scholarly journals TT-301 Inhibits Microglial Activation and Improves Outcome after Central Nervous System Injury in Adult Mice

2012 ◽  
Vol 116 (6) ◽  
pp. 1299-1311 ◽  
Author(s):  
Michael L. James ◽  
Haichen Wang ◽  
Viviana Cantillana ◽  
Beilei Lei ◽  
Dawn N. Kernagis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Functional Outcome ◽  
Differential Gene Expression ◽  
Morris Water Maze ◽  
Water Maze ◽  
Murine Models ◽  
Differential Gene

Background Microglial inhibition may reduce secondary tissue injury and improve functional outcome following acute brain injury. Utilizing clinically relevant murine models of traumatic brain injury and intracerebral hemorrhage, neuroinflammatory responses and functional outcome were examined in the presence of a potential microglial inhibitor, TT-301. Methods TT-301 or saline was administered following traumatic brain injury or intracerebral hemorrhage, and then for four subsequent days. The effect of TT-301 on neuroinflammatory responses and neuronal viability was assessed, as well as short-term vestibulomotor deficit (Rotorod) and long-term neurocognitive impairment (Morris water maze). Finally differential gene expression profiles of mice treated with TT-301 were compared with those of vehicle. Results Reduction in F4/80+ staining was demonstrated at 1 and 10 days, but not 28 days, after injury in mice treated with TT-301 (n = 6). These histologic findings were associated with improved neurologic function as assessed by Rotorod, which improved by 52.7% in the treated group by day 7, and Morris water maze latencies, which improved by 232.5% as a function of treatment (n = 12; P < 0.05). Similar benefit was demonstrated following intracerebral hemorrhage, in which treatment with TT-301 was associated with functional neurologic improvement of 39.6% improvement in Rotorod and a reduction in cerebral edema that was independent of hematoma volume (n = 12; P < 0.05). Differential gene expression was evaluated following treatment with TT-301, and hierarchical cluster analysis implicated involvement of the Janus kinase-Signal Transducer and Activator of Transcription pathway after administration of TT-301 (n = 3/group). Conclusions Modulation of neuroinflammatory responses through TT-301 administration improved histologic and functional parameters in murine models of acute neurologic injury.

scholarly journals Differential Gene Expression Associated with Meningeal Injury in Acute Mild Traumatic Brain Injury

2017 ◽  
Vol 34 (4) ◽  
pp. 853-860 ◽  
Author(s):  
Whitney S. Livingston ◽  
Jessica M. Gill ◽  
Martin R. Cota ◽  
Anlys Olivera ◽  
Jessica L. O'Keefe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Differential Gene Expression ◽  
Mild Traumatic Brain Injury ◽  
Differential Gene

Nefiracetam improves Morris water maze performance following traumatic brain injury in rats

2001 ◽  
Vol 69 (3-4) ◽  
pp. 611-616 ◽  
Author(s):  
S.Michelle DeFord ◽  
Margaret S Wilson ◽  
Cynthia J Gibson ◽  
Anya Baranova ◽  
Robert J Hamm
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Morris Water Maze ◽  
Water Maze ◽  
Maze Performance

Morris Water Maze Deficits in Rats following Traumatic Brain Injury: Lateral Controlled Cortical Impact

1997 ◽  
Vol 14 (9) ◽  
pp. 615-627 ◽  
Author(s):  
STEPHEN W. SCHEFF ◽  
STANLEY A. BALDWIN ◽  
RUSSELL W. BROWN ◽  
PHILIPP J. KRAEMER
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Morris Water Maze ◽  
Water Maze ◽  
Controlled Cortical Impact ◽  
Cortical Impact

Abstract T P240: Sex-specific Differential Gene Expression in a Murine Model of Experimental Intracerebral Hemorrhage

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Sankalp Gokhale ◽  
Dawn Kernagis ◽  
Beilei Lei ◽  
Yi-Ju Li ◽  
David Warner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intracerebral Hemorrhage ◽  
Differential Gene Expression ◽  
Mouse Genome ◽  
Differential Analysis ◽  
Genome Wide ◽  
Collagenase Injection ◽  
Differential Gene ◽  
Males And Females ◽  
Genome Wide Expression

