Publications by authors named "Jason D Huber"

59 Publications

The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke.

Pharm Res 2021 May 12;38(5):803-817. Epub 2021 May 12.

Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Drive, Morgantown, West Virginia, 26506, USA.

Purpose: Therapeutic strategies to treat ischemic stroke are limited due to the heterogeneity of cerebral ischemic injury and the mechanisms that contribute to the cell death. Since oxidative stress is one of the primary mechanisms that cause brain injury post-stroke, we hypothesized that therapeutic targets that modulate mitochondrial function could protect against reperfusion-injury after cerebral ischemia, with the focus here on a mitochondrial protein, mitoNEET, that modulates cellular bioenergetics.

Method: In this study, we evaluated the pharmacology of the mitoNEET ligand NL-1 in an in vivo therapeutic role for NL-1 in a C57Bl/6 murine model of ischemic stroke.

Results: NL-1 decreased hydrogen peroxide production with an IC of 5.95 μM in neuronal cells (N2A). The in vivo activity of NL-1 was evaluated in a murine 1 h transient middle cerebral artery occlusion (t-MCAO) model of ischemic stroke. We found that mice treated with NL-1 (10 mg/kg, i.p.) at time of reperfusion and allowed to recover for 24 h showed a 43% reduction in infarct volume and 68% reduction in edema compared to sham-injured mice. Additionally, we found that when NL-1 was administered 15 min post-t-MCAO, the ischemia volume was reduced by 41%, and stroke-associated edema by 63%.

Conclusion: As support of our hypothesis, as expected, NL-1 failed to reduce stroke infarct in a permanent photothrombotic occlusion model of stroke. This report demonstrates the potential therapeutic benefits of using mitoNEET ligands like NL-1 as novel mitoceuticals for treating reperfusion-injury with cerebral stroke.
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http://dx.doi.org/10.1007/s11095-021-03046-4DOI Listing
May 2021

Low-intensity Blast Wave Model for Preclinical Assessment of Closed-head Mild Traumatic Brain Injury in Rodents.

J Vis Exp 2020 11 6(165). Epub 2020 Nov 6.

Neuro-research, Dallas, TX;

Traumatic brain injury (TBI) is a large-scale public health problem. Mild TBI is the most prevalent form of neurotrauma and accounts for a large number of medical visits in the United States. There are currently no FDA-approved treatments available for TBI. The increased incidence of military-related, blast-induced TBI further accentuates the urgent need for effective TBI treatments. Therefore, new preclinical TBI animal models that recapitulate aspects of human blast-related TBI will greatly advance the research efforts into the neurobiological and pathophysiological processes underlying mild to moderate TBI as well as the development of novel therapeutic strategies for TBI. Here we present a reliable, reproducible model for the investigation of the molecular, cellular, and behavioral effects of mild to moderate blast-induced TBI. We describe a step-by-step protocol for closed-head, blast-induced mild TBI in rodents using a bench-top setup consisting of a gas-driven shock tube equipped with piezoelectric pressure sensors to ensure consistent test conditions. The benefits of the setup that we have established are its relative low-cost, ease of installation, ease of use and high-throughput capacity. Further advantages of this non-invasive TBI model include the scalability of the blast peak overpressure and the generation of controlled reproducible outcomes. The reproducibility and relevance of this TBI model has been evaluated in a number of downstream applications, including neurobiological, neuropathological, neurophysiological and behavioral analyses, supporting the use of this model for the characterization of processes underlying the etiology of mild to moderate TBI.
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http://dx.doi.org/10.3791/61244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179023PMC
November 2020

Exposure to mild blast forces induces neuropathological effects, neurophysiological deficits and biochemical changes.

Mol Brain 2018 11 9;11(1):64. Epub 2018 Nov 9.

Departments of Surgery, Neurobiology, and Neurology, The University of Alabama at Birmingham Medical Center, 1720 2nd Ave S, THT 1052, Birmingham, AL, 35294, USA.

Direct or indirect exposure to an explosion can induce traumatic brain injury (TBI) of various severity levels. Primary TBI from blast exposure is commonly characterized by internal injuries, such as vascular damage, neuronal injury, and contusion, without external injuries. Current animal models of blast-induced TBI (bTBI) have helped to understand the deleterious effects of moderate to severe blast forces. However, the neurological effects of mild blast forces remain poorly characterized. Here, we investigated the effects caused by mild blast forces combining neuropathological, histological, biochemical and neurophysiological analysis. For this purpose, we employed a rodent blast TBI model with blast forces below the level that causes macroscopic neuropathological changes. We found that mild blast forces induced neuroinflammation in cerebral cortex, striatum and hippocampus. Moreover, mild blast triggered microvascular damage and axonal injury. Furthermore, mild blast caused deficits in hippocampal short-term plasticity and synaptic excitability, but no impairments in long-term potentiation. Finally, mild blast exposure induced proteolytic cleavage of spectrin and the cyclin-dependent kinase 5 activator, p35 in hippocampus. Together, these findings show that mild blast forces can cause aberrant neurological changes that critically impact neuronal functions. These results are consistent with the idea that mild blast forces may induce subclinical pathophysiological changes that may contribute to neurological and psychiatric disorders.
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http://dx.doi.org/10.1186/s13041-018-0408-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225689PMC
November 2018

Reduction of Endothelial Nitric Oxide Increases the Adhesiveness of Constitutive Endothelial Membrane ICAM-1 through Src-Mediated Phosphorylation.

Front Physiol 2017 10;8:1124. Epub 2018 Jan 10.

Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, United States.

