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ABSTRACT: Dissections of the cervical arteries cause about 20% of total juvenile strokes. Approximately 4% of the carotid artery dissections are due to a (poly)trauma such as car accidents. Despite improved diagnostic facilities, traumatic dissections are often underdiagnosed or diagnosed too late due to a lack of awareness of potential initial signs and symptoms. We report here a case of a delayed embolic stroke after a car accident caused by a dissection of the carotid artery and subsequent pseudoaneurysm. To reduce the long-term morbidity or mortality of multiple trauma patients, an early detection of cervical carotid and vertebral dissections is strictly necessary.
Case Reports in Neurology 01/2013; 5(1):21-5.
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ABSTRACT: Photothrombosis was introduced as a model of ischemic stroke by Watson et al. in 1985. In the present paper, we describe a protocol to induce photothrombotic infarcts in rats.
The photosensitive dye Bengal Rose is intravenously administered and a laser beam is stereotactically positioned onto the skull. Illumination through the intact skull leads to local activation of Bengal Rose, which results in free radical formation, disturbance of endothelial function and thrombus formation in illuminated small cortical vessels.
Photochemically induced infarcts cause long-term sensorimotor deficits, allow long-term survival and are particularly suitable to assess the effectiveness of neuroregenerative therapies in chronic stroke studies.
Experimental and Translational Stroke Medicine 08/2012; 4(1):13.
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ABSTRACT: The neuroprotective potential of citicoline in acute ischemic stroke has been shown in many experimental studies and, although the exact mechanisms are still unknown, a clinical Phase III trial is currently underway. Our present study was designed to check whether citicoline also enhances neuroregeneration after experimental stroke.
Forty Wistar rats were subjected to photothrombotic stroke and treated either with daily injections of citicoline (100 mg/kg) or vehicle for 10 consecutive days starting 24 hours after ischemia induction. Sensorimotor tests were performed after an adequate training period at Days 1, 10, 21, and 28 after stroke. Then brains were removed and analyzed for infarct size, glial scar formation, neurogenesis, and ligand binding densities of excitatory and inhibitory neurotransmitter receptors.
Animals treated with citicoline showed a significantly better neurological outcome at Days 10, 21, and 28 after ischemia, which could not be attributed to differences in infarct volumes or glial scar formation. However, neurogenesis in the dentate gyrus, subventricular zone, and peri-infarct area was significantly increased by citicoline. Furthermore, enhanced neurological outcome after citicoline treatment was associated with a shift toward excitation in the perilesional cortex.
Our present data demonstrate that, apart from the well-known neuroprotective effects in acute ischemic stroke, citicoline also possesses a substantial neuroregenerative potential. Thanks to its multimodal effects, easy applicability, and history as a well-tolerated drug, promising possibilities of neurological treatment including chronic stroke open up.
Stroke 05/2012; 43(7):1931-40. · 5.73 Impact Factor
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ABSTRACT: Both application of granulocyte-colony stimulating factor (G-CSF) and constraint-induced movement therapy (CIMT) have been shown to improve outcome after experimental stroke. The aim of the present study was to determine whether concurrent or sequential combination of both therapies will further enhance therapeutic benefit and whether specific modifications in the abundance of various neurotransmitter receptors do occur.
Adult male Wistar rats were subjected to photothrombotic ischemia and assigned to the following treatment groups (n=20 each): (1) ischemic control (saline); (2) CIMT (CIMT between poststroke Days 2 and 11; (3) G-CSF (10 μg/kg G-CSF daily between poststroke Days 2 and 11; (4) combined concurrent group (CIMT plus 10 μg/kg G-CSF daily between poststroke Days 2 and 11; and (5) combined sequential group (CIMT between poststroke Days 2 and 11 and 10 μg/kg G-CSF daily between poststroke Days 12 and 21, respectively). Rats were functionally tested before and up to 4 weeks after ischemia. Quantitative receptor autography was performed for N-methyl-d-aspartate, AMPA, and GABA(A) receptors.
Significant improvement of functional outcome was seen in all groups treated with G-CSF alone and in either combination with CIMT, whereas CIMT alone failed to enhance recovery. Infarct sizes and remaining cortical tissue did not differ in the various treatment groups. Failure of significant benefit in the CIMT group was associated with a shift toward inhibition in perilesional and remote cortical regions.
