Lucke-Wold, B P; Turner, R C; Logsdon, A F; Nguyen, L; Bailes, J E; Lee, J M; Robson, M J; Omalu, B I; Huber, J D; Rosen, C L
Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy Journal Article
In: Journal of Neurosurgery, vol. 124, no. 3, pp. 687–702, 2016.
Abstract | BibTeX | Tags: *Blast Injuries/px [Psychology], *Brain Injury, *Endoplasmic Reticulum Stress/ph [Physiology], *Football/in [Injuries], *Wrestling/in [Injuries], adult, animal, Animals, Blast Injuries/et [Etiology], Blast Injuries/pa [Pathology], Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Chronic/px [Psychology], Disease Models, Humans, Male, Rats, Sprague-Dawley
@article{Lucke-Wold2016,
title = {Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy},
author = {Lucke-Wold, B P and Turner, R C and Logsdon, A F and Nguyen, L and Bailes, J E and Lee, J M and Robson, M J and Omalu, B I and Huber, J D and Rosen, C L},
year = {2016},
date = {2016-01-01},
journal = {Journal of Neurosurgery},
volume = {124},
number = {3},
pages = {687--702},
abstract = {OBJECTIVE: Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. METHODS: The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. RESULTS: The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3beta. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p \< 0.05), improved cognition (t = 6.532, p \< 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p \< 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. CONCLUSIONS: Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.},
keywords = {*Blast Injuries/px [Psychology], *Brain Injury, *Endoplasmic Reticulum Stress/ph [Physiology], *Football/in [Injuries], *Wrestling/in [Injuries], adult, animal, Animals, Blast Injuries/et [Etiology], Blast Injuries/pa [Pathology], Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Chronic/px [Psychology], Disease Models, Humans, Male, Rats, Sprague-Dawley},
pubstate = {published},
tppubtype = {article}
}
Stemper, B D; Shah, A S; Pintar, F A; McCrea, M; Kurpad, S N; Glavaski-Joksimovic, A; Olsen, C; Budde, M D
Head Rotational Acceleration Characteristics Influence Behavioral and Diffusion Tensor Imaging Outcomes Following Concussion Journal Article
In: Annals of Biomedical Engineering, vol. 43, no. 5, pp. 1071–1088, 2015.
Abstract | Links | BibTeX | Tags: Acceleration, Accidents, BEHAVIORAL assessment, Behavioral assessments, Behavioral outcomes, Biomechanics, brain, Cognitive deficits, Diffusion, Diffusion Tensor Imaging, Diffusion tensor imaging (DTI), fractional anisotropy, Full factorial design, Magnetic Resonance Imaging, Microstructure, Motor vehicle crashes, neuroimaging, Rats, Rotational acceleration, Tensors, Traumatic Brain Injuries, Traumatic brain injury (mTBI)
@article{Stemper2015,
title = {Head Rotational Acceleration Characteristics Influence Behavioral and Diffusion Tensor Imaging Outcomes Following Concussion},
author = {Stemper, B D and Shah, A S and Pintar, F A and McCrea, M and Kurpad, S N and Glavaski-Joksimovic, A and Olsen, C and Budde, M D},
doi = {10.1007/s10439-014-1171-9},
year = {2015},
date = {2015-01-01},
journal = {Annals of Biomedical Engineering},
volume = {43},
number = {5},
pages = {1071--1088},
abstract = {A majority of traumatic brain injuries (TBI) in motor vehicle crashes and sporting environments are mild and caused by high-rate acceleration of the head. For injuries caused by rotational acceleration, both magnitude and duration of the acceleration pulse were shown to influence injury outcomes. This study incorporated a unique rodent model of rotational acceleration-induced mild TBI (mTBI) to quantify independent effects of magnitude and duration on behavioral and neuroimaging outcomes. Ninety-two Sprague\textendashDawley rats were exposed to head rotational acceleration at peak magnitudes of 214 or 350 krad/s2 and acceleration pulse durations of 1.6 or 3.4 ms in a full factorial design. Rats underwent a series of behavioral tests including the Composite Neuroscore (CN), Elevated Plus Maze (EPM), and Morris Water Maze (MWM). Ex vivo diffusion tensor imaging (DTI) of the fixed brains was conducted to assess the effects of rotational injury on brain microstructure