Nitric oxide (NO) is a known anti-adhesive molecule that prevents platelet aggregation and leukocyte adhesion to endothelial cells (ECs). The mechanism has been attributed to its role in the regulation of adhesion molecules on leukocytes and the adhesive properties of platelets. Our previous study conducted in rat venules found that reduction of EC basal NO synthesis caused EC ICAM-1-mediated firm adhesion of leukocytes within 10-30 min. This quick response occurred in the absence of alterations of adhesion molecules on leukocytes and also opposes the classical pattern of ICAM-1-mediated leukocyte adhesion that requires protein synthesis and occurs hours after stimulation. The objective of this study is to investigate the underlying mechanisms of reduced basal NO-induced EC-mediated rapid leukocyte adhesion observed in intact microvessels. The relative levels of ICAM-1 at different cell regions and their activation status were determined with cellular fractionation and western blot using cultured human umbilical vein ECs. ICAM-1 adhesiveness was determined by immunoprecipitation in non-denatured proteins to assess the changes in ICAM-1 binding to its inhibitory antibody, mAb1A29, and antibody against total ICAM-1 with and without NO reduction. The adhesion strength of EC ICAM-1 was assessed by atomic force microscopy (AFM) on live cells. Results showed that reduction of EC basal NO caused by the application of caveolin-1 scaffolding domain (AP-CAV) or NOS inhibitor, L-NMMA, for 30 min significantly increased phosphorylated ICAM-1 and its binding to mAb1A29 in the absence of altered ICAM-1 expression and its distribution at subcellular regions. The Src inhibitor, PP1, inhibited NO reduction-induced increases in ICAM-1 phosphorylation and adhesive binding. AFM detected significant increases in the binding force between AP-CAV-treated ECs and mAb1A29-coated probes. These results demonstrated that reduced EC basal NO lead to a rapid increase in ICAM-1 adhesive binding via Src-mediated phosphorylation without protein synthesis and translocation. This study suggests that a NO-dependent conformational change of constitutive EC membrane ICAM-1 might be the mechanism of rapid ICAM-1 dependent leukocyte adhesion observed . This new mechanistic insight provides a better understanding of EC/leukocyte interaction-mediated vascular inflammation under many disease conditions that encounter reduced basal NO in the circulation system.
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http://dx.doi.org/10.3389/fphys.2017.01124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768177PMC
January 2018

A mouse Model of Focal Vascular Injury Induces Astrocyte Reactivity, Tau Oligomers, and Aberrant Behavior.

Arch Neurosci 2017 Apr 30;4(2). Epub 2017 Apr 30.

Department of Pharmaceutical Sciences, West Virginia University School of Medicine, Morgantown, WV 26506-9530, USA.

Neuropsychiatric symptom development has become more prevalent with 270,000 blast exposures occurring in the past 10 years in the United States. How blast injury leads to neuropsychiatric symptomology is currently unknown. Preclinical models of blast-induced traumatic brain injury have been used to demonstrate blood-brain barrier disruption, degenerative pathophysiology, and behavioral deficits. Vascular injury is a primary effect of neurotrauma that can trigger secondary injury cascades and neurodegeneration. Here we present data from a novel scaled and clinically relevant mouse blast model that was specifically developed to assess the outcome of vascular injury. We look at the biochemical effects and behavioral changes associated with blast injury in young-adult male BALB/c mice. We report that blast exposure causes focal vascular injury in the Somatosensory Barrel Field cortex, which leads to perivascular astrocyte reactivity, as well as acute aberrant behavior. Biochemical analysis revealed that mild blast exposure also invokes tauopathy, neuroinflammation, and oxidative stress. Overall, we propose our model to be used to evaluate focal blood-brain barrier disruption and to discover novel therapies for human neuropsychiatric symptoms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529099PMC
http://dx.doi.org/10.5812/archneurosci.44254DOI Listing
April 2017

The role for infarct volume as a surrogate measure of functional outcome following ischemic stroke.

J Syst Integr Neurosci 2016 Dec 11;2(4). Epub 2016 Oct 11.

Department of Neurosurgery, School of Medicine, West Virginia University, Morgantown, West Virginia 26506, USA; Center for Neuroscience, School of Medicine, West Virginia University, Morgantown, West Virginia 26506, USA.

The failed translation of proposed therapeutic agents for ischemic stroke from preclinical to clinical studies has led to increased scrutiny of preclinical studies, namely the model and outcome measures utilized. Preclinical studies routinely use infarct volume as an experimental endpoint or measure in studies employing young-adult, healthy male animals despite the fact that clinically, ischemic stroke is a disease of the elderly and improvements in functional outcome from pre- to post-intervention remains the most widely utilized assessment. The validity of infarct volume as a surrogate measure for functional outcome remains unclear in clinical studies as well as preclinical studies, particularly those utilizing a more clinically relevant aged thromboembolic model. In this work, we will address the relationship between acute and chronic functional outcome and infarct volume using a variety of functional assessments ranging from more simplistic, subjective measurements such as the modified Neurologic Severity Score (mNSS), to more complex, objective measurements such as grip strength and inclined plane.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347398PMC
http://dx.doi.org/10.15761/JSIN.1000136DOI Listing
December 2016

Single low-dose lipopolysaccharide preconditioning: neuroprotective against axonal injury and modulates glial cells.

Neuroimmunol Neuroinflamm 2017 Jan 20;4:6-15. Epub 2017 Jan 20.

Department of Neurosurgery, West Virginia University, School of Medicine, Morgantown, WV 26506, USA; Center for Neuroscience, West Virginia University, School of Medicine, Morgantown, WV 26506, USA.

Aim: Over 7 million traumatic brain injuries (TBI) are reported each year in the United States. However, treatments and neuroprotection following TBI are limited because secondary injury cascades are poorly understood. Lipopolysaccharide (LPS) administration before controlled cortical impact can contribute to neuroprotection. However, the underlying mechanisms and whether LPS preconditioning confers neuroprotection against closed-head injuries remains unclear.

Methods: The authors hypothesized that preconditioning with a low dose of LPS (0.2 mg/kg) would regulate glial reactivity and protect against diffuse axonal injury induced by weight drop. LPS was administered 7 days prior to TBI. LPS administration reduced locomotion, which recovered completely by time of injury.

Results: LPS preconditioning significantly reduced the post-injury gliosis response near the corpus callosum, possibly by downregulating the oncostatin M receptor. These novel findings demonstrate a protective role of LPS preconditioning against diffuse axonal injury. LPS preconditioning successfully prevented neurodegeneration near the corpus callosum, as measured by fluorojade B.