Introduction: Decreased mortality and improved functional outcome in female compared to male mice after experimental intracerebral hemorrhage (ICH) has been demonstrated. We postulate that sex-specific differences in post-ICH gene expression may provide mechanistic insight. Methods: Ten to 12 week old C57/Bl6 male (M) and female in low estrus (LE-F) or high estrous state (HE-F) mice (n=3/group) underwent ICH induction via left intrastriatal collagenase injection. Whole brain samples were collected at baseline, immediately after sham injury and 6 hours after injury. Genome-wide expression profiling was performed with Affymetrix GeneChip Mouse Genome 2.0 to identify genes differentially expressed between baseline and 6 hours in males and females. Probes showing expression levels greater than log2 (10) for all samples were selected for differential analysis. Comparisons were made between baseline and 6-hour time points to determine significant differential gene expression in both sexes. An adjusted p < 0.05 was considered significant. Results: A total of 12136 probes qualified for our filtering criteria, representing 9830 genes. Of the genes tested, 119 in M, 76 in LE-F, and 420 in HE-F were expressed differently at 6 hours as compared to baseline. Of these genes, a total of 37 were shared in M and HE-F groups, 32 in M and LE-F groups, and 42 in HE-F and LE-F groups. Several pathways were identified based on the top list of genes in each group comparison, including coagulation and inflammatory mediator signaling. Conclusions: Sex-specific differential gene expression exists at 6 hours after experimental ICH. Further experiments will be designed to test whether these observed differences in gene expression are associated with outcome after experimental ICH and, thus, may yield novel therapeutic targets for translation into the human disease.

scholarly journals Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury

2015 ◽  
Vol 122 (4) ◽  
pp. 856-867 ◽  
Author(s):  
Yanlu Zhang ◽  
Michael Chopp ◽  
Yuling Meng ◽  
Mark Katakowski ◽  
Hongqi Xin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Dentate Gyrus ◽  
Morris Water Maze ◽  
Mesenchymal Stromal Cells ◽  
Functional Recovery ◽  
Stromal Cells ◽  
Water Maze ◽  
Morris Water Maze Test ◽  
Neurovascular Remodeling

OBJECT Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). In this study the authors tested a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI. METHODS Two groups of 8 Wistar rats were subjected to TBI, followed 24 hours later by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle (phosphate-buffered saline). A third group of 8 rats was used as sham-injured, sham-treated controls. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, modified Neurological Severity Score, and foot-fault tests were performed. Animals were killed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. RESULTS Compared with the saline-treated group, exosome-treated rats with TBI showed significant improvement in spatial learning at 34–35 days as measured by the modified Morris water maze test (p < 0.05), and sensorimotor functional recovery (i.e., reduced neurological deficits and foot-fault frequency) was observed at 14–35 days postinjury (p < 0.05). Exosome treatment significantly increased the number of newly generated endothelial cells in the lesion boundary zone and dentate gyrus and significantly increased the number of newly formed immature and mature neurons in the dentate gyrus as well as reducing neuroinflammation. CONCLUSIONS The authors demonstrate for the first time that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and by reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly for other neurological diseases.

scholarly journals Transcriptional Pathology Evolves Over Time in Rat Hippocampus Following Lateral Fluid Percussion Traumatic Brain Injury

2021 ◽  
Author(s):  
Rinaldo Catta-Preta ◽  
Iva Zdillar ◽  
Bradley Jenner ◽  
Emily T. Doisy ◽  
Kayleen Tercovich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Injury Severity ◽  
Cholesterol Metabolism ◽  
Fluid Percussion ◽  
Differential Gene ◽  
Lateral Fluid Percussion ◽  
The Brain

