scholarly journals 3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

2021 ◽  
Vol 22 (15) ◽  
pp. 8276
Author(s):  
Pen-Sen Huang ◽  
Ping-Yen Tsai ◽  
Ling-Yu Yang ◽  
Daniela Lecca ◽  
Weiming Luo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Short Term Memory ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Cognitive Behaviors ◽  
Moderate Traumatic Brain Injury ◽  
Short And Long Term ◽  
Behavioral Impairments ◽  
Hippocampal Neurodegeneration

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6′-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.

Neuropsychiatric Predictors of Post-Injury Headache After Mild-Moderate Traumatic Brain Injury in Veterans

2016 ◽  
Vol 56 (4) ◽  
pp. 699-710 ◽  
Author(s):  
Jessica Bomyea ◽  
Ariel J. Lang ◽  
Lisa Delano-Wood ◽  
Amy Jak ◽  
Karen L. Hanson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Post Injury ◽  
Moderate Traumatic Brain Injury

scholarly journals Increased Vulnerability of NFH-LacZ Transgenic Mouse to Traumatic Brain Injury-Induced Behavioral Deficits and Cortical Damage

1999 ◽  
Vol 19 (7) ◽  
pp. 762-770 ◽  
Author(s):  
Michio Nakamura ◽  
Kathryn E. Saatman ◽  
James E. Galvin ◽  
Uwe Scherbel ◽  
Ramesh Raghupathi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Dysfunction ◽  
Tissue Loss ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Beam Balance ◽  
Brain Injured ◽  
Neuromotor Function ◽  
Histopathologic Analysis

The authors evaluated the neurobehavioral and neuropathologic sequelae after traumatic brain injury (TBI) in transgenic (TG) mice expressing truncated high molecular weight neurofilament (NF) protein fused to beta-galactosidase (NFH-LacZ), which develop Lewy body-like NF-rich inclusions throughout the CNS. TG mice and their wild-type (WT) littermates were subjected to controlled cortical impact brain injury (TG, n=19; WT, n=17) or served as uninjured controls (TG, n =11; WT, n =11). During a 3-week period, mice were evaluated with an array of neuromotor function tests including neuroscore, beam balance, and both fast and slow acceleration rotarod. Brain-injured WT and TG mice showed significant motor dysfunction until 15 days and 21 days post-injury, respectively ( P < .025). Compared with brain-injured WT mice, brain-injured TG mice had significantly greater motor dysfunction as assessed by neuroscore ( P < .01) up to and including 15 days post-injury. Similarly, brain-injured TG mice performed significantly worse than brain-injured WT mice on slow acceleration rotarod at 2, 8, and 15 days post-injury ( P < .05), and beam balance over 2 weeks post-injury ( P < .01). Histopathologic analysis showed significantly greater tissue loss in the injured hemisphere in TG mice at 4 weeks post-injury ( P < .01). Together these data show that NFH-LacZ TG mice are more behaviorally and histologically vulnerable to TBI than WT mice, suggesting that the presence of NF-rich inclusions may exacerbate neuromotor dysfunction and cell death after TBI.

scholarly journals Impaired visual working memory and reduced connectivity in undergraduates with a history of mild traumatic brain injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hector Arciniega ◽  
Jorja Shires ◽  
Sarah Furlong ◽  
Alexandrea Kilgore-Gomez ◽  
Adelle Cerreta ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Working Memory ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Resting State Fmri ◽  
Underlying Mechanism ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Specific Outcome ◽  
History Of

AbstractMild traumatic brain injury (mTBI), or concussion, accounts for 85% of all TBIs. Yet survivors anticipate full cognitive recovery within several months of injury, if not sooner, dependent upon the specific outcome/measure. Recovery is variable and deficits in executive function, e.g., working memory (WM) can persist years post-mTBI. We tested whether cognitive deficits persist in otherwise healthy undergraduates, as a conservative indicator for mTBI survivors at large. We collected WM performance (change detection, n-back tasks) using various stimuli (shapes, locations, letters; aurally presented numbers and letters), and wide-ranging cognitive assessments (e.g., RBANS). We replicated the observation of a general visual WM deficit, with preserved auditory WM. Surprisingly, visual WM deficits were equivalent in participants with a history of mTBI (mean 4.3 years post-injury) and in undergraduates with recent sports-related mTBI (mean 17 days post-injury). In seeking the underlying mechanism of these behavioral deficits, we collected resting state fMRI (rsfMRI) and EEG (rsEEG). RsfMRI revealed significantly reduced connectivity within WM-relevant networks (default mode, central executive, dorsal attention, salience), whereas rsEEG identified no differences (modularity, global efficiency, local efficiency). In summary, otherwise healthy current undergraduates with a history of mTBI present behavioral deficits with evidence of persistent disconnection long after full recovery is expected.