Conclusion: Further work is required to elucidate whether LPS preconditioning confers long-term protection against behavioral deficits and to elucidate the biochemical mechanisms responsible for LPS-induced neuroprotective effects.
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http://dx.doi.org/10.20517/2347-8659.2016.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289820PMC
January 2017

Endoplasmic Reticulum Stress Modulation as a Target for Ameliorating Effects of Blast Induced Traumatic Brain Injury.

J Neurotrauma 2017 09 27;34(S1):S62-S70. Epub 2017 Feb 27.

1 Department of Neurosurgery, West Virginia University School of Medicine , Morgantown, West Virginia.

Blast traumatic brain injury (bTBI) has been shown to contribute to progressive neurodegenerative disease. Recent evidence suggests that endoplasmic reticulum (ER) stress is a mechanistic link between acute neurotrauma and progressive tauopathy. We propose that ER stress contributes to extensive behavioral changes associated with a chronic traumatic encephalopathy (CTE)-like phenotype. Targeting ER stress is a promising option for the treatment of neurotrauma-related neurodegeneration, which warrants investigation. Utilizing our validated and clinically relevant Sprague-Dawley blast model, we investigated a time course of mechanistic changes that occur following bTBI (50 psi) including: ER stress activation, iron-mediated toxicity, and tauopathy via Western blot and immunohistochemistry. These changes were associated with behavioral alterations measured by the Elevated Plus Maze (EPM), Forced Swim Test (FST), and Morris Water Maze (MWM). Following characterization, salubrinal, an ER stress modulator, was given at a concentration of 1 mg/kg post-blast, and its mechanism of action was determined in vitro. bTBI significantly increased markers of injury in the cortex of the left hemisphere: p-PERK and p-eIF2α at 30 min, p-T205 tau at 6 h, and iron at 24 h. bTBI animals spent more time immobile on the FST at 72 h and more time in the open arm of the EPM at 7 days. Further, bTBI caused a significant learning disruption measured with MWM at 21 days post-blast, with persistent tau changes. Salubrinal successfully reduced ER stress markers in vivo and in vitro while significantly improving performance on the EPM. bTBI causes robust biochemical changes that contribute to neurodegeneration, but these changes may be targeted with ER stress modulators.
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http://dx.doi.org/10.1089/neu.2016.4680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749601PMC
September 2017

Elucidating the role of compression waves and impact duration for generating mild traumatic brain injury in rats.

Brain Inj 2017 23;31(1):98-105. Epub 2016 Nov 23.

c Department of Aerospace Engineering , College of Engineering, Iowa State University , Ames , IA , USA.

Background: In total, 3.8 million concussions occur each year in the US leading to acute functional deficits, but the underlying histopathologic changes that occur are relatively unknown. In order to improve understanding of acute injury mechanisms, appropriately designed pre-clinical models must be utilized.

Methods: The clinical relevance of compression wave injury models revolves around the ability to produce consistent histopathologic deficits. Mild traumatic brain injuries activate similar neuroinflammatory cascades, cell death markers and increases in amyloid precursor protein in both humans and rodents. Humans, however, infrequently succumb to mild traumatic brain injuries and, therefore, the intensity and magnitude of impacts must be inferred. Understanding compression wave properties and mechanical loading could help link the histopathologic deficits seen in rodents to what might be happening in human brains following concussions.

Results: While the concept of linking duration and intensity of impact to subsequent histopathologic deficits makes sense, numerical modelling of compression waves has not been performed in this context. In this interdisciplinary work, numerical simulations were performed to study the creation of compression waves in an experimental model.

Conclusion: This work was conducted in conjunction with a repetitive compression wave injury paradigm in rats in order to better understand how the wave generation correlates with histopathologic deficits.
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http://dx.doi.org/10.1080/02699052.2016.1218547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247354PMC
January 2018

Behavioral and biochemical effects of ketamine and dextromethorphan relative to its antidepressant-like effects in Swiss Webster mice.

Neuroreport 2016 Sep;27(14):1004-11

Departments of aPharmaceutical SciencesbBehavioral Medicine and PsychiatrycPhysiology and PharmacologydNeurosurgery, School of Medicine and Pharmacy, West Virginia University, Morgantown, West VirginiaeCollege of Pharmacy, Touro University California, Vallejo, California, USA.

Ketamine has been shown to produce rapid and robust antidepressant effects in depressed individuals; however, its abuse potential and adverse psychotomimetic effects limit its widespread use. Dextromethorphan (DM) may serve as a safer alternative on the basis of pharmacodynamic similarities to ketamine. In this proof-of-concept study, behavioral and biochemical analyses were carried out to evaluate the potential involvement of brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of DM in mice, with comparisons to ketamine and imipramine. Male Swiss, Webster mice were injected with DM, ketamine, or imipramine and their behaviors were evaluated in the forced-swim test and the open-field test. Western blots were used to measure BDNF and its precursor, pro-BDNF, protein expression in the hippocampus and the frontal cortex of these mice. Our results show that both DM and imipramine reduced immobility time in the forced-swim test without affecting locomotor activity, whereas ketamine reduced immobility time and increased locomotor activity. Ketamine also rapidly (within 40 min) increased pro-BDNF expression in an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-dependent manner in the hippocampus, whereas DM and imipramine did not alter pro-BDNF or BDNF levels in either the hippocampus or the frontal cortex within this timeframe. These data show that DM shares some features with both ketamine and imipramine. Additional studies examining DM may aid in the development of more rapid, safe, and efficacious antidepressant treatments.
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http://dx.doi.org/10.1097/WNR.0000000000000646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020901PMC
September 2016

Salubrinal reduces oxidative stress, neuroinflammation and impulsive-like behavior in a rodent model of traumatic brain injury.

Brain Res 2016 07 27;1643:140-51. Epub 2016 Apr 27.