as revealed by the parameter fractional anisotropy (FA). While the injury did not cause significant locomotor or cognitive deficits measured with the CN and MWM, respectively, a main effect of duration was consistently observed for the EPM. Increased duration caused significantly greater activity and exploratory behaviors measured as open arm time and number of arm changes. DTI demonstrated significant effects of both magnitude and duration, with the FA of the amygdala related to both the magnitude and duration. Increased duration also caused FA changes at the interface of gray and white matter. Collectively, the findings demonstrate that the consequences of rotational acceleration mTBI were more closely associated with duration of the rotational acceleration impulse, which is often neglected as an independent factor, and highlight the need for animal models of TBI with strong biomechanical foundations to associate behavioral outcomes with brain microstructure. © 2014, Biomedical Engineering Society (Outside the U.S.).},
keywords = {Acceleration, Accidents, BEHAVIORAL assessment, Behavioral assessments, Behavioral outcomes, Biomechanics, brain, Cognitive deficits, Diffusion, Diffusion Tensor Imaging, Diffusion tensor imaging (DTI), fractional anisotropy, Full factorial design, Magnetic Resonance Imaging, Microstructure, Motor vehicle crashes, neuroimaging, Rats, Rotational acceleration, Tensors, Traumatic Brain Injuries, Traumatic brain injury (mTBI)},
pubstate = {published},
tppubtype = {article}
}
Jin, Y; Bouyer, J; Haas, C; Fischer, I
Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion Journal Article
In: Experimental Neurology, vol. 271, pp. 175–188, 2015.
Abstract | BibTeX | Tags: *Gait Disorders, *Spinal Cord Injuries/co [Complications], *Spinal Cord Injuries/pa [Pathology], *Spinal Cord/pa [Pathology], 0 (Antigens, 0 (Ectodysplasins), 0 (Glial Fibrillary Acidic Protein), ANALYSIS of variance, animal, Animals, Antigens, CD31), CD31/me [Metabolism], Contusions/co [Complications], Disease Models, EC 2-7-11-13 (Protein Kinase C), Ectodysplasins/me [Metabolism], Exploratory Behavior/ph [Physiology], Female, Glial Fibrillary Acidic Protein/me [Metabolism], Muscle Strength/ph [Physiology], Neurologic/et [Etiology], PAIN measurement, Protein Kinase C/me [Metabolism], Rats, Spinal Cord Injuries/et [Etiology], Spinal Cord/me [Metabolism], Sprague-Dawley
@article{Jin2015,
title = {Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion},
author = {Jin, Y and Bouyer, J and Haas, C and Fischer, I},
year = {2015},
date = {2015-01-01},
journal = {Experimental Neurology},
volume = {271},
pages = {175--188},
abstract = {Spinal cord concussion is characterized by a transient loss of motor and sensory function that generally resolves without permanent deficits. Spinal cord concussions usually occur during vehicular accidents, falls, and sport activity, but unlike brain concussions, have received much less attention despite the potential for repeated injury leading to permanent neurological sequelae. Consequently, there is no consensus regarding decisions related to return to play following an episode of spinal concussion, nor an understanding of the short- and long-term consequences of repeated injury. Importantly, there are no models of spinal concussion to study the anatomical and functional sequelae of single or repeated injury. We have developed a new model of spinal cord concussion focusing on the anatomical and behavioral outcomes of single and repeated injury. Rats received a very mild (50 kdyn, IH impactor) spinal contusion at C5 and were separated into two groups three weeks after the initial injury--C1, which received a second, sham surgery, and C2, which received a second contusion at the same site. To track motor function and recovery, animals received weekly behavioral tests--BBB, CatWalkTM, cylinder, and Von Frey. Analysis of locomotor activity by BBB demonstrated that rats rapidly recovered, regaining near-normal function by one week after the first and second injury, which was confirmed using the more detailed CatWalkTM analysis. The cylinder test showed that a single contusion did not induce significant