Cognitive and neurobehavioral functioning after mild versus moderate traumatic brain injury in older adults

2001 ◽  
Vol 7 (3) ◽  
pp. 373-383 ◽  
Author(s):  
FELICIA C. GOLDSTEIN ◽  
HARVEY S. LEVIN ◽  
WILLIAM P. GOLDMAN ◽  
ALLISON N. CLARK ◽  
TRACY KENEHAN ALTONEN
Keyword(s):  
Older Adults ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Outcome ◽  
Cognitive Measures ◽  
Post Injury ◽  
Mild Tbi ◽  
Moderate Traumatic Brain Injury ◽  
Comparable Control ◽  
Neurobehavioral Outcomes

This study evaluated the early cognitive and neurobehavioral outcomes of older adults with mild versus moderate traumatic brain injury (TBI). Thirty-five patients who were age 50 years and older and sustained mild or moderate TBI were prospectively recruited from acute care hospitals. Patients were administered cognitive and neurobehavioral measures up to 2 months post-injury. Demographically comparable control participants received the same measures. Patients and controls did not have previous histories of substance abuse, neuropsychiatric disturbance, dementia, or neurologic illness. Moderate TBI patients performed significantly poorer than mild TBI patients and controls on most cognitive measures, whereas the mild patients performed comparably to controls. In contrast, both mild and moderate patients exhibited significantly greater depression and anxiety/somatic concern than controls. The results indicate that the classification of TBI as mild versus moderate is prognostically meaningful as applied to older adults. The findings extend previous investigations in young adults by demonstrating a relatively good cognitive outcome on objective measures, but subjective complaints after a single, uncomplicated mild TBI in older persons. (JINS, 2001, 7, 373–383.)

scholarly journals Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice

2021 ◽  
Vol 22 (2) ◽  
pp. 907
Author(s):  
Saef Izzy ◽  
Alexander Brown-Whalen ◽  
Taha Yahya ◽  
Aliyah Sarro-Schwartz ◽  
Gina Jin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Behavioral Outcomes ◽  
Closed Head Injury ◽  
Tau Pathology ◽  
Post Injury ◽  
Behavioral Deficits ◽  
Tau Mutation ◽  
Injury Causes

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

scholarly journals Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent vs adult mice

2019 ◽  
Author(s):  
Fernanda Guilhaume-Correa ◽  
Shelby M. Cansler ◽  
Emily M. Shalosky ◽  
Michael D. Goodman ◽  
Nathan K. Evanson
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Recognition Performance ◽  
Memory Performance ◽  
Health Concern ◽  
Post Injury ◽  
Adult Mice ◽  
Closed Head ◽  
Old Adult ◽  
Hippocampal Neurodegeneration

AbstractIntroductionTraumatic brain injury (TBI) is a major public health concern affecting 2.8 million people per year, of which about 1 million are children under 19 years old. Animal models of TBI have been developed and used in multiple ages of animals, but direct comparisons of adult and adolescent populations are rare. The current studies were undertaken to directly compare outcomes between adult and adolescent mice, using a closed head, single impact model of TBI.MethodsSix-week-old adolescent and 9-week-old adult male mice were subjected to TBI using a closed head weight drop model. Histological measures for neurodegeneration, gliosis, and microglial neuroinflammation, and behavioral tests of locomotion and memory were performed.ResultsAdolescent TBI mice have increased mortality (X2= 20.72, p < 0.001) compared to adults. There is also evidence of hippocampal neurodegeneration in adolescents, but not adults. Presence of hippocampal neurodegeneration correlates with histologic activation of microglia, but not with increased markers of astrogliosis. Adults and adolescents have similar locomotion deficits after TBI that recover by 16 days post-injury. Adolescents have memory deficits as evidenced by impaired novel object recognition performance 3 and 16 days post injury (F1,26 = 5.23, p = 0.031) while adults do not.ConclusionsAdults and adolescents within a close age range (6-9 weeks) respond to TBI differently. Adolescents are more severely affected by mortality, neurodegeneration, and inflammation in the hippocampus compared to adults. Adolescents, but not adults, have worse memory performance after TBI that lasts up to 16 days post injury.

scholarly journals (-)-Phenserine Ameliorates Contusion Volume, Neuroinflammation, and Behavioral Impairments Induced by Traumatic Brain Injury in Mice