Department of Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, One Medical Center Drive, Morgantown, WV, United States; Department of Neurosurgery, School of Medicine, West Virginia University, Morgantown, WV, United States; Centers for Neuroscience, School of Medicine, West Virginia University, Morgantown, WV, United States. Electronic address:

Traumatic brain injury (TBI) is the leading cause of trauma related morbidity in the developed world. TBI has been shown to trigger secondary injury cascades including endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation. The link between secondary injury cascades and behavioral outcome following TBI is poorly understood warranting further investigation. Using our validated rodent blast TBI model, we examined the interaction of secondary injury cascades following single injury and how these interactions may contribute to impulsive-like behavior after a clinically relevant repetitive TBI paradigm. We targeted these secondary pathways acutely following single injury with the cellular stress modulator, salubrinal (SAL). We examined the neuroprotective effects of SAL administration on significantly reducing ER stress: janus-N-terminal kinase (JNK) phosphorylation and C/EBP homology protein (CHOP), oxidative stress: superoxide and carbonyls, and neuroinflammation: nuclear factor kappa beta (NFκB) activity, inducible nitric oxide synthase (iNOS) protein expression, and pro-inflammatory cytokines at 24h post-TBI. We then used the more clinically relevant repeat injury paradigm and observed elevated NFκB and iNOS activity. These injury cascades were associated with impulsive-like behavior measured on the elevated plus maze. SAL administration attenuated secondary iNOS activity at 72h following repetitive TBI, and most importantly prevented impulsive-like behavior. Overall, these results suggest a link between secondary injury cascades and impulsive-like behavior that can be modulated by SAL administration.
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http://dx.doi.org/10.1016/j.brainres.2016.04.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578618PMC
July 2016

Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review.

Int J Mol Sci 2016 Apr 2;17(4):497. Epub 2016 Apr 2.

Departments of Neurosurgery, Pathology, and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red blood cell breakdown products can lead to the release of inflammatory cytokines that trigger vasospasm and tissue injury. Preclinical models have been used successfully to improve understanding about neuroinflammation following aneurysmal rupture. The focus of this review is to provide an overview of how neuroinflammation relates to secondary outcomes such as vasospasm after aneurysmal rupture and to critically discuss pharmaceutical agents that warrant further investigation for the treatment of subarachnoid hemorrhage. We provide a concise overview of the neuroinflammatory pathways that are upregulated following aneurysmal rupture and how these pathways correlate to long-term outcomes. Treatment of aneurysm rupture is limited and few pharmaceutical drugs are available. Through improved understanding of biochemical mechanisms of injury, novel treatment solutions are being developed that target neuroinflammation. In the final sections of this review, we highlight a few of these novel treatment approaches and emphasize why targeting neuroinflammation following aneurysmal subarachnoid hemorrhage may improve patient care. We encourage ongoing research into the pathophysiology of aneurysmal subarachnoid hemorrhage, especially in regards to neuroinflammatory cascades and the translation to randomized clinical trials.
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http://dx.doi.org/10.3390/ijms17040497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848953PMC
April 2016

Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery.

Front Neurol 2015 26;6:223. Epub 2015 Oct 26.

Department of Neurosurgery, West Virginia University School of Medicine , Morgantown, WV , USA ; Center for Neuroscience, West Virginia University School of Medicine , Morgantown, WV , USA.

Despite the extensive media coverage associated with the diagnosis of chronic traumatic encephalopathy (CTE), our fundamental understanding of the disease pathophysiology remains in its infancy. Only recently have scientific laboratories and personnel begun to explore CTE pathophysiology through the use of preclinical models of neurotrauma. Some studies have shown the ability to recapitulate some aspects of CTE in rodent models, through the use of various neuropathological, biochemical, and/or behavioral assays. Many questions related to CTE development, however, remain unanswered. These include the role of impact severity, the time interval between impacts, the age at which impacts occur, and the total number of impacts sustained. Other important variables such as the location of impacts, character of impacts, and effect of environment/lifestyle and genetics also warrant further study. In this work, we attempt to address some of these questions by exploring work previously completed using single- and repetitive-injury paradigms. Despite some models producing some deficits similar to CTE symptoms, it is clear that further studies are required to understand the development of neuropathological and neurobehavioral features consistent with CTE-like features in rodents. Specifically, acute and chronic studies are needed that characterize the development of tau-based pathology.
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http://dx.doi.org/10.3389/fneur.2015.00223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620695PMC
November 2015

The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience.

Front Neurol 2015 20;6:222. Epub 2015 Oct 20.

Division of Neurosurgery, Rochester Regional Health , Rochester, NY , USA.

Chronic neurodegeneration following a history of neurotrauma is frequently associated with neuropsychiatric and cognitive symptoms. In order to enhance understanding about the underlying pathophysiology linking neurotrauma to neurodegeneration, a multi-model preclinical approach must be established to account for the different injury paradigms and pathophysiologic mechanisms. We investigated the development of tau pathology and behavioral changes using a multi-model and multi-institutional approach, comparing the preclinical results to tauopathy patterns seen in post-mortem human samples from athletes diagnosed with chronic traumatic encephalopathy (CTE). We utilized a scaled and validated blast-induced traumatic brain injury model in rats and a modified pneumatic closed-head impact model in mice. Tau hyperphosphorylation was evaluated by western blot and immunohistochemistry. Elevated-plus maze and Morris water maze were employed to measure impulsive-like behavior and cognitive deficits respectively. Animals exposed to single blast (~50 PSI reflected peak overpressure) exhibited elevated AT8 immunoreactivity in the contralateral hippocampus at 1 month compared to controls (q = 3.96, p < 0.05). Animals exposed to repeat blast (six blasts over 2 weeks) had increased AT8 (q = 8.12, p < 0.001) and AT270 (q = 4.03, p < 0.05) in the contralateral hippocampus at 1 month post-injury compared to controls. In the modified controlled closed-head impact mouse model, no significant difference in AT8 was seen at 7 days, however a significant elevation was detected at 1 month following injury in the ipsilateral hippocampus compared to control (q = 4.34, p < 0.05). Elevated-plus maze data revealed that rats exposed to single blast (q = 3.53, p < 0.05) and repeat blast (q = 4.21, p < 0.05) spent more time in seconds exploring the open arms compared to controls. Morris water maze testing revealed a significant difference between groups in acquisition times on days 22-27. During the probe trial, single blast (t = 6.44, p < 0.05) and repeat blast (t = 8.00, p < 0.05) rats spent less time in seconds exploring where the platform had been located compared to controls. This study provides a multi-model example of replicating tau and behavioral changes in animals and provides a foundation for future investigation of CTE disease pathophysiology and therapeutic development.
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http://dx.doi.org/10.3389/fneur.2015.00222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611965PMC
November 2015

Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure.

