Alan I. Faden

University of Maryland, Baltimore, Baltimore, Maryland, United States

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Publications (397)1952.19 Total impact

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    ABSTRACT: Aeromedical evacuation, an important component in the care of many traumatic brain injury patients, particularly in war zones, exposes them to prolonged periods of hypobaria. The effects of such exposure on pathophysiological changes and outcome following traumatic brain injury are largely unexplored. The objective of this study was to investigate whether prolonged hypobaria in rats subjected to traumatic brain injury alters behavioral and histological outcomes. Adult male Sprague-Dawley rats were subjected to fluid percussion induced injury at 1.5-1.9 atmospheres of pressure. The effects of hypobaric exposure (6 hour duration; equivalent to 0.75 atmospheres) at 6, 24, and 72 hours, or 7 days after TBI were evaluated with regard to sensorimotor, cognitive and histological changes. Additional groups were evaluated to determine the effects of two hypobaric exposures after traumatic brain injury, representing primary simulated aeromedical evacuation (6 hour duration at 24 hours after injury) and secondary evacuation (10 hour duration at 72 hours after injury), as well as the effects of 100% inspired oxygen concentrations (hyperoxia) during simulated evacuation. Hypobaric exposure up to 7 days following injury significantly worsened cognitive deficits, hippocampal neuronal cell loss and microglial/astrocyte activation in comparison to injured controls not exposed to hypobaria. Hyperoxia during hypobaric exposure, or two exposures to prolonged hypobaric conditions further exacerbated spatial memory deficits. These findings indicate that exposure to prolonged hypobaria up to 7 days after traumatic brain injury, even while maintaining physiological oxygen concentration, worsens long-term cognitive function and neuroinflammation. Multiple exposures or use of 100% oxygen further exacerbates these pathophysiological effects.
    Journal of Neurotrauma 11/2015; DOI:10.1089/neu.2015.4189 · 3.71 Impact Factor
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    ABSTRACT: Traumatic spinal cord injury (SCI) induces cell cycle activation (CCA) that contributes to secondary injury and related functional impairments such as motor deficits and hyperpathia. E2F1 and E2F2 are members of the activator sub-family of E2F transcription factors that play an important role in proliferating cells and in cell cycle-related neuronal death, but no comprehensive study have been performed in SCI to determine the relative importance of these factors. Here we examined the temporal distribution and cell-type specificity of E2F1 and E2F2 expression following mouse SCI, as well as the effects of genetic deletion of E2F1-2 on neuronal cell death, neuroinflammation and associated neurological dysfunction. SCI significantly increased E2F1 and E2F2 expression in active caspase-3(%) neurons/oligodendrocytes as well as in activated microglia/astrocytes. Injury-induced up-regulation of cell cycle-related genes and protein was significantly reduced by intrathecal injection of high specificity E2F decoy oligodeoxynucleotides against the E2F-binding site or in E2F1-2 null mice. Combined E2F1%2 siRNA treatment show greater neuroprotection in vivo than E2F1 or E2F2 single siRNA treatment. Knockout of both E2F1 and E2F2 genes (E2Fdko) significantly reduced neuronal death, neuroinflammation, and tissue damage, as well as limiting motor dysfunction and hyperpathia after SCI. Both CCA reduction and functional improvement in E2Fdko mice were greater than those in E2F2ko model. These studies demonstrate that SCI-induced activation of E2F1-2 mediates CCA, contributing to gliopathy and neuronal/tissue loss associated with motor impairments and post-traumatic hyperesthesia. Thus, E2F1-2 provide a therapeutic target for decreasing secondary tissue damage and promoting recovery of function after SCI.
    Cell cycle (Georgetown, Tex.) 10/2015; DOI:10.1080/15384101.2015.1104436 · 4.57 Impact Factor
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    ABSTRACT: Activated microglia and macrophages exert dual beneficial and detrimental roles after CNS injury, which are thought to be due to their polarization along a continuum from a classical pro-inflammatory M1-like state to an alternative anti-inflammatory M2-like state. The goal of the present study was to analyze the temporal dynamics of microglia/macrophage polarization within the lesion microenvironment following traumatic brain injury (TBI), using a moderate-level controlled cortical impact model in mice. We performed a detailed phenotypic analysis of M1- and M2-like polarized microglia/macrophages, as well as NADPH oxidase (NOX2) expression, through 7 days post-injury using qPCR, flow cytometry and image analyses. We demonstrated that microglia/macrophages express both M1- and M2-like phenotypic markers early after TBI, but the transient up-regulation of the M2-like phenotype was replaced by a predominant M1- or mixed Mtransition (Mtran) phenotype that expressed high levels of NOX2 at 7 days post-injury. The shift towards the M1-like and Mtran phenotype was associated with increased cortical and hippocampal neurodegeneration. In a follow up study we administered a selective NOX2 inhibitor, gp91ds-tat, to CCI mice starting at 24 hours post-injury to investigate the relationship between NOX2 and M1-like/Mtran phenotypes. Delayed gp91ds-tat treatment altered M1-/M2-like balance in favor of the anti-inflammatory M2-like phenotype, and significantly reduced oxidative damage in neurons at 7 days post-injury. Therefore, our data suggest that despite M1-like and M2-like polarized microglia/macrophages being activated after TBI, the early M2-like response becomes dysfunctional over time resulting in development of pathological M1-like and Mtran phenotypes driven by increased NOX2 activity.