Traumatic brain injury (TBI) causes acute and lasting impacts on the brain, driving pathology along anatomical, cellular, and behavioral dimensions. Rodent models offer the opportunity to study TBI in a controlled setting, and enable analysis of the temporal progression that occurs from injury to recovery. We applied transcriptomic and epigenomic analysis, characterize gene expression and in ipsilateral hippocampus at 1 and 14 days following moderate lateral fluid percussion (LFP) injury. This approach enabled us to identify differential gene expression (DEG) modules with distinct expression trajectories across the two time points. The major DEG modules represented genes that were up- or downregulated acutely, but largely recovered by 14 days. As expected, DEG modules with acute upregulation were associated with cell death and astrocytosis. Interestingly, acutely downregulated DEGs related to neurotransmission mostly recovered by two weeks. Upregulated DEG modules related to inflammation were not necessarily elevated acutely, but were strongly upregulated after two weeks. We identified a smaller DEG module with delayed upregulation at 14 days including genes related to cholesterol metabolism and amyloid beta clearance. Finally, differential expression was paralleled by changes in H3K4me3 at the promoters of differentially expressed genes at one day following TBI. Following TBI, changes in cell viability, function and ultimately behavior are dynamic processes. Our results show how transcriptomics in the preclinical setting has the potential to identify biomarkers for injury severity and/or recovery, to identify potential therapeutic targets, and, in the future, to evaluate efficacy of an intervention beyond measures of cell death or spatial learning.

scholarly journals Hypertonic Resuscitation Improves Neuronal and Behavioral Outcomes after Traumatic Brain Injury plus Hemorrhage

2008 ◽  
Vol 108 (5) ◽  
pp. 873-881 ◽  
Author(s):  
Stacy L. Sell ◽  
Marcela A. Avila ◽  
Guangxiang Yu ◽  
Leoncio Vergara ◽  
Donald S. Prough ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Hypertonic Saline ◽  
Morris Water Maze ◽  
Normal Saline ◽  
Water Maze ◽  
Neuronal Survival ◽  
Behavioral Outcomes ◽  
Hemorrhagic Hypotension

Background : Resuscitation with hypertonic saline or hypertonic saline plus l-arginine acutely improves cerebral blood flow after traumatic brain injury (TBI) followed by hemorrhagic hypotension. The authors investigated whether hypertonic saline or hypertonic l-arginine would improve long-term neuronal survival and behavioral outcomes 15 days after TBI and hemorrhagic hypotension. Methods : Mean arterial pressure, arterial blood gases, pH, plasma glucose, hematocrit, and hemoglobin were measured in male Sprague-Dawley rats before and after moderate (2.0 atm) fluid percussion TBI. Rats were assigned to one of six groups: (1) sham TBI, (2) hemorrhage only, (3) TBI only, (4) TBI plus hemorrhage and resuscitation with 0.9% saline, (5) TBI plus hemorrhage and resuscitation with hypertonic saline (7.5%), or (6) TBI plus hemorrhage and resuscitation with l-arginine (100 mg/kg) in hypertonic saline. On postinjury days 1-5, vestibulomotor function was assessed using beam balance and beam walking tasks. On postinjury days 11-15, spatial memory function was assessed using the Morris water maze. After behavioral testing, neuronal counting was performed bilaterally on specific hippocampal regions. Results : Groups receiving hypertonic saline (P &lt; 0.05, day 15 vs. day 11) or hypertonic l-arginine (P &lt; 0.05, days 13-15 vs. day 11) showed improved performance over time on the Morris water maze, as well as significantly improved neuronal survival in the contralateral hippocampus (P &lt; 0.05, hypertonic saline or hypertonic l-arginine vs. normal saline) compared with untreated TBI or normal saline-treated TBI plus hemorrhage groups. Conclusions : Hypertonic saline and hypertonic l-arginine were both effective at promoting long-term neuronal survival and behavioral recovery. The slightly earlier improvement in Morris water maze performance in the hypertonic l-arginine group warrants further studies to determine whether higher doses of l-arginine provide additional improvement. This study supports the therapeutic benefits of hypertonic resuscitation after TBI plus hemorrhagic hypotension.

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