deficits of the affected limb, but that repeated injury resulted in significant alteration in paw preference, with animals favoring the unaffected limb. Intriguingly, Von Frey analysis demonstrated an increased sensitivity in the contralateral hindlimb in the C2 group vs. the C1 group. Anatomical analyses revealed that while the lesion volume of both groups was minimal, the area of spared white matter in the C2 group was significantly reduced 1 and 2mm rostral to the lesion epicenter. Reactive astrocytes were present in both groups, with the majority found at the lesion epicenter in the C1 group, whereas the C2 group demonstrated increased reactive astrocytes extending 1mm caudal to the lesion epicenter. Macrophages accumulated within the injured, dorsal and ipsilateral spinal cord, with significant increases at 2 and 3mm rostral to the epicenter in the C2 group. Our model is designed to represent the clinical presentation of spinal cord concussion, and highlight the susceptibility and functional sequelae of repeated injury. Future experiments will examine the temporal and spatial windows of vulnerability for repeated injuries.Copyright © 2015. Published by Elsevier Inc.},
keywords = {*Gait Disorders, *Spinal Cord Injuries/co [Complications], *Spinal Cord Injuries/pa [Pathology], *Spinal Cord/pa [Pathology], 0 (Antigens, 0 (Ectodysplasins), 0 (Glial Fibrillary Acidic Protein), ANALYSIS of variance, animal, Animals, Antigens, CD31), CD31/me [Metabolism], Contusions/co [Complications], Disease Models, EC 2-7-11-13 (Protein Kinase C), Ectodysplasins/me [Metabolism], Exploratory Behavior/ph [Physiology], Female, Glial Fibrillary Acidic Protein/me [Metabolism], Muscle Strength/ph [Physiology], Neurologic/et [Etiology], PAIN measurement, Protein Kinase C/me [Metabolism], Rats, Spinal Cord Injuries/et [Etiology], Spinal Cord/me [Metabolism], Sprague-Dawley},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Naser, Z J; Logsdon, A F; Turner, R C; Smith, K E; Robson, M J; Bailes, J E; Lee, J M; Rosen, C L; Huber, J D
Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury Journal Article
In: Translational Research: The Journal Of Laboratory & Clinical Medicine, vol. 166, no. 6, pp. 509–528.e1, 2015.
Abstract | BibTeX | Tags: *Blast Injuries/pa [Pathology], *Brain Injuries/pa [Pathology], *NADPH Oxidase/me [Metabolism], *Oxidative Stress, 73Y7P0K73Y (Thioctic Acid), Animals, Apoptosis, Blast Injuries/en [Enzymology], Blast Injuries/me [Metabolism], Brain Injuries/en [Enzymology], Brain Injuries/me [Metabolism], EC 1-6-3-1 (NADPH Oxidase), Male, Rats, Sprague-Dawley, Thioctic Acid/pd [Pharmacology]
@article{Lucke-Wold2015,
title = {Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury},
author = {Lucke-Wold, B P and Naser, Z J and Logsdon, A F and Turner, R C and Smith, K E and Robson, M J and Bailes, J E and Lee, J M and Rosen, C L and Huber, J D},
year = {2015},
date = {2015-01-01},
journal = {Translational Research: The Journal Of Laboratory \& Clinical Medicine},
volume = {166},
number = {6},
pages = {509--528.e1},
abstract = {A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P \< 0.05) and heme oxygenase 1 (t = 8.169, P \< 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P \< 0.05), caspase 12 (t = 6.157, P \< 0.001), and caspase 3 (t = 4.573, P \< 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P \< 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration. Copyright © 2015 Elsevier Inc. All rights reserved.},
keywords = {*Blast Injuries/pa [Pathology], *Brain Injuries/pa [Pathology], *NADPH Oxidase/me [Metabolism], *Oxidative Stress, 73Y7P0K73Y (Thioctic Acid), Animals, Apoptosis, Blast Injuries/en [Enzymology], Blast Injuries/me [Metabolism], Brain Injuries/en [Enzymology], Brain Injuries/me [Metabolism], EC 1-6-3-1 (NADPH Oxidase), Male, Rats, Sprague-Dawley, Thioctic Acid/pd [Pharmacology]},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Turner, R C; Logsdon, A F; Nguyen, L; Bailes, J E; Lee, J M; Robson, M J; Omalu, B I; Huber, J D; Rosen, C L
Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy Journal Article
In: Journal of Neurosurgery, vol. 124, no. 3, pp. 687–702, 2016.