    Journal of neurotrauma 10/2015; DOI:10.1089/neu.2015.4268 · 3.71 Impact Factor
  • B Sabirzhanov · B A Stoica · Z Zhao · D J Loane · J Wu · S G Dorsey · A I Faden ·
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    ABSTRACT: Traumatic brain injury (TBI) is a leading cause of mortality and disability. MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression at post-transcriptional level and may be key modulators of neuronal apoptosis, yet their role in secondary injury after TBI remains largely unexplored. Changes in miRs after controlled cortical impact (CCI) in mice were examined during the first 72 h using miR arrays and qPCR. One selected miR (711) was examined with regard to its regulation and relation to cell death; effects of miR-711 modulation were evaluated after CCI and using in vitro cell death models of primary cortical neurons. Levels of miR-711 were increased in the cortex early after TBI and in vitro models through rapid upregulation of miR-711 transcription (pri-miR-711) rather than catabolism. Increases coincided with downregulation of the pro-survival protein Akt, a predicted target of miR-711, with sequential activation of forkhead box O3 (FoxO3)a/glycogen synthase kinase 3 (GSK3)α/β, pro-apoptotic BH3-only molecules PUMA (Bcl2-binding component 3) and Bim (Bcl2-like 11 (apoptosis facilitator)), and mitochondrial release of cytochrome c and AIF. miR-711 and Akt (mRNA) co-immunoprecipitated with the RNA-induced silencing complex (RISC). A miR-711 hairpin inhibitor attenuated the apoptotic mechanisms and decreased neuronal death in an Akt-dependent manner. Conversely, a miR-711 mimic enhanced neuronal apoptosis. Central administration of the miR-711 hairpin inhibitor after TBI increased Akt expression and attenuated apoptotic pathways. Treatment reduced cortical lesion volume, neuronal cell loss in cortex and hippocampus, and long-term neurological dysfunction. miR-711 changes contribute to neuronal cell death after TBI, in part by inhibiting Akt, and may serve as a novel therapeutic target.Cell Death and Differentiation advance online publication, 16 October 2015; doi:10.1038/cdd.2015.132.
    Cell death and differentiation 10/2015; DOI:10.1038/cdd.2015.132 · 8.18 Impact Factor
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    ABSTRACT: Neuroinflammation following traumatic brain injury (TBI) is increasingly recognized to contribute to chronic tissue loss and neurologic dysfunction. Circulating levels of S100B increase after TBI and have been used as a biomarker. S100B is produced by activated astrocytes and can promote microglial activation; signaling by S100B through interaction with the multiligand advanced glycation end product-specific receptor (AGER) has been implicated in brain injury and microglial activation during chronic neurodegeneration. We examined the effects of S100B inhibition in a controlled cortical impact model, using S100B knockout mice or administration of neutralizing S100B antibody. Both interventions significantly reduced TBI-induced lesion volume, improved retention memory function, and attenuated microglial activation. The neutralizing antibody also significantly reduced sensorimotor deficits and improved neuronal survival in the cortex. However, S100B did not alter microglial activation in BV2 cells or primary microglial cultures stimulated by lipopolysaccharide or interferon gamma. Further, proximity ligation assays did not support direct interaction in the brain between S100B and AGER following TBI. Future studies are needed to elucidate specific pathways underlying S100B-mediated neuroinflammatory actions after TBI. Our results strongly implicate S100B in TBI-induced neuroinflammation, cell loss, and neurologic dysfunction, thereby indicating that it is a potential therapeutic target for TBI.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 July 2015; doi:10.1038/jcbfm.2015.165.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2015; DOI:10.1038/jcbfm.2015.165 · 5.41 Impact Factor
  • Alan I Faden · Junfang Wu · Bogdan A Stoica · David J Loane ·
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    ABSTRACT: Traumatic brain injury (TBI) has been linked to dementia and chronic neurodegeneration. Described initially in boxers and currently recognized across high contact sports, the association between repeated concussion (mild TBI) and progressive neuropsychiatric abnormalities has recently received widespread attention, and has been termed chronic traumatic encephalopathy (CTE). Less well appreciated are cognitive changes associated with neurodegeneration in the brain after isolated spinal cord injury (SCI). Also under-recognized is the role of sustained neuroinflammation after brain or spinal cord trauma, even though this relationship has been known since the 1950's and is supported by more recent pre-clinical and clinical studies. These pathological mechanisms, manifested by extensive microglial and astroglial activation and appropriately termed chronic traumatic brain inflammation (CTBI) or chronic traumatic inflammatory encephalopathy (CTIE), may be among the most important causes of posttraumatic neurodegeneration in terms of prevalence. Importantly, emerging experimental work demonstrates that persistent neuroinflammation can cause progressive neurodegeneration that may be treatable even weeks after traumatic injury. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13179 · 4.84 Impact Factor
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    ABSTRACT: Neuroprotective strategies that limit secondary tissue loss and/or improve functional outcomes have been identified in multiple animal models of ischemic, hemorrhagic, traumatic and nontraumatic cerebral lesions. However, use of these potential interventions in human randomized controlled studies has generally given disappointing results. In this paper, we summarize the current status in terms of neuroprotective strategies, both in the immediate and later stages of acute brain injury in adults. We also review potential new strategies and highlight areas for future research.