Our findings disclose G-CSF as the major player for enhanced recovery after experimental stroke, preventing a shift toward inhibition as seen in the CIMT group.
Stroke 01/2012; 43(1):185-92. · 5.73 Impact Factor
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Stroke 12/2011; 43(2):295-6. · 5.73 Impact Factor
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Jens Minnerup,
Martin Andreas Ritter,
Heike Wersching,
André Kemmling,
Angelika Okegwo,
Antje Schmidt,
Matthias Schilling,
E Bernd Ringelstein, Wolf Rüdiger Schäbitz,
Peter Young,
Rainer Dziewas
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ABSTRACT: Sleep-related breathing disorders occur frequently after stroke. We assessed the feasibility of continuous positive airway pressure (CPAP) treatment initiated in the first night after stroke.
In this open-label, parallel-group trial, 50 patients were randomly assigned to the CPAP therapy or to the control group. All patients underwent polysomnography in the fourth night. Intervention patients received CPAP therapy for 3 nights starting the first night after stroke onset and for an additional 4 nights when polysomnography revealed an apnea-hypopnea index >10/hour. The primary end point was feasibility defined as apnea-hypopnea index reduction under CPAP treatment, nursing workload, and CPAP adherence.
The apnea-hypopnea index under CPAP treatment was significantly reduced (32.2±25.3-9.8±6.6, P=0.0001). Nursing workload did not significantly differ between the CPAP (n=25) and the control group (n=25; P=0.741). Ten patients (40.0%) had excellent CPAP use, 14 patients (56.0%) had some use, and 1 patient (4.0%) had no use. There was a trend toward greater National Institutes of Health Stroke Scale score improvement until Day 8 in patients on CPAP (2.00 versus 1.40, P=0.092) and a significantly greater National Institutes of Health Stroke Scale score improvement in patients with excellent CPAP use when compared with control patients (2.30 versus 1.40, P=0.022).
CPAP therapy initiated in the first night after stroke seems to be feasible and was not associated with neurological deterioration. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT00151177.
Stroke 12/2011; 43(4):1137-9. · 5.73 Impact Factor
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ABSTRACT: Early decompressive surgery in patients with malignant middle cerebral artery (MCA) infarction improves outcome. Elevation of intracranial pressure depends on both the space occupying brain edema and the intracranial volume reserve (cerebrospinal fluid [CSF]). However, CSF volume was not investigated as a predictor of malignant infarction so far. We hypothesize that assessment of CSF volume in addition to admission infarct size improves early prediction of malignant MCA infarction.
Stroke patients with carotid-T or MCA main stem occlusion and ischemic lesion (reduced cerebral blood volume [CBV]) on perfusion CT were considered for the analysis. The end point malignant MCA infarction was defined by clinical signs of herniation. Volumes of CSF and CBV lesion were determined on admission. Receiver-operator characteristics analysis was used to calculate predictive values for radiological and clinical measurements.
Of 52 patients included, 26 (50%) developed malignant MCA infarction. Age, a decreased level of consciousness on admission, CBV lesion volume, CSF volume, and the ratio of CBV lesion volume to CSF volume were significantly different between malignant and nonmalignant groups. The best predictor of a malignant course was the ratio of CBV lesion volume to CSF volume with a cut-off value of 0.92 (96.2% sensitivity, 96.2% specificity, 96.2% positive predictive value, and 96.2% negative predictive value).
Based on admission native CT and perfusion CT measurements, the ratio of ischemic lesion volume to CSF volume predicts the development of malignant MCA infarction with higher accuracy than other known predictors, including ischemic lesion volume or clinical characteristics.
Stroke 09/2011; 42(12):3403-9. · 5.73 Impact Factor
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Stroke 08/2011; 42(9):2385-6. · 5.73 Impact Factor
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ABSTRACT: The European Cooperative Acute Stroke Study (ECASS) III extended the thrombolysis time window for patients with stroke from 3 to 4.5 hours after symptom onset. We investigated the effect of the extended thrombolysis time window on the proportion of recombinant tissue-type plasminogen activator-treated stroke patients and on the time of treatment initiation after hospital arrival.
The present study was based on a prospective database of 93 hospitals of the Stroke Register of Northwestern Germany, which included 91 805 patients with ischemic stroke admitted between January 2007 and December 2009. Main outcome measures were the use of recombinant tissue-type plasminogen activator among patients with stroke and the door-to-needle time before and after the publication of ECASS III in September 2008 and subsequent changes of the German guidelines in May 2009.