@article{Lucke-Wold2016,
title = {Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy},
author = {Lucke-Wold, B P and Turner, R C and Logsdon, A F and Nguyen, L and Bailes, J E and Lee, J M and Robson, M J and Omalu, B I and Huber, J D and Rosen, C L},
year = {2016},
date = {2016-01-01},
journal = {Journal of Neurosurgery},
volume = {124},
number = {3},
pages = {687--702},
abstract = {OBJECTIVE: Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. METHODS: The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. RESULTS: The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3beta. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p \< 0.05), improved cognition (t = 6.532, p \< 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p \< 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. CONCLUSIONS: Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Stemper, B D; Shah, A S; Pintar, F A; McCrea, M; Kurpad, S N; Glavaski-Joksimovic, A; Olsen, C; Budde, M D
Head Rotational Acceleration Characteristics Influence Behavioral and Diffusion Tensor Imaging Outcomes Following Concussion Journal Article
In: Annals of Biomedical Engineering, vol. 43, no. 5, pp. 1071–1088, 2015.
@article{Stemper2015,
title = {Head Rotational Acceleration Characteristics Influence Behavioral and Diffusion Tensor Imaging Outcomes Following Concussion},
author = {Stemper, B D and Shah, A S and Pintar, F A and McCrea, M and Kurpad, S N and Glavaski-Joksimovic, A and Olsen, C and Budde, M D},
doi = {10.1007/s10439-014-1171-9},
year = {2015},
date = {2015-01-01},
journal = {Annals of Biomedical Engineering},
volume = {43},
number = {5},
pages = {1071--1088},
abstract = {A majority of traumatic brain injuries (TBI) in motor vehicle crashes and sporting environments are mild and caused by high-rate acceleration of the head. For injuries caused by rotational acceleration, both magnitude and duration of the acceleration pulse were shown to influence injury outcomes. This study incorporated a unique rodent model of rotational acceleration-induced mild TBI (mTBI) to quantify independent effects of magnitude and duration on behavioral and neuroimaging outcomes. Ninety-two Sprague\textendashDawley rats were exposed to head rotational acceleration at peak magnitudes of 214 or 350 krad/s2 and acceleration pulse durations of 1.6 or 3.4 ms in a full factorial design. Rats underwent a series of behavioral tests including the Composite Neuroscore (CN), Elevated Plus Maze (EPM), and Morris Water Maze (MWM). Ex vivo diffusion tensor imaging (DTI) of the fixed brains was conducted to assess the effects of rotational injury on brain microstructure as revealed by the parameter fractional anisotropy (FA). While the injury did not cause significant locomotor or cognitive deficits measured with the CN and MWM, respectively, a main effect of duration was consistently observed for the EPM. Increased duration caused significantly greater activity and exploratory behaviors measured as open arm time and number of arm changes. DTI demonstrated significant effects of both magnitude and duration, with the FA of the amygdala related to both the magnitude and duration. Increased duration also caused FA changes at the interface of gray and white matter. Collectively, the findings demonstrate that the consequences of rotational acceleration mTBI were more closely associated with duration of the rotational acceleration impulse, which is often neglected as an independent factor, and highlight the need for animal models of TBI with strong biomechanical foundations to associate behavioral outcomes with brain microstructure. © 2014, Biomedical Engineering Society (Outside the U.S.).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Jin, Y; Bouyer, J; Haas, C; Fischer, I
Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion Journal Article
In: Experimental Neurology, vol. 271, pp. 175–188, 2015.
@article{Jin2015,
title = {Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion},
author = {Jin, Y and Bouyer, J and Haas, C and Fischer, I},
year = {2015},
date = {2015-01-01},
journal = {Experimental Neurology},
volume = {271},
pages = {175--188},
abstract = {Spinal cord concussion is characterized by a transient loss of motor and sensory function that generally resolves without permanent deficits. Spinal cord concussions usually occur during vehicular accidents, falls, and sport activity, but unlike brain concussions, have received much less attention despite the potential for repeated injury leading to permanent neurological sequelae. Consequently, there is no consensus regarding decisions related to return to play following an episode of spinal concussion, nor an understanding of the short- and long-term consequences of repeated injury. Importantly, there are no models of spinal concussion to study the anatomical and functional sequelae of single or repeated injury. We have developed a new model of spinal cord concussion focusing on the anatomical and behavioral outcomes of single and repeated injury. Rats received a very mild (50 kdyn, IH impactor) spinal contusion at C5 and were separated into two groups three weeks after the initial injury--C1, which received a second, sham surgery, and C2, which received a second contusion at the same site. To track motor function and recovery, animals received weekly behavioral tests--BBB, CatWalkTM, cylinder, and Von Frey. Analysis of locomotor activity by BBB demonstrated that rats rapidly recovered, regaining near-normal function by one week after the first and second injury, which was confirmed using the more detailed CatWalkTM analysis. The cylinder test showed that a single contusion did not induce significant deficits of the affected limb, but that repeated injury resulted in significant alteration in paw preference, with animals favoring the unaffected limb. Intriguingly, Von Frey analysis demonstrated an increased sensitivity in the contralateral hindlimb in the C2 group vs. the C1 group. Anatomical analyses revealed that while the lesion volume of both groups was minimal, the area of spared white matter in the C2 group was significantly reduced 1 and 2mm rostral to the lesion epicenter. Reactive astrocytes were present in both groups, with the majority found at the lesion epicenter in the C1 group, whereas the C2 group demonstrated increased reactive astrocytes extending 1mm caudal to the lesion epicenter. Macrophages accumulated within the injured, dorsal and ipsilateral spinal cord, with significant increases at 2 and 3mm rostral to the epicenter in the C2 group. Our model is designed to represent the clinical presentation of spinal cord concussion, and highlight the susceptibility and functional sequelae of repeated injury. Future experiments will examine the temporal and spatial windows of vulnerability for repeated injuries.Copyright © 2015. Published by Elsevier Inc.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Naser, Z J; Logsdon, A F; Turner, R C; Smith, K E; Robson, M J; Bailes, J E; Lee, J M; Rosen, C L; Huber, J D
Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury Journal Article
In: Translational Research: The Journal Of Laboratory & Clinical Medicine, vol. 166, no. 6, pp. 509–528.e1, 2015.
@article{Lucke-Wold2015,
title = {Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury},
author = {Lucke-Wold, B P and Naser, Z J and Logsdon, A F and Turner, R C and Smith, K E and Robson, M J and Bailes, J E and Lee, J M and Rosen, C L and Huber, J D},
year = {2015},
date = {2015-01-01},
journal = {Translational Research: The Journal Of Laboratory \& Clinical Medicine},
volume = {166},
number = {6},
pages = {509--528.e1},
abstract = {A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P \< 0.05) and heme oxygenase 1 (t = 8.169, P \< 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P \< 0.05), caspase 12 (t = 6.157, P \< 0.001), and caspase 3 (t = 4.573, P \< 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P \< 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration. Copyright © 2015 Elsevier Inc. All rights reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Turner, R C; Logsdon, A F; Nguyen, L; Bailes, J E; Lee, J M; Robson, M J; Omalu, B I; Huber, J D; Rosen, C L
Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy Journal Article
In: Journal of Neurosurgery, vol. 124, no. 3, pp. 687–702, 2016.