Seizure 2015 Dec 29;33:13-23. Epub 2015 Oct 29.

Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV 26506, USA; The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV 26506, USA. Electronic address:

Post-traumatic epilepsy continues to be a major concern for those experiencing traumatic brain injury. Post-traumatic epilepsy accounts for 10-20% of epilepsy cases in the general population. While seizure prophylaxis can prevent early onset seizures, no available treatments effectively prevent late-onset seizure. Little is known about the progression of neural injury over time and how this injury progression contributes to late onset seizure development. In this comprehensive review, we discuss the epidemiology and risk factors for post-traumatic epilepsy and the current pharmacologic agents used for treatment. We highlight limitations with the current approach and offer suggestions for remedying the knowledge gap. Critical to this pursuit is the design of pre-clinical models to investigate important mechanistic factors responsible for post-traumatic epilepsy development. We discuss what the current models have provided in terms of understanding acute injury and what is needed to advance understanding regarding late onset seizure. New model designs will be used to investigate novel pathways linking acute injury to chronic changes within the brain. Important components of this transition are likely mediated by toll-like receptors, neuroinflammation, and tauopathy. In the final section, we highlight current experimental therapies that may prove promising in preventing and treating post-traumatic epilepsy. By increasing understanding about post-traumatic epilepsy and injury expansion over time, it will be possible to design better treatments with specific molecular targets to prevent late-onset seizure occurrence following traumatic brain injury.
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http://dx.doi.org/10.1016/j.seizure.2015.10.002DOI Listing
December 2015

Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury.

Transl Res 2015 Dec 8;166(6):509-528.e1. Epub 2015 Sep 8.

The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa; Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WVa. Electronic address:

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.
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http://dx.doi.org/10.1016/j.trsl.2015.08.005DOI Listing
December 2015

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy.

J Neurosurg 2016 Mar 18;124(3):687-702. Epub 2015 Sep 18.

Department of Neurosurgery, West Virginia University School of Medicine;

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-3β. 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.
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http://dx.doi.org/10.3171/2015.3.JNS141802DOI Listing
March 2016

Bryostatin extends tPA time window to 6 h following middle cerebral artery occlusion in aged female rats.

Eur J Pharmacol 2015 Oct 17;764:404-412. Epub 2015 Jul 17.

Department of Basic Pharmaceutical Science, School of Pharmacy, United States. Electronic address:

Blood-brain barrier (BBB) disruption and hemorrhagic transformation (HT) following ischemic/reperfusion injury contributes to post-stroke morbidity and mortality. Bryostatin, a potent protein kinase C (PKC) modulator, has shown promise in treating neurological injury. In the present study, we tested the hypothesis that administration of bryostatin would reduce BBB disruption and HT following acute ischemic stroke; thus, prolonging the time window for administering recombinant tissue plasminogen activator (r-tPA). Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18-20-month-old female rats using an autologous blood clot with delayed r-tPA reperfusion. Bryostatin (or vehicle) was administered at 2 h post-MCAO and r-tPA was administered at 6 h post-MCAO. Functional assessment, lesion volume, and hemispheric swelling measurements were performed at 24 h post-MCAO. Assessment of BBB permeability, measurement of hemoglobin, assessment of matrix metalloproteinase (MMP) levels by gel zymography, and measurement of PKCε, PKCα, PKCδ expression by western blot were conducted at 24 h post-MCAO. Rats treated with bryostatin prior to r-tPA administration had decreased mortality and hemispheric swelling when compared with rats treated with r-tPA alone. Administration of bryostatin also limited BBB disruption and HT and down-regulated MMP-9 expression while up-regulating PKCε expression at 24 h post-MCAO. Bryostatin administration ameliorates BBB disruption and reduces the risk of HT by down-regulating MMP-9 activation and up-regulating PKCε. In this proof-of-concept study, bryostatin treatment lengthened the time-to-treatment window and enhanced the efficacy and safety of thrombolytic therapy.
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http://dx.doi.org/10.1016/j.ejphar.2015.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698807PMC
October 2015

Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury.

Compr Physiol 2015 Jul;5(3):1147-60

Department of Physiology and Pharmacology, West Virginia University, Health Sciences Center, Morgantown, West Virginia, USA.

Traumatic brain injury (TBI) is acquired from an external force, which can inflict devastating effects to the brain vasculature and neighboring neuronal cells. Disruption of vasculature is a primary effect that can lead to a host of secondary injury cascades. The primary effects of TBI are rapidly occurring while secondary effects can be activated at later time points and may be more amenable to targeting. Primary effects of TBI include diffuse axonal shearing, changes in blood-brain barrier (BBB) permeability, and brain contusions. These mechanical events, especially changes to the BBB, can induce calcium perturbations within brain cells producing secondary effects, which include cellular stress, inflammation, and apoptosis. These secondary effects can be potentially targeted to preserve the tissue surviving the initial impact of TBI. In the past, TBI research had focused on neurons without any regard for glial cells and the cerebrovasculature. Now a greater emphasis is being placed on the vasculature and the neurovascular unit following TBI. A paradigm shift in the importance of the vascular response to injury has opened new avenues of drug-treatment strategies for TBI. However, a connection between the vascular response to TBI and the development of chronic disease has yet to be elucidated. Long-term cognitive deficits are common amongst those sustaining severe or multiple mild TBIs. Understanding the mechanisms of cellular responses following TBI is important to prevent the development of neuropsychiatric symptoms. With appropriate intervention following TBI, the vascular network can perhaps be maintained and the cellular repair process possibly improved to aid in the recovery of cellular homeostasis.
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http://dx.doi.org/10.1002/cphy.c140057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573402PMC
July 2015

Sleep disruption and the sequelae associated with traumatic brain injury.