Overall, 9262 patients (10.1%) were treated with recombinant tissue-type plasminogen activator. The proportion of thrombolyzed patients increased from 8.6% in 2007 to 11.7% in 2009. This increase was pronounced for patients admitted between 3 and 6 hours after symptom onset after the third quarter of 2008 (OR, 1.88; 95% CI, 1.24 to 2.85) and after the second and third quarters of 2009 (OR, 2.50; 95% CI, 1.69 to 3.69 and OR, 3.02; 95% CI, 2.07 to 4.41) compared with the first half year 2007. The proportion of patients with stroke with a door-to-needle time<60 minutes increased after publication of ECASS III (OR, 1.49; 95% CI, 1.37 to 1.63).
Results of ECASS III were rapidly implemented in routine stroke care. Concerns of a delay in recombinant tissue-type plasminogen activator treatment initiation after the extension of the thrombolysis time window were not confirmed.
Stroke 08/2011; 42(10):2838-43. · 5.73 Impact Factor
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ABSTRACT: Interferon-β (IFN-β) stabilizes the blood-brain barrier (BBB) in vitro. Here we investigated the effect of serum from 15 IFN-β-1b-treated multiple sclerosis (MS) patients on the permeability read-outs of small solutes in an in vitro BBB model consisting of human brain microvascular endothelial cells in co-culture with rat astrocytes. The addition of sera from IFN-β-treated patients resulted in a significantly (p < 0.05) reduced permeability as compared with untreated patients. Our findings show that sera from IFN-β-1b-treated MS patients have a stabilizing effect on the in vitro BBB. We suggest an unknown potentially pro-inflammatory factor in the serum of MS patients that may lead to a BBB dysfunction and can be modulated by IFN-β.
Multiple Sclerosis 08/2011; 18(2):236-9. · 4.26 Impact Factor
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Jens Minnerup,
Jeong Beom Kim,
Antje Schmidt,
Kai Diederich,
Henrike Bauer,
Matthias Schilling,
Jan-Kolja Strecker,
E Bernd Ringelstein,
Clemens Sommer,
Hans R Schöler, Wolf-Rüdiger Schäbitz
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ABSTRACT: Intravenous neural progenitor cell (NPC) treatment was shown to improve functional recovery after experimental stroke. The underlying mechanisms, however, are not completely understood so far. Here, we investigated the effects of systemic NPC transplantation on endogenous neurogenesis and dendritic plasticity of host neurons.
Twenty-four hours after photothrombotic ischemia, adult rats received either 5 million NPC or placebo intravenously. Behavioral tests were performed weekly up to 4 weeks after ischemia. Endogenous neurogenesis, dendritic length, and dendritic branching of cortical pyramid cells and microglial activation were quantified.
NPC treatment led to a significantly improved sensorimotor function measured by the adhesive removal test. The dendritic length and the amount of branch points were significantly increased after NPC transplantation, whereas endogenous neurogenesis was decreased compared to placebo therapy. Decreased endogenous neurogenesis was associated with an increased number of activated microglial cells.
Our findings suggest that an increased dendritic plasticity might be the structural basis of NPC-induced functional recovery. The decreased endogenous neurogenesis after NPC treatment seems to be mediated by microglial activation.
Stroke 06/2011; 42(6):1757-63. · 5.73 Impact Factor
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ABSTRACT: Endothelial progenitor cell (EPC) mobilization from the bone marrow was considered to improve outcome after ischemic stroke. Erythropoietin (EPO) might be a potential candidate stroke drug that increases the number of circulating EPCs. In the previous issue of Critical Care, Yip and colleagues investigated the effect of EPO in stroke patients on both clinical outcome and EPC stimulation. Although beneficial effects of EPO were observed, several issues regarding EPO's suitability as a stroke drug remain.