2019 ◽  
Vol 28 (9-10) ◽  
pp. 1183-1196 ◽  
Author(s):  
Shih-Chang Hsueh ◽  
Daniela Lecca ◽  
Nigel H. Greig ◽  
Jia-Yi Wang ◽  
Warren Selman ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Coordination ◽  
Acetylcholinesterase Inhibitor ◽  
Acetylcholinesterase Activity ◽  
Phase Iii ◽  
Acetylcholinesterase Inhibition ◽  
Motor Asymmetry ◽  
Post Injury ◽  
Behavioral Impairments

Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer’s disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateral ventricular size increase, motor asymmetry, motor coordination, and balance function, suggesting the improvement of these histological and behavioral tests by Phen treatment occur via pathways other than anti-acetylcholinesterase inhibition. However, the reduction of lesion size and improvement of sensorimotor function by Posiphen were much smaller than with equivalent doses of Phen. Taken together, these results show that post-injury treatment with Phen over 5 days significantly ameliorates severity of TBI. These data suggest a potential development of this compound for clinical use in TBI therapy.

scholarly journals Pattern of Neuronal and Axonal Damage, Glial Response, and Synaptic Changes in Rat Cerebellum within the First Week following Traumatic Brain Injury

2020 ◽  
Vol 79 (11) ◽  
pp. 1163-1182
Author(s):  
Petra Dolenec ◽  
Kristina Pilipović ◽  
Tamara Janković ◽  
Gordana Župan
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Damage ◽  
Cell Loss ◽  
Axonal Damage ◽  
Post Injury ◽  
Rat Cerebellum ◽  
Fluid Percussion Injury ◽  
Fluoro Jade B ◽  
Moderate Traumatic Brain Injury

Abstract We examined damage and repair processes in the rat cerebellum within the first week following moderate traumatic brain injury (TBI) induced by lateral fluid percussion injury (LFPI) over the left parietal cortex. Rats were killed 1, 3, or 7 days after the injury or sham procedure. Fluoro-Jade B staining revealed 2 phases of neurodegenerative changes in the cell bodies and fibers: first, more focal, 1 day after the LFPI, and second, widespread, starting on post-injury day 3. Purkinje cell loss was detected in posterior lobule IX 1 day following LFPI. Apoptosis was observed in the cerebellar cortex, on days 1 and 7 following LFPI, and was not caspase- or apoptosis-inducing factor (AIF)-mediated. AIF immunostaining indicated axonal damage in the cerebellar white matter tracts 3- and 7-days post-injury. Significant astrocytosis and microgliosis were noticed on day 7 following LFPI at the sites of neuronal damage and loss. Immunohistochemical labeling with the presynaptic markers synaptophysin and growth-associated protein-43 revealed synaptic perturbations already on day 1 that were more pronounced at later time points following LFPI. These results provide new insights into pathophysiological alterations in the cerebellum and their mechanisms following cerebral TBI.

scholarly journals Intranasal insulin treatment of an experimental model of moderate traumatic brain injury

2017 ◽  
Vol 37 (9) ◽  
pp. 3203-3218 ◽  
Author(s):  
Fiona Brabazon ◽  
Colin M Wilson ◽  
Shalini Jaiswal ◽  
John Reed ◽  
William H Frey ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Glucose Uptake ◽  
Male Rats ◽  
Lesion Volume ◽  
Intranasal Insulin ◽  
Post Injury ◽  
Fdg Uptake ◽  
Moderate Traumatic Brain Injury ◽  
18F Fdg

Traumatic brain injury (TBI) results in learning and memory dysfunction. Cognitive deficits result from cellular and metabolic dysfunction after injury, including decreased cerebral glucose uptake and inflammation. This study assessed the ability of intranasal insulin to increase cerebral glucose uptake after injury, reduce lesion volume, improve memory and learning function and reduce inflammation. Adult male rats received a controlled cortical impact (CCI) injury followed by intranasal insulin or saline treatment daily for 14 days. PET imaging of [18F]-FDG uptake was performed at baseline and at 48 h and 10 days post-injury and MRI on days three and nine post injury. Motor function was tested with the beam walking test. Memory function was assessed with Morris water maze. Intranasal insulin after CCI significantly improved several outcomes compared to saline. Insulin-treated animals performed better on beam walk and demonstrated significantly improved memory. A significant increase in [18F]-FDG uptake was observed in the hippocampus. Intranasal insulin also resulted in a significant decrease in hippocampus lesion volume and significantly less microglial immunolabeling in the hippocampus. These data show that intranasal insulin improves memory, increases cerebral glucose uptake and decreases neuroinflammation and hippocampal lesion volume, and may therefore be a viable therapy for TBI.

Sign in / Sign up

Export Citation Format

Share Document