    Critical care (London, England) 04/2015; 19(1):186. DOI:10.1186/s13054-015-0887-8 · 4.48 Impact Factor
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    ABSTRACT: Positive allosteric modulators (PAMs) binding to the transmembrane (TM) domain of metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for psychiatric disorders and traumatic brain injury (TBI). Novel PAMs based on a trans-2-phenylcyclopropane amide scaffold have been designed and synthesized. Facilitating ligand design and allowing estimation of binding affinities to the mGluR5 TM domain was the novel computational strategy, site identification by ligand competitive saturation (SILCS). The potential protective activity of the new compounds was evaluated using nitric oxide (NO) production in BV2 microglial cell cultures treated with lipopolysaccharide (LPS), and the toxicity of the new compounds tested using a cell viability assay. One of the new compounds, 3a, indicated promising activity with potency of 30μM, which is 4.5-fold more potent than its lead compound 3,3'-difluorobenzaldazine (DFB), and showed no detectable toxicity with concentrations as high as 1000μM. Thus this compound represents a new lead for possible development as treatment for TBI and related neurodegenerative disorders. Copyright © 2015. Published by Elsevier Ltd.
    Bioorganic & medicinal chemistry letters 04/2015; 25(11). DOI:10.1016/j.bmcl.2015.04.042 · 2.42 Impact Factor
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    Marta M Lipinski · Junfang Wu · Alan I Faden · Chinmoy Sarkar ·
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    ABSTRACT: Significance: Traumatic brain injury (TBI) and spinal cord injury (SCI) are major causes of death and long-term disability worldwide. Despite important pathophysiological differences between these disorders, in many respects, mechanisms of injury are similar. During both TBI and SCI, some cells are directly mechanically injured, but more die as a result of injury-induced biochemical changes (secondary injury). Autophagy, a lysosome-dependent cellular degradation pathway with neuroprotective properties, has been implicated both clinically and experimentally in the delayed response to TBI and SCI. However, until recently, its mechanisms and function remained unknown, reflecting in part the difficulty of isolating autophagic processes from ongoing cell death and other cellular events. Recent advances: Emerging data suggest that depending on the location and severity of traumatic injury, autophagy flux-defined as the progress of cargo through the autophagy system and leading to its degradation-may be either increased or decreased after central nervous system trauma. Critical issues: While increased autophagy flux may be protective after mild injury, after more severe trauma inhibition of autophagy flux may contribute to neuronal cell death, indicating disruption of autophagy as a part of the secondary injury mechanism. Future directions: Augmentation and/or restoration of autophagy flux may provide a potential therapeutic target for treatment of TBI and SCI. Development of those treatments will require thorough characterization of changes in autophagy flux, its mechanisms and function over time after injury. Antioxid. Redox Signal. 23, 565-577.
    Antioxidants & Redox Signaling 03/2015; 23(6). DOI:10.1089/ars.2015.6306 · 7.41 Impact Factor
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    ABSTRACT: Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for treating traumatic brain injury (TBI). Using computational and medicinal methods, the structure-activity relationship of a class of acyl-2-aminobenzimidazoles (1-26) is reported. The new compounds are designed based on the chemical structure of 3,3'-difluorobenzaldazine (DFB), a known mGluR5 PAM. Ligand design and prediction of binding affinities of the new compