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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 (3×10(6)) or hMSCs (3×10(6)) 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.
Journal of neurotrauma 03/2011; 28(7):1199-207. · 4.25 Impact Factor
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ABSTRACT: This study was designed to investigate the long-term effects of simvastatin treatment after traumatic brain injury (TBI) in rats.
Adult female Wistar rats (n = 24) were injured with controlled cortical impact and divided into 3 groups. The first 2 groups were treated with simvastatin (0.5 or 1.0 mg/kg) administered orally for 14 days starting 1 day after TBI. The third group (control) received phosphate-buffered saline orally for 14 days. Neurological functional outcome was measured with modified neurological severity scores performed 1 day before TBI; on days 1, 4, 7, 14 after TBI; and biweekly thereafter. All animals were sacrificed 3 months after TBI. Brain tissues of half of the animals were processed for preparation of paraffin-embedded sections for immunohistological studies. The remaining half were frozen for enzyme-linked immunosorbent assay studies for quantification of brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex.
The results showed that both doses of simvastatin significantly improved functional outcome compared with the control, with no difference between the 2 doses. Simvastatin treatment of 1.0 mg/kg increased the number of morphologically intact neurons in the hippocampus, but treatment of 0.5 mg/kg had no significant effect. Enzyme-linked immunosorbent assay studies showed that 0.5 mg/kg simvastatin significantly increased BDNF levels within the hippocampus, but 1.0 mg/kg had no significant effect. Neither dose had any effect on BDNF levels within the cortex.
Simvastatin treatment provides long-lasting functional improvement after TBI in rats. It also enhances neuronal survival in the hippocampus and increases BDNF levels in the hippocampus secondary to simvastatin treatment.
Neurosurgery 08/2009; 65(1):187-91; discussion 191-2. · 2.79 Impact Factor
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ABSTRACT: 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).
Eight C57BL/6 J mice were injured with controlled cortical impact and received transplantation into the lesion cavity of 0.3 x 10(6) 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.
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.
Collagen scaffolds populated with hMSCs may be a new way to reconstruct injured brain tissue and improve neurological function after TBI.
Journal of Neurosurgery 06/2009; 111(4):658-65. · 2.96 Impact Factor
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ABSTRACT: This study was designed to investigate the beneficial effects of combination therapy of simvastatin and marrow stromal cells (MSCs) in improving functional outcome after traumatic brain injury (TBI) in rats. Adult female Wistar rats (n=72 and 8, per group) were injured with controlled cortical impact and treated either with monotherapy of MSCs or simvastatin or a combination therapy of these two agents. Different combination doses were tested, and nine groups of animals were studied. Neurological function was evaluated using Modified Neurological Severity Score (MNSS), and animals were sacrificed 3 months after injury. Coronal brain sections were stained with standard hematoxylin and eosin immunohistochemistry. Our results showed that, though functional improvement was seen with monotherapies of MSCs and simvastatin, the combination therapy when used in optimal doses was significantly better in improving functional outcome. This improvement was long lasting and persisted until the end of the trial (3 months). The optimum combination dose was 0.5mg of simvastatin combined with 2 x 10(6) MSCs. Post mortem analysis showed the presence of donor MSCs within the injured cortex. Endogenous cellular proliferation induced by the neurorestorative treatments was also observed in the lesion boundary zone. Our data show that MSCs and simvastatin have a synergistic effect in improving functional outcome after TBI.
Journal of Neurotrauma 01/2009; 25(12):1441-7. · 3.65 Impact Factor
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ABSTRACT: This study was designed to investigate the beneficial effects of recombinant human erythropoietin (rhEPO) treatment of traumatic brain injury (TBI) in mice.
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.
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.
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.
Journal of Neurosurgery 10/2008; 109(3):510-21. · 2.96 Impact Factor
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ABSTRACT: Erythropoietin (EPO) and its receptor (EPOR), essential for erythropoiesis, are expressed in the nervous system. Recombinant human EPO treatment promotes functional outcome after traumatic brain injury (TBI) and stroke, suggesting that the endogenous EPO/EPOR system plays an important role in neuroprotection and neurorestoration. This study was designed to investigate effects of the EPOR on histological and functional outcomes after TBI. Experimental TBI was induced in adult EPOR-null and wild-type mice by controlled cortical impact. Neurological function was assessed using the modified Morris Water Maze and footfault tests. Animals were sacrificed 35 days after injury and brain sections stained for immunohistochemistry. As compared to the wild-type injured mice, EPOR-null mice did not exhibit higher susceptibility to TBI as exemplified by tissue loss in the cortex, cell loss in the dentate gyrus, impaired spatial learning, angiogenesis and cell proliferation. We observed that less cortical neurogenesis occurred and that sensorimotor function (i.e., footfault) was more impaired in the EPOR-null mice after TBI. Co-accumulation of amyloid precursor protein (axonal injury marker) and calcium was observed in the ipsilateral thalamus in both EPOR-null and wild-type mice after TBI with more calcium deposits present in the wild-type mice. This study demonstrates for the first time that EPOR null in the nervous system aggravates sensorimotor deficits, impairs cortical neurogenesis and reduces thalamic calcium precipitation after TBI.
Brain Research 09/2008; 1230:247-57. · 2.73 Impact Factor
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ABSTRACT: This study was designed to investigate the potential beneficial effects of bone marrow stromal cell (MSC) treatment of traumatic brain injury (TBI) in mice. 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 (0.3x10(6)) intravenously one day after TBI, whereas the control group was injected with saline. MSCs were harvested from male mice, and male to female transplantation was 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. 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 a significant increase in vascular density in the lesion boundary zone and hippocampus of MSC-treated mice compared to control mice. This is the first study to show beneficial effects of MSC treatment after TBI in mice.
Brain Research 06/2008; 1208:234-9. · 2.73 Impact Factor
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ABSTRACT: The aim of this study was to investigate the role of gender in histological and functional outcome, angiogenesis, neurogenesis and therapeutic effects of recombinant human erythropoietin (rhEPO) in mice after traumatic brain injury (TBI). TBI caused both tissue loss in the cortex and cell loss in the dentate gyrus (DG) in the injured hemisphere at day 35 post TBI without a significant gender difference. After TBI, sensorimotor deficits were significantly larger in male mice compared to females, while similar spatial learning deficits were present in both genders. TBI alone significantly stimulated angiogenesis and neurogenesis in the cortex and in the DG of injured hemispheres in both genders. rhEPO at a dose of 5000 units/kg body weight administered intraperitoneally at 6 h, and 3 and 7 days after injury significantly reduced lesion volume and DG cell loss examined at day 35 after TBI as well as dramatically improved sensorimotor and spatial learning performance without an obvious gender proclivity. rhEPO significantly enhanced neurogenesis in the cortex and the DG of the ipsilateral hemisphere in male TBI mice. rhEPO did not affect angiogenesis in the ipsilateral cortex and DG in both genders after TBI. The present data demonstrate that posttraumatic administration of rhEPO improves histological and functional outcome in both genders, which may be mediated by reducing cortical tissue damage and DG cell loss in the ipsilateral hemisphere. In addition, the major gender propensity observed in the present study with mice after TBI without treatment is limited to sensorimotor deficits and cell proliferation.
Brain Research 01/2008; 1185:301-12. · 2.73 Impact Factor
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ABSTRACT: Traumatic brain injury (TBI) remains a major public health problem globally. Presently, there is no way to restore cognitive deficits caused by TBI. In this study, we seek to evaluate the effect of statins (simvastatin and atorvastatin) on the spatial learning and neurogenesis in rats subjected to controlled cortical impact. Rats were treated with atorvastatin and simvastatin 1 day after TBI and daily for 14 days. Morris water maze tests were performed during weeks 2 and 5 after TBI. Bromodeoxyuridine (BrdU; 50 mg/kg) was intraperitoneally injected 1 day after TBI and daily for 14 days. Brain tissue was processed for immunohistochemical staining to identify newly generated cells and vessels. Our data show that (1) treatment of TBI with statins improves spatial learning on days 31-35 after onset of TBI; (2) in the non-neurogenic region of the hippocampal CA3 region, statin treatment reduces the neuronal loss after TBI, demonstrating the neuroprotective effect of statins; (3) in the neurogenic region of the dentate gyrus, treatment of TBI with statins enhances neurogenesis; (4) statin treatment augments TBI-induced angiogenesis; and (5) treatment with simvastatin at the same dose provides a therapeutic effect superior to treatment with atorvastatin. These results suggest that statins may be candidates for treatment of TBI.
Journal of Neurotrauma 08/2007; 24(7):1132-46. · 3.65 Impact Factor
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ABSTRACT: 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.
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).
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.
These data demonstrate that at the doses used, EPO and CEPO are equally effective in enhancing spatial learning and promoting neural plasticity after TBI.
Journal of Neurosurgery 08/2007; 107(2):392-7. · 2.96 Impact Factor
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ABSTRACT: This study investigated the effects of a combination therapy of marrow stromal cells (MSCs) and statins (atorvastatin) after traumatic brain injury in rats.
Thirty-two female Wistar rats were injured by controlled cortical impact and divided into four groups. Group I was injected with MSCs (1 x 10(6)) intravenously 24 hrs after traumatic brain injury. Group II was administered atorvastatin (0.5 mg/kg) orally for 14 days starting 24 hours after traumatic brain injury. Group III received MSCs (1 x 10(6)) combined with atorvastatin (0.5 mg/kg). Group IV (control) was injected with saline. MSCs were harvested from the bone marrow of male rats to identify male donor cells within female recipient animals by localization of Y chromosomes. Functional analysis was performed using modified neurological severity scores and the Morris water maze test. Animals were sacrificed 35 days after injury and brain sections stained with immunohistochemistry.
No functional improvement was seen in animals treated with MSCs or atorvastatin alone (Groups I and II). However, functional improvement was seen with both testing modalities (modified neurological severity scores and Morris water maze) in animals receiving combination therapy (Group III). Microscopic analysis showed that significantly more MSCs were present in animals receiving combination therapy than in those receiving MSCs alone. Also, significantly more endogenous cellular proliferation was seen in the hippocampus and injury boundary zone of the combination therapy group than in the monotherapy or control groups.
When administered in combination with MSCs, atorvastatin increases MSC access and/or survival within the injured brain and enhances functional recovery compared with monotherapy.
Neurosurgery 04/2007; 60(3):546-53; discussion 553-4. · 2.79 Impact Factor
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ABSTRACT: 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.
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 x 10(6), 4 x 10(6), or 8 x 10(6) 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 x 10(6) or 8 x 10(6) BMSCs than in animals that received 2 x 10(6) BMSCs. The cells were primarily distributed around the lesion boundary zone. Functional outcome was significantly better in rats that received 4 x 10(6) or 8 x 10(6) BMSCs, compared with control animals, although no improvement was seen in animals that received 2 x 10(6) 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 x 10(6) or 8 x 10(6) BMSCs than in controls or animals that received 2 x 10(6) BMSCs.
In summary, when injected in rats after TBI, BMSCs are present in the brain 3 months later and significantly improve functional outcome.
Journal of Neurosurgery 03/2006; 104(2):272-7. · 2.96 Impact Factor
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ABSTRACT: 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.
Atorvastatin (1 mg/kg/day) was orally administered for 7 consecutive days in female Wistar rats starting I 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.
. These data indicate that atorvastatin is beneficial in the treatment of TBI in female rats, although the effect may differ between sexes.
Journal of Neurosurgery 11/2005; 103(4):695-701. · 2.96 Impact Factor
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ABSTRACT: This study was designed to investigate the effects of human bone marrow stromal cell (hMSC) administration in rats for 3 months after traumatic brain injury (TBI).
Adult male Wistar rats (n = 60) were injured with controlled cortical impact and divided into four groups. The three treatment groups (n = 10 each) were injected with 2 x 10, 4 x 10, and 8 x 10 hMSCs, respectively, intravenously, whereas the control group (n = 30) received phosphate-buffered saline. All injections were performed 1 day after injury into the tail veins of rats. Neurological functional evaluation of animals was performed before and after injury by use of Neurological Severity Scores. Animals were sacrificed 3 months after TBI, and brain sections were stained by immunohistochemistry.
Statistically significant improvement in functional outcome was observed in all three treatment groups compared with control values (P < 0.05). This benefit was visible 14 days after TBI and persisted until 3 months (end of trial). There was no difference in functional outcome among the three treatment groups. Histological analysis showed that hMSCs were present in the lesion boundary zone at 3 months with all three doses tested.
hMSCs injected in rats after TBI survive until 3 months and provide long-lasting functional benefit. Functional improvement may be attributed to stimulation of endogenous neurorestorative functions such as neurogenesis and synaptogenesis.
Neurosurgery 11/2005; 57(5):1026-31; discussion 1026-31. · 2.79 Impact Factor
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ABSTRACT: Erythropoietin (EPO) is neuroprotective in models of stroke and traumatic brain injury (TBI) when administered prior to or within the first few hours after injury. We seek to demonstrate that EPO also has neurorestorative effects when administered late (i.e., 1 day) after TBI in the rat. Twelve rats were subjected to TBI. Six rats were treated with EPO daily for 14 days starting 1 day after injury, and an additional six rats were treated with saline. Bromodeoxyuridine (BrdU) was administered daily for 14 days. Memory tests using a Morris Water Maze were performed prior to and after injury and treatment. Animals were sacrificed at 15 days after TBI, and their brains were prepared for histological analysis of damage to the dentate gyrus (DG) and for evaluation of newly formed neurons using double labeling of BrdU and MAP-2. The data revealed a significant improvement in spatial memory and significant increase in the number of newly formed neurons with EPO treatment compared with control animals. These data suggest that EPO treatment initiated 1 day after TBI is neurorestorative by enhancing neurogenesis, as well as neuroprotective.
Journal of Neurotrauma 10/2005; 22(9):1011-7. · 3.65 Impact Factor
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ABSTRACT: Secondary thrombosis may contribute to cerebral ischemia caused by traumatic brain injury (TBI). In this study, we sought to investigate the temporal and spatial profiles of intravascular thrombosis and to evaluate the effect of atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor, on thrombosis after TBI. Young male Wistar rats weighing 350-400 g were subjected to controlled cortical impact injury, and were sacrificed at 1 and 4 h, and 1, 3, 8, and 15 days after TBI (5 rats/time point), respectively. For the evaluation of the effects of atorvastatin on intravascular thrombosis, rats were subjected to TBI, and subsequently atorvastatin (1 mg/kg) was orally administered starting 1 day after TBI and then daily until sacrifice at 3, 8, and 15 days after TBI (5 rats/time point). Before sacrifice of animals, blood was withdrawn and employed for the measurement of von Willibrand factor and platelet activity using enzyme-linked immunoabsorbant assay (ELISA). Brain tissues were prepared for histological analysis. The data show that (1) delayed thrombosis is present in the lesion boundary zone and in the hippocampal CA3 region, starting at 1-4 h, peaking at 1-3 days, and then declining at 8 and 15 days after TBI; (2) intravascular thrombosis also occurs in the other areas of cortex, striatum, and corpus callosum, but with a scattered distribution; (3) delayed thrombi are composed of platelets, fibrin, and vWF; and (4) reduction of the plasma vWF level and platelet activity by atorvastatin decreases delayed thrombosis after TBI. These data suggest that atorvastatin reduces intravascular thrombosis attributed to hemostatic disturbances caused by TBI.
Journal of Neurotrauma 01/2005; 21(12):1756-66. · 3.65 Impact Factor
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ABSTRACT: Atorvastatin, a beta-hydroxy-beta-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.
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.
These results indicated that atorvastatin warrants investigation as a potential therapeutic drug for TBI.
Journal of Neurosurgery 11/2004; 101(5):813-21. · 2.96 Impact Factor
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ABSTRACT: Atorvastatin, a beta-hydroxy-beta-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.
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.
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.
Journal of Neurosurgery 11/2004; 101(5):822-5. · 2.96 Impact Factor
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ABSTRACT: Statins administered postischemia promote functional improvement in rats, independent of their capability to lower cholesterol. We therefore tested the effect of statin treatment on traumatic brain injury (TBI) in rats. Atorvastatin was orally administered (1 mg/kg/day) to Wistar rats starting 1 day after TBI for 7 consecutive days. Control animals received saline. Modified Neurological Severity Scores and Corner tests were utilized to evaluate functional response to treatment. Bromodeoxyuridine (BrdU, 100 mg/kg) was also intraperitoneally injected daily for 14 consecutive days to label the newly generated endothelial cells. Rats were sacrificed at day 14 after TBI, and the brain samples were processed for immunohistochemical staining. Atorvastatin administration after brain injury significantly reduced the neurological functional deficits, increased neuronal survival and synaptogenesis in the boundary zone of the lesion and in the CA3 regions of the hippocampus, and induced angiogenesis in these regions. The results suggest that atorvastatin may provide beneficial effects in experimental TBI.
Journal of Neurotrauma 02/2004; 21(1):21-32. · 3.65 Impact Factor
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ABSTRACT: In an effort to elucidate the molecular mechanisms underlying cerebral vascular alteration after stroke, the authors measured the spatial and temporal profiles of blood-brain barrier (BBB) leakage, angiogenesis, vascular endothelial growth factor (VEGF), associated receptors, and angiopoietins and receptors after embolic stroke in the rat. Two to four hours after onset of ischemia, VEGF mRNA increased, whereas angiopoietin 1 (Ang 1) mRNA decreased. Three-dimensional immunofluorescent analysis revealed spatial coincidence between increases of VEGF immunoreactivity and BBB leakage in the ischemic core. Two to 28 days after the onset of stroke, increased expression of VEGF/VEGF receptors and Ang/Tie2 was detected at the boundary of the ischemic lesion. Concurrently, enlarged and thin-walled vessels were detected at the boundary of the ischemic lesion, and these vessels developed into smaller vessels via sprouting and intussusception. Three-dimensional quantitative analysis of cerebral vessels at the boundary zone 14 days after ischemia revealed a significant (P < 0.05) increase in numbers of vessels (n = 365) compared with numbers (n = 66) in the homologous tissue of the contralateral hemisphere. Furthermore, capillaries in the penumbra had a significantly smaller diameter (4.8 +/- 2.0 microm) than capillaries (5.4 +/- 1.5 microm) in the homologous regions of the contralateral hemisphere. Together, these data suggest that acute alteration of VEGF and Ang 1 in the ischemic core may mediate BBB leakage, whereas upregulation of VEGF/VEGF receptors and Ang/Tie2 at the boundary zone may regulate neovascularization in ischemic brain.
Journal of Cerebral Blood Flow & Metabolism 05/2002; 22(4):379-92. · 5.01 Impact Factor
