that intraparenchymal and intraventricular hemorrhages are present 1 day after TBI and are absorbed at 15 days after TBI. Furthermore, atorvastatin reduces the volume of intracranial hematoma 8 days after TBI.

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

Object. Atorvastatin administered after traumatic brain injury (TBI) induced by controlled cortical impact promotes functional improvement in male rats. Note, however, that parallel studies have not been performed in female rats. Therefore, the authors tested the effect of atorvastatin on TBI in female rats.

Methods. Atorvastatin (1 mg/kg/day) was orally administered for 7 consecutive days in female Wistar rats starting 1 day after TBI; control animals received saline. Modified neurological severity scores, the corner turn test, and the Morris water maze test were used to evaluate functional response to treatment. Rats were killed on Day 15 post-TBI, and brain tissue samples were processed for immunohistochemical staining. Atorvastatin administration after brain injury significantly promoted the restoration of spatial memory but did not reduce sensorimotor functional deficits. Treatment of TBI with atorvastatin increased neuronal survival in the CA3 region and the lesion boundary zone and prevented the loss of neuronal processes of damaged neurons in the hippocampal CA3 region but not in the lesion boundary zone on Day 15 after TBI. The protective effect of atorvastatin on the injured neurons perhaps is mediated by increasing the density of vessels in the lesion boundary zone and the hippocampus after TBI.

Conclusions. These data indicate that atorvastatin is beneficial in the treatment of TBI in female rats, although the effect may differ between sexes.

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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.

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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.

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Asim Mahmood, Dunyue Lu, Changsheng Qu, Anton Goussev, Zheng Gang Zhang, Chang Lu, and Michael Chopp

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.

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Dunyue Lu, Asim Mahmood, Anton Goussev, Timothy Schallert, Changsheng Qu, Zheng Gang Zhang, Yi Li, Mei Lu, and Michael Chopp

Object. Atorvastatin, a β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor, has pleiotropic effects, such as promoting angiogenesis, increasing fibrinolysis, and reducing inflammatory responses, and has shown promise in enhancing recovery in animals with traumatic brain injury (TBI) and stroke. The authors tested the effect of atorvastatin on vascular changes after TBI.

Methods. Male Wistar rats subjected to controlled cortical impact injury were perfused at different time points with fluorescein isothiocyanate (FITC)—conjugated dextran 1 minute before being killed. Spatial memory function had been measured using a Morris Water Maze test at various points before and after TBI. The temporal profile of intravascular thrombosis and vascular changes was measured on brain tissue sections by using a microcomputer imaging device and a laser confocal microscopy. The study revealed the following results. 1) Vessels in the lesion boundary zone and hippocampal CA3 region showed a variety of damage, morphological alterations, reduced perfusion, and intraluminal microthrombin formation. 2) Atorvastatin enhanced FITC—dextran perfusion of vessels and reduced intravascular coagulation. 3) Atorvastatin promoted the restoration of spatial memory function.

Conclusions. These results indicated that atorvastatin warrants investigation as a potential therapeutic drug for TBI.