Abstract | BibTeX | Tags: *Blast Injuries/px [Psychology], *Brain Injury, *Endoplasmic Reticulum Stress/ph [Physiology], *Football/in [Injuries], *Wrestling/in [Injuries], adult, animal, Animals, Blast Injuries/et [Etiology], Blast Injuries/pa [Pathology], Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Chronic/px [Psychology], Disease Models, Humans, Male, Rats, Sprague-Dawley
@article{Lucke-Wold2016,
title = {Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy},
author = {Lucke-Wold, B P and Turner, R C and Logsdon, A F and Nguyen, L and Bailes, J E and Lee, J M and Robson, M J and Omalu, B I and Huber, J D and Rosen, C L},
year = {2016},
date = {2016-01-01},
journal = {Journal of Neurosurgery},
volume = {124},
number = {3},
pages = {687--702},
abstract = {OBJECTIVE: Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. METHODS: The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. RESULTS: The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3beta. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p \< 0.05), improved cognition (t = 6.532, p \< 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p \< 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. CONCLUSIONS: Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.},
keywords = {*Blast Injuries/px [Psychology], *Brain Injury, *Endoplasmic Reticulum Stress/ph [Physiology], *Football/in [Injuries], *Wrestling/in [Injuries], adult, animal, Animals, Blast Injuries/et [Etiology], Blast Injuries/pa [Pathology], Brain Injury, Chronic/et [Etiology], Chronic/pa [Pathology], Chronic/px [Psychology], Disease Models, Humans, Male, Rats, Sprague-Dawley},
pubstate = {published},
tppubtype = {article}
}
Stemper, B D; Shah, A S; Pintar, F A; McCrea, M; Kurpad, S N; Glavaski-Joksimovic, A; Olsen, C; Budde, M D
Head Rotational Acceleration Characteristics Influence Behavioral and Diffusion Tensor Imaging Outcomes Following Concussion Journal Article
In: Annals of Biomedical Engineering, vol. 43, no. 5, pp. 1071–1088, 2015.
Abstract | Links | BibTeX | Tags: Acceleration, Accidents, BEHAVIORAL assessment, Behavioral assessments, Behavioral outcomes, Biomechanics, brain, Cognitive deficits, Diffusion, Diffusion Tensor Imaging, Diffusion tensor imaging (DTI), fractional anisotropy, Full factorial design, Magnetic Resonance Imaging, Microstructure, Motor vehicle crashes, neuroimaging, Rats, Rotational acceleration, Tensors, Traumatic Brain Injuries, Traumatic brain injury (mTBI)
@article{Stemper2015,
title = {Head Rotational Acceleration Characteristics Influence Behavioral and Diffusion Tensor Imaging Outcomes Following Concussion},
author = {Stemper, B D and Shah, A S and Pintar, F A and McCrea, M and Kurpad, S N and Glavaski-Joksimovic, A and Olsen, C and Budde, M D},
doi = {10.1007/s10439-014-1171-9},
year = {2015},
date = {2015-01-01},
journal = {Annals of Biomedical Engineering},
volume = {43},
number = {5},
pages = {1071--1088},
abstract = {A majority of traumatic brain injuries (TBI) in motor vehicle crashes and sporting environments are mild and caused by high-rate acceleration of the head. For injuries caused by rotational acceleration, both magnitude and duration of the acceleration pulse were shown to influence injury outcomes. This study incorporated a unique rodent model of rotational acceleration-induced mild TBI (mTBI) to quantify independent effects of magnitude and duration on behavioral and neuroimaging outcomes. Ninety-two Sprague\textendashDawley rats were exposed to head rotational acceleration at peak magnitudes of 214 or 350 krad/s2 and acceleration pulse durations of 1.6 or 3.4 ms in a full factorial design. Rats underwent a series of behavioral tests including the Composite Neuroscore (CN), Elevated Plus Maze (EPM), and Morris Water Maze (MWM). Ex vivo diffusion tensor imaging (DTI) of the fixed brains was conducted to assess the effects of rotational injury on brain microstructure as revealed by the parameter fractional anisotropy (FA). While the injury did not cause significant locomotor or cognitive deficits measured with the CN and MWM, respectively, a main effect of duration was consistently observed for the EPM. Increased duration caused significantly greater activity and exploratory behaviors measured as open arm time and number of arm changes. DTI demonstrated significant effects of both magnitude and duration, with the FA of the amygdala related to both the magnitude and duration. Increased duration also caused FA changes at the interface of gray and white matter. Collectively, the findings demonstrate that the consequences of rotational acceleration mTBI were more closely associated with duration of the rotational acceleration impulse, which is often neglected as an independent factor, and highlight the need for animal models of TBI with strong biomechanical foundations to associate behavioral outcomes with brain microstructure. © 2014, Biomedical Engineering Society (Outside the U.S.).},
keywords = {Acceleration, Accidents, BEHAVIORAL assessment, Behavioral assessments, Behavioral outcomes, Biomechanics, brain, Cognitive deficits, Diffusion, Diffusion Tensor Imaging, Diffusion tensor imaging (DTI), fractional anisotropy, Full factorial design, Magnetic Resonance Imaging, Microstructure, Motor vehicle crashes, neuroimaging, Rats, Rotational acceleration, Tensors, Traumatic Brain Injuries, Traumatic brain injury (mTBI)},
pubstate = {published},
tppubtype = {article}
}
Jin, Y; Bouyer, J; Haas, C; Fischer, I
Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion Journal Article
In: Experimental Neurology, vol. 271, pp. 175–188, 2015.