Neurosci Biobehav Rev 2015 Aug 6;55:68-77. Epub 2015 May 6.

The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV 26506, USA; Centers for Disease Control and Prevention-National Institute for Occupational Safety and Health, Morgantown, WV, USA. Electronic address:

Sleep disruption, which includes a loss of sleep as well as poor quality fragmented sleep, frequently follows traumatic brain injury (TBI) impacting a large number of patients each year in the United States. Fragmented and/or disrupted sleep can worsen neuropsychiatric, behavioral, and physical symptoms of TBI. Additionally, sleep disruption impairs recovery and can lead to cognitive decline. The most common sleep disruption following TBI is insomnia, which is difficulty staying asleep. The consequences of disrupted sleep following injury range from deranged metabolomics and blood brain barrier compromise to altered neuroplasticity and degeneration. There are several theories for why sleep is necessary (e.g., glymphatic clearance and metabolic regulation) and these may help explain how sleep disruption contributes to degeneration within the brain. Experimental data indicate disrupted sleep allows hyperphosphorylated tau and amyloid β plaques to accumulate. As sleep disruption may act as a cellular stressor, target areas warranting further scientific investigation include the increase in endoplasmic reticulum and oxidative stress following acute periods of sleep deprivation. Potential treatment options for restoring the normal sleep cycle include melatonin derivatives and cognitive behavioral therapy.
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http://dx.doi.org/10.1016/j.neubiorev.2015.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721255PMC
August 2015

Aging, the metabolic syndrome, and ischemic stroke: redefining the approach for studying the blood-brain barrier in a complex neurological disease.

Adv Pharmacol 2014 12;71:411-49. Epub 2014 Sep 12.

The Center for Neuroscience, West Virginia University, School of Medicine, Morgantown, West Virginia, USA; Department of Basic Pharmaceutical Sciences, West Virginia University, School of Pharmacy, Morgantown, West Virginia, USA. Electronic address:

The blood-brain barrier (BBB) has many important functions in maintaining the brain's immune-privileged status. Endothelial cells, astrocytes, and pericytes have important roles in preserving vasculature integrity. As we age, cell senescence can contribute to BBB compromise. The compromised BBB allows an influx of inflammatory cytokines to enter the brain. These cytokines lead to neuronal and glial damage. Ultimately, the functional changes within the brain can cause age-related disease. One of the most prominent age-related diseases is ischemic stroke. Stroke is the largest cause of disability and is third largest cause of mortality in the United States. The biggest risk factors for stroke, besides age, are results of the metabolic syndrome. The metabolic syndrome, if unchecked, quickly advances to outcomes that include diabetes, hypertension, cardiovascular disease, and obesity. The contribution from these comorbidities to BBB compromise is great. Some of the common molecular pathways activated include: endoplasmic reticulum stress, reactive oxygen species formation, and glutamate excitotoxicity. In this chapter, we examine how age-related changes to cells within the central nervous system interact with comorbidities. We then look at how comorbidities lead to increased risk for stroke through BBB disruption. Finally, we discuss key molecular pathways of interest with a focus on therapeutic targets that warrant further investigation.
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http://dx.doi.org/10.1016/bs.apha.2014.07.001DOI Listing
June 2015

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury.

Mol Neurobiol 2015 Dec 10;52(3):1119-1134. Epub 2014 Oct 10.

Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, 26506, USA.

Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCε (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.
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http://dx.doi.org/10.1007/s12035-014-8902-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000781PMC
December 2015

Common mechanisms of Alzheimer's disease and ischemic stroke: the role of protein kinase C in the progression of age-related neurodegeneration.

J Alzheimers Dis 2015 ;43(3):711-24

Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, USA The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA.

Ischemic stroke and Alzheimer's disease (AD), despite being distinct disease entities, share numerous pathophysiological mechanisms such as those mediated by inflammation, immune exhaustion, and neurovascular unit compromise. An important shared mechanistic link is acute and chronic changes in protein kinase C (PKC) activity. PKC isoforms have widespread functions important for memory, blood-brain barrier maintenance, and injury repair that change as the body ages. Disease states accelerate PKC functional modifications. Mutated forms of PKC can contribute to neurodegeneration and cognitive decline. In some cases the PKC isoforms are still functional but are not successfully translocated to appropriate locations within the cell. The deficits in proper PKC translocation worsen stroke outcome and amyloid-β toxicity. Cross talk between the innate immune system and PKC pathways contribute to the vascular status within the aging brain. Unfortunately, comorbidities such as diabetes, obesity, and hypertension disrupt normal communication between the two systems. The focus of this review is to highlight what is known about PKC function, how isoforms of PKC change with age, and what additional alterations are consequences of stroke and AD. The goal is to highlight future therapeutic targets that can be applied to both the treatment and prevention of neurologic disease. Although the pathology of ischemic stroke and AD are different, the similarity in PKC responses warrants further investigation, especially as PKC-dependent events may serve as an important connection linking age-related brain injury.
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http://dx.doi.org/10.3233/JAD-141422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446718PMC
August 2015

Sesamol: a Treatment for Diabetes-Associated Blood-Brain Barrier Dysfunction.

Postdoc J 2014 Jul;2(7):13-22

School of Pharmacy, West Virginia University, 5706 Medical Center Dr, Morgantown, WV 26505, USA.

Diabetes is a long-standing disease that leads to secondary complications of capillaries such as retinopathy, nephropathy and neuropathy. Emerging evidence suggests that diabetes may also affect the cerebromicrovasculature, the blood-brain barrier (BBB), and lead to changes in the brain that affect cognition and mood. Therefore, it is important to identify natural compounds that may have therapeutic benefit for reducing BBB dysfunction and improve patient quality of life. Preclinical evidence suggests that sesamol, a natural antioxidant in sesame seed oil, could have therapeutic benefit for treating BBB dysfunction during diabetes. Similarly, paroxetine, which shares a methylenedioxy moiety with sesamol shows clinical benefit for treating neuropathic pain associated with diabetes. This review emphasizes BBB dysfunction as a treatable secondary complication associated with diabetes and examines the evidence for the use of natural compounds like sesamol or existing therapies like paroxetine to help restore BBB function.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542572PMC
July 2014

Combination treatment of r-tPA and an optimized human apyrase reduces mortality rate and hemorrhagic transformation 6h after ischemic stroke in aged female rats.

Eur J Pharmacol 2014 Sep 13;738:368-73. Epub 2014 Jun 13.

Department of Neurosurgery, West Virginia University School of Medicine, Health Sciences Center, One Medical Center Drive, Suite 4300, PO Box 9183, Morgantown, WV 26506-9183, USA. Electronic address:

Recombinant tissue plasminogen activator (r-tPA) is the only FDA-approved drug treatment for ischemic stroke and must be used within 4.5h. Thrombolytic treatment with r-tPA has deleterious effects on the neurovascular unit that substantially increases the risk of intracerebral hemorrhage if administered too late. These therapeutic shortcomings necessitate additional investigation into agents that can extend the therapeutic window for safe use of thrombolytics. In this study, combination of r-tPA and APT102, a novel form of human apyrase/ADPase, was investigated in a clinically-relevant aged-female rat embolic ischemic stroke model. We propose that successfully extending the therapeutic window of r-tPA administration would represent a significant advance in the treatment of ischemic stroke due to a significant increase in the number of patients eligible for treatment. Results of our study showed significantly reduced mortality from 47% with r-tPA alone to 16% with co-administration of APT102 and r-tPA. Co-administration decreased cortical (47 ± 5% vs. 29 ± 5%), striatal (50 ± 2%, vs. 40 ± 3%) and total (48 ± 3%vs. 33 ± 4%) hemispheric infarct volume compared to r-tPA alone. APT102 improved neurological outcome (8.9±0.6, vs. 6.8 ± 0.8) and decreased hemoglobin extravasation in cortical tissue (1.9 ± 0.1mg/dl vs. 1.4 ± 0.1mg/dl) striatal tissue (2.1 ± 0.3mg/dl vs. 1.4 ± 0.1mg/dl) and whole brain tissue (2.0 ± 0.2mg/dl vs. 1.4 ± 0.1mg/dl). These data suggest that APT102 can safely extend the therapeutic window for r-tPA mediated reperfusion to 6h following experimental stroke without increased hemorrhagic transformation. APT102 offers to be a viable adjunct therapeutic option to increase the number of clinical patients eligible for thrombolytic treatment after ischemic stroke.
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http://dx.doi.org/10.1016/j.ejphar.2014.05.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126582PMC
September 2014

Ischemic stroke injury is mediated by aberrant Cdk5.

J Neurosci 2014 Jun;34(24):8259-67

Department of Psychiatry, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390,

Ischemic stroke is one of the leading causes of morbidity and mortality. Treatment options are limited and only a minority of patients receive acute interventions. Understanding the mechanisms that mediate neuronal injury and death may identify targets for neuroprotective treatments. Here we show that the aberrant activity of the protein kinase Cdk5 is a principal cause of neuronal death in rodents during stroke. Ischemia induced either by embolic middle cerebral artery occlusion (MCAO) in vivo or by oxygen and glucose deprivation in brain slices caused calpain-dependent conversion of the Cdk5-activating cofactor p35 to p25. Inhibition of aberrant Cdk5 during ischemia protected dopamine neurotransmission, maintained field potentials, and blocked excitotoxicity. Furthermore, pharmacological inhibition or conditional knock-out (CKO) of Cdk5 prevented neuronal death in response to ischemia. Moreover, Cdk5 CKO dramatically reduced infarctions following MCAO. Thus, targeting aberrant Cdk5 activity may serve as an effective treatment for stroke.
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http://dx.doi.org/10.1523/JNEUROSCI.4368-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051977PMC
June 2014

Metabolic Syndrome and its Profound Effect on Prevalence of Ischemic Stroke.

Am Med Stud Res J 2014 ;1(1):29-38

Department of Neurosurgery, West Virginia University, School of Medicine, Morgantown, West Virginia; The Center for Neuroscience, West Virginia University, School of Medicine, Morgantown, West Virginia.

Ischemic stroke represents a leading cause of death worldwide and the leading cause of disability in the United States. Greater than 8% of all deaths are attributed to ischemic stroke. This rate is consistent with the heightened burden of cardiovascular disease deaths. Treatments for acute ischemic stroke remain limited to tissue plasminogen activator and mechanical thrombolysis, both of which require significant medical expertise and can only be applied to a select number of patients based on time of presentation, imaging, and absence of contraindications. Over 1,000 compounds that were successful in treating ischemic stroke in animal models have failed to correlate to success in clinical trials. The search for alternative treatments is ongoing, drawing greater attention to the importance of preclinical models that more accurately represent the clinical population through incorporation of common risk factors. This work reviews the contribution of these commonly observed risk factors in the clinical population highlighting both the pathophysiology as well as current clinical diagnosis and treatment standards. We also highlight future potential therapeutic targets, areas requiring further investigation, and recent changes in best-practice clinical care.
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http://dx.doi.org/10.15422/amsrj.2014.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896644PMC
January 2014

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation.

Exp Neurol 2014 Apr 6;254:180-9. Epub 2014 Feb 6.

Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA; Center for Neuroscience, School of Medicine, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA. Electronic address:

Methamphetamine (METH) exposure results in dopaminergic neurotoxicity in striatal regions of the brain, an effect that has been linked to an increased risk of Parkinson's disease. Various aspects of neuroinflammation, including astrogliosis, are believed to be contributory factors in METH neurotoxicity. METH interacts with sigma receptors at physiologically relevant concentrations and treatment with sigma receptor antagonists has been shown to mitigate METH-induced neurotoxicity in rodent models. Whether these compounds alter the responses of glial cells within the central nervous system to METH however has yet to be determined. Therefore, the purpose of the current study was to determine whether the sigma receptor antagonist, SN79, mitigates METH-induced striatal reactive astrogliosis. Male, Swiss Webster mice treated with a neurotoxic regimen of METH exhibited time-dependent increases in striatal gfap mRNA and concomitant increases in GFAP protein, indicative of astrogliosis. This is the first report that similar to other neurotoxicants that induce astrogliosis through the activation of JAK2/STAT3 signaling by stimulating gp-130-linked cytokine signaling resulting from neuroinflammation, METH treatment also increases astrocytic oncostatin m receptor (OSMR) expression and the phosphorylation of STAT3 (Tyr-705) in vivo. Pretreatment with SN79 blocked METH-induced increases in OSMR, STAT3 phosphorylation and astrocyte activation within the striatum. Additionally, METH treatment resulted in striatal cellular degeneration as measured by Fluoro-Jade B, an effect that was mitigated by SN79. The current study provides evidence that sigma receptor antagonists attenuate METH-induced astrocyte activation through a pathway believed to be shared by various neurotoxicants.
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http://dx.doi.org/10.1016/j.expneurol.2014.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241368PMC
April 2014

Elucidating the severity of preclinical traumatic brain injury models: a role for functional assessment?

Neurosurgery 2014 Apr;74(4):382-94; discussion 394

*Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, West Virginia; ‡The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, West Virginia; §Department of Nursing, West Virginia University School of Medicine, Morgantown, West Virginia; ‖Department of Neurosurgery, NorthShore University Health System, University of Chicago Pritzker School of Medicine, Evanston, Illinois; ¶Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, West Virginia.

Background: Concussion remains a symptom-based diagnosis clinically, yet preclinical studies investigating traumatic brain injury, of which concussion is believed to represent a "mild" form, emphasize histological end points with functional assessments often minimized or ignored all together. Recently, clinical studies have identified the importance of cognitive and neuropsychiatric symptoms, in addition to somatic concerns, following concussion. How these findings may translate to preclinical studies is unclear at present.

Objective: To address the contrasting end points used clinically compared with those in preclinical studies and the potential role of functional assessments in a commonly used model of diffuse axonal injury (DAI).

Methods: Animals were subjected to DAI by the use of the impact-acceleration model. Functional and behavioral assessments were conducted during 1 week following DAI before the completion of the histological assessment at 1 week post-DAI.

Results: We show, despite the suggestion that this model represents concussive injury, no functional impairments as determined by using the common measures of motor, sensorimotor, cognitive, and neuropsychiatric function following injury over the course of 1 week. The lack of functional deficits is in sharp contrast to neuropathological findings indicating neural degeneration, astrocyte reactivity, and microglial activation.

Conclusion: Future studies are needed to identify functional assessments, neurophysiologic techniques, and imaging assessments more apt to distinguish differences following so-called "mild" traumatic brain injury in preclinical models and determine whether these models are truly studying concussive or subconcussive injury. These studies are needed not only to understand the mechanism of injury and production of subsequent deficits, but also to rigorously evaluate potential therapeutic agents.
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http://dx.doi.org/10.1227/NEU.0000000000000292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890645PMC
April 2014

A review of sleep deprivation studies evaluating the brain transcriptome.

Springerplus 2014 11;3:728. Epub 2014 Dec 11.

Toxicology and Molecular Biology Branch, CDC-NIOSH, 1095 Willowdale Rd, Morgantown, WV 26505 USA.

Epidemiological studies show a positive association between adequate sleep and good health. Further, disrupted sleep may increase the risk for CNS diseases, such as stroke and Alzheimer's disease. However, there has been limited progress in determining how sleep is linked to brain health or how sleep disruption may increase susceptibility to brain insult and disease. Animal studies can aid in understanding these links. In reviewing the animal literature related to the effects of sleep disruption on the brain, we found most of the work was directed toward investigating and characterizing the role of various brain areas or structures in initiating and regulating sleep. In contrast, limited effort has been directed towards understanding how sleep disruption alters the brain's health or susceptibility to insult. We also note many current studies have determined the changes in the brain following compromised sleep by examining, for example, the brain transcriptome or to a more limited extent the proteome. However, these studies have utilized almost exclusively total sleep deprivation (e.g., 24 out of 24 hours) paradigms or single short periods of limited acute sleep deprivation (e.g., 3 out of 24 hours). While such strategies are beneficial in understanding how sleep is controlled, they may not have much translational value for determining links between sleep and brain health or for determining how sleep disruption may increase brain susceptibility to insult. Surprisingly, few studies have determined how the duration and recurrence of sleep deprivation influence the effects seen after sleep deprivation. Our aim in this review was to identify relevant rodent studies from 1980 through 2012 and analyze those that use varying durations of sleep deprivation or restriction in their effort to evaluate the effects of sleep deprivation on the brain transcriptome and to a more limited extent the proteome. We examined how differences in the duration of sleep deprivation affect gene and protein expression to better understand the full consequences of repeated sleep disruption on the brain. Future research needs to consider and emphasize how the type and extent of the sleep deprivation exposure impacts the conclusions reached concerning the influence of sleep disruption on the brain. We identified relevant studies between 1980 and 2012 by searching the electronic databases of PubMed, Medline (Ovid), Embase (Ovid), and Web of Science using the terms "sleep" AND "disrupt", "deprivation", "restrict", "fragment", "loss", "disturb", "disorder", "dysfunction", "brain", "cortex", striatum", hypothalamus", "hippocampus", "gene", "protein", "genomics", "proteomics", "polymerase chain reaction", "pcr", "microarray", "molecular", "rodent" "rat", "rats", "mouse", "mice". All searches were limited to rodent studies in English and the reference lists of retrieved articles were searched for additional pertinent studies.
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http://dx.doi.org/10.1186/2193-1801-3-728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409616PMC
May 2015