Critical care (London, England) 03/2011; 15(2):129. · 4.61 Impact Factor
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ABSTRACT: Monocyte chemoattractant protein-1 (MCP-1), a chemokine secreted by neurons and astrocytes following stroke is known to aggravate ischemia-related damage. Previous studies revealed that MCP-1-deficient mice develop smaller infarcts and have an improved neurological outcome, whereas mice overexpressing MCP-1 show worsened brain damage and impaired neurological function. The aim of the present study was to elucidate the molecular background of the enhanced recovery in MCP-1-deficient mice after stroke. For this purpose, we (1) performed expression analyses on crucial post-stroke related inflammatory genes in MCP-1-deficient mice compared to wildtype controls, (2) analyzed a possible impact of MCP-1 on astrocyte activation (3) investigated the cellular origin of respective inflammatory cytokines and (4) analyzed the impact of MCP-1 secretion on the migration of both neutrophil granulocytes and T-cells. Here we report that MCP-1-deficiency leads to a shift towards a less inflammatory state following experimental occlusion of the middle cerebral artery including an impaired induction of interleukin-6, interleukin-1β and granulocyte-colony stimulating factor expression as well as a subsequent diminished influx of hematogenous cells. Additionally, MCP-1-deficient mice developed smaller infarcts 36 hours after experimental stroke. Investigations revealed no differences in transcription of tumor necrosis factor-α and astrogliosis 12 and 36 hours after onset of ischemia. These novel results help to understand post ischemic, inflammatory mechanisms and might give further arguments towards therapeutical interventions by modulation of MCP-1 expression in post stroke inflammation.
PLoS ONE 01/2011; 6(10):e25863. · 4.09 Impact Factor
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ABSTRACT: Expression and transport activity of Sodium-dependent Vitamin C Transporter 2 (SVCT2) was shown in various tissues and organs. Vitamin C was shown to be cerebroprotective in several animal models of stroke. Data on expression, localization and transport activity of SVCT2 after cerebral ischemia, however, has been scarce so far. Thus, we studied the expression of SVCT2 after middle cerebral artery occlusion (MCAO) in mice by immunohistochemistry. We found an upregulation of SVCT2 after stroke. Co-stainings with Occludin, Von-Willebrand Factor and CD34 demonstrated localization of SVCT2 in brain capillary endothelial cells in the ischemic area after stroke. Time-course analyses of SVCT2 expression by immunohistochemistry and western blots showed upregulation in the subacute phase of 2-5 days. Radioactive uptake assays using (14)C-labelled ascorbic acid showed a significant increase of ascorbic acid uptake into the brain after stroke. Taken together, these results provide evidence for the expression and transport activity of SVCT2 in brain capillary endothelial cells after transient ischemia in mice. These results may lead to the development of novel neuroprotective strategies in stroke therapy.
PLoS ONE 01/2011; 6(2):e17139. · 4.09 Impact Factor
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Thomas Duning,
Hagen Schiffbauer,
Tobias Warnecke,
Siawoosh Mohammadi,
Agnes Floel,
Katja Kolpatzik,
Harald Kugel,
Armin Schneider,
Stefan Knecht,
Michael Deppe, Wolf Rüdiger Schäbitz
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ABSTRACT: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and -regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.
Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 µg/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.
Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.
Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors.
ClinicalTrials.gov NCT00298597.
PLoS ONE 01/2011; 6(3):e17770. · 4.09 Impact Factor
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Agnes Floel,
Tobias Warnecke,
Thomas Duning,
Yvonne Lating,
Jan Uhlenbrock,
Armin Schneider,
Gerhard Vogt,
Rico Laage,
Winfried Koch,
Stefan Knecht, Wolf-Rüdiger Schäbitz
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ABSTRACT: G-CSF has been shown in animal models of stroke to promote functional and structural regeneration of the central nervous system. It thus might present a therapy to promote recovery in the chronic stage after stroke.
Here, we assessed the safety and tolerability of G-CSF in chronic stroke patients with concomitant vascular disease, and explored efficacy data. 41 patients were studied in a double-blind, randomized approach to either receive 10 days of G-CSF (10 µg/kg body weight/day), or placebo. Main inclusion criteria were an ischemic infarct >4 months prior to inclusion, and white matter hyperintensities on MRI. Primary endpoint was number of adverse events. We also explored changes in hand motor function for activities of daily living, motor and verbal learning, and finger tapping speed, over the course of the study.
Adverse events (AEs) were more frequent in the G-CSF group, but were generally graded mild or moderate and from the known side-effect spectrum of G-CSF. Leukocyte count rose after day 2 of G-CSF dosing, reached a maximum on day 8 (mean 42/nl), and returned to baseline 1 week after treatment cessation. No significant effect of treatment was detected for the primary efficacy endpoint, the test of hand motor function.
These results demonstrate the feasibility, safety and reasonable tolerability of subcutaneous G-CSF in chronic stroke patients. This study thus provides the basis to explore the efficacy of G-CSF in improving chronic stroke-related deficits.
ClinicalTrials.gov NCT00298597.
PLoS ONE 01/2011; 6(5):e19767. · 4.09 Impact Factor
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ABSTRACT: Hematopoietic growth factors are known for their bolstering effects on the growth, survival, and differentiation of blood progenitor cells. Several of these cytokines also influence the proliferation of neural stem/progenitor cells, paralleling cellular mechanisms in analogy to their function in the hematopoietic system. Erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), thrombopoietin (TPO), and their respective receptors are all expressed in the hippocampus of the mammalian brain. Recent studies have confirmed EPO and G-CSF as vital neurotrophic and neuroprotective factors, and ascertained their role in neuroprotection and neuroregeneration as pertaining to the most prominent neurodegenerative diseases. The aims of this review are to discuss newly discovered properties of G-CSF, EPO, and TPO beyond their known functions in the hematopoietic system, to create an overview of the accumulating data on the role of these factors in hippocampal function, and to highlight any potential clinical implications.
Hippocampus 12/2010; 22(5):1051-7. · 5.18 Impact Factor
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ABSTRACT: Following cerebral ischemia both neuronal precursors and hematogenous cells migrate along chemokine gradients towards the injured tissue. Bone marrow derived cells are involved in the stroke related inflammatory and restaurative processes and newly born neurons are known to proliferate and migrate from the subventricular zone to the ischemic lesion. In the present study, we investigated whether hematogenous cells contribute to subpopulations of neuronal precursors using green fluorescent protein-transgenic bone marrow chimeric mice. In our experiments we found no blood-borne neuronal precursors within the ischemic site indicating that detected neuronal progenitor cells are only of brain parenchymal origin.
Neuroscience Research 11/2010; 68(3):256-9. · 2.25 Impact Factor
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ABSTRACT: Omitting quality characteristics in animal stroke studies leads to an overestimation of the efficacy of candidate stroke drugs. Nevertheless, the methodological quality of preclinical stroke studies is often limited. As publishing of research results in high-impact journals is an important motivation for scientists, we analyzed whether study quality predicts high-impact publishing. Animal stroke studies of neuroprotective drugs that were recently investigated in clinical phase II/III trials were included in the analysis. Data on the study quality and other important study characteristics were extracted. Regression analyses were performed to estimate the effect of the study characteristics on the journal's impact factor. We identified 117 studies that investigated 12 different drugs. Study quality was not associated with the impact factor before (beta=-0.2, P=0.50) and after adjustment for other study characteristics (beta=-0.3, P=0.19). There was a significant association of the number of investigated mechanisms and applied techniques with the impact factor (beta=1.4, P<0.0001). Our findings show that the quality of animal experimental stroke studies is not relevant for publishing in high-impact journals. The major predictor for accepting preclinical stroke studies in high-impact journals is the complexity of the investigation into a stroke drug's mode of action.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 09/2010; 30(9):1619-24. · 5.46 Impact Factor
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ABSTRACT: In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. Granulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of growth factors, promotes brain neurogenesis and improves functional outcome after stroke in young animals. We tested the hypothesis that G-CSF provides a restorative therapeutic benefit in aged animals.
Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 19- to 20-month-old male Sprague-Dawley rats. One hour after reperfusion, the aged rats were treated daily with 15 microg/kg G-CSF and for 15 days total. Rats were behaviorally tested and the brains removed for analysis at 28 days poststroke.
G-CSF treatment after stroke exerted a robust and sustained beneficial effect on survival rate and running function. Transient improvement after G-CSF treatment could be observed for coordinative motor function on the inclined plane test and for working memory in the radial-arm maze test. At the cellular level, G-CSF treatment increased the number of proliferating cells in the subventricular zone and dentate gyrus and also increased the number of newborn neurons in the subventricular zone ipsilateral to the lesion.
These results suggest that G-CSF treatment in aged rats has a survival-enhancing capacity and a beneficial effect on functional outcome, most likely through supportive cellular processes such as neurogenesis.
Stroke 04/2010; 41(5):1027-31. · 5.73 Impact Factor