Abstract | BibTeX | Tags: *Gait Disorders, *Spinal Cord Injuries/co [Complications], *Spinal Cord Injuries/pa [Pathology], *Spinal Cord/pa [Pathology], 0 (Antigens, 0 (Ectodysplasins), 0 (Glial Fibrillary Acidic Protein), ANALYSIS of variance, animal, Animals, Antigens, CD31), CD31/me [Metabolism], Contusions/co [Complications], Disease Models, EC 2-7-11-13 (Protein Kinase C), Ectodysplasins/me [Metabolism], Exploratory Behavior/ph [Physiology], Female, Glial Fibrillary Acidic Protein/me [Metabolism], Muscle Strength/ph [Physiology], Neurologic/et [Etiology], PAIN measurement, Protein Kinase C/me [Metabolism], Rats, Spinal Cord Injuries/et [Etiology], Spinal Cord/me [Metabolism], Sprague-Dawley
@article{Jin2015,
title = {Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion},
author = {Jin, Y and Bouyer, J and Haas, C and Fischer, I},
year = {2015},
date = {2015-01-01},
journal = {Experimental Neurology},
volume = {271},
pages = {175--188},
abstract = {Spinal cord concussion is characterized by a transient loss of motor and sensory function that generally resolves without permanent deficits. Spinal cord concussions usually occur during vehicular accidents, falls, and sport activity, but unlike brain concussions, have received much less attention despite the potential for repeated injury leading to permanent neurological sequelae. Consequently, there is no consensus regarding decisions related to return to play following an episode of spinal concussion, nor an understanding of the short- and long-term consequences of repeated injury. Importantly, there are no models of spinal concussion to study the anatomical and functional sequelae of single or repeated injury. We have developed a new model of spinal cord concussion focusing on the anatomical and behavioral outcomes of single and repeated injury. Rats received a very mild (50 kdyn, IH impactor) spinal contusion at C5 and were separated into two groups three weeks after the initial injury--C1, which received a second, sham surgery, and C2, which received a second contusion at the same site. To track motor function and recovery, animals received weekly behavioral tests--BBB, CatWalkTM, cylinder, and Von Frey. Analysis of locomotor activity by BBB demonstrated that rats rapidly recovered, regaining near-normal function by one week after the first and second injury, which was confirmed using the more detailed CatWalkTM analysis. The cylinder test showed that a single contusion did not induce significant deficits of the affected limb, but that repeated injury resulted in significant alteration in paw preference, with animals favoring the unaffected limb. Intriguingly, Von Frey analysis demonstrated an increased sensitivity in the contralateral hindlimb in the C2 group vs. the C1 group. Anatomical analyses revealed that while the lesion volume of both groups was minimal, the area of spared white matter in the C2 group was significantly reduced 1 and 2mm rostral to the lesion epicenter. Reactive astrocytes were present in both groups, with the majority found at the lesion epicenter in the C1 group, whereas the C2 group demonstrated increased reactive astrocytes extending 1mm caudal to the lesion epicenter. Macrophages accumulated within the injured, dorsal and ipsilateral spinal cord, with significant increases at 2 and 3mm rostral to the epicenter in the C2 group. Our model is designed to represent the clinical presentation of spinal cord concussion, and highlight the susceptibility and functional sequelae of repeated injury. Future experiments will examine the temporal and spatial windows of vulnerability for repeated injuries.Copyright © 2015. Published by Elsevier Inc.},
keywords = {*Gait Disorders, *Spinal Cord Injuries/co [Complications], *Spinal Cord Injuries/pa [Pathology], *Spinal Cord/pa [Pathology], 0 (Antigens, 0 (Ectodysplasins), 0 (Glial Fibrillary Acidic Protein), ANALYSIS of variance, animal, Animals, Antigens, CD31), CD31/me [Metabolism], Contusions/co [Complications], Disease Models, EC 2-7-11-13 (Protein Kinase C), Ectodysplasins/me [Metabolism], Exploratory Behavior/ph [Physiology], Female, Glial Fibrillary Acidic Protein/me [Metabolism], Muscle Strength/ph [Physiology], Neurologic/et [Etiology], PAIN measurement, Protein Kinase C/me [Metabolism], Rats, Spinal Cord Injuries/et [Etiology], Spinal Cord/me [Metabolism], Sprague-Dawley},
pubstate = {published},
tppubtype = {article}
}
Lucke-Wold, B P; Naser, Z J; Logsdon, A F; Turner, R C; Smith, K E; Robson, M J; Bailes, J E; Lee, J M; Rosen, C L; Huber, J D
Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury Journal Article
In: Translational Research: The Journal Of Laboratory & Clinical Medicine, vol. 166, no. 6, pp. 509–528.e1, 2015.
Abstract | BibTeX | Tags: *Blast Injuries/pa [Pathology], *Brain Injuries/pa [Pathology], *NADPH Oxidase/me [Metabolism], *Oxidative Stress, 73Y7P0K73Y (Thioctic Acid), Animals, Apoptosis, Blast Injuries/en [Enzymology], Blast Injuries/me [Metabolism], Brain Injuries/en [Enzymology], Brain Injuries/me [Metabolism], EC 1-6-3-1 (NADPH Oxidase), Male, Rats, Sprague-Dawley, Thioctic Acid/pd [Pharmacology]
@article{Lucke-Wold2015,
title = {Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury},
author = {Lucke-Wold, B P and Naser, Z J and Logsdon, A F and Turner, R C and Smith, K E and Robson, M J and Bailes, J E and Lee, J M and Rosen, C L and Huber, J D},
year = {2015},
date = {2015-01-01},
journal = {Translational Research: The Journal Of Laboratory \& Clinical Medicine},
volume = {166},
number = {6},
pages = {509--528.e1},
abstract = {A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United States, but available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining methods, we found a visible increase in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely and increased antiapoptotic markers B-cell lymphoma 2 (t = 3.079, P \< 0.05) and heme oxygenase 1 (t = 8.169, P \< 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic markers Bax (t = 4.483, P \< 0.05), caspase 12 (t = 6.157, P \< 0.001), and caspase 3 (t = 4.573, P \< 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P \< 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic intervention, and alpha-lipoic acid warrants further investigation as a therapeutic for prevention of chronic neurodegeneration. Copyright © 2015 Elsevier Inc. All rights reserved.},
keywords = {*Blast Injuries/pa [Pathology], *Brain Injuries/pa [Pathology], *NADPH Oxidase/me [Metabolism], *Oxidative Stress, 73Y7P0K73Y (Thioctic Acid), Animals, Apoptosis, Blast Injuries/en [Enzymology], Blast Injuries/me [Metabolism], Brain Injuries/en [Enzymology], Brain Injuries/me [Metabolism], EC 1-6-3-1 (NADPH Oxidase), Male, Rats, Sprague-Dawley, Thioctic Acid/pd [Pharmacology]},
pubstate = {published},
tppubtype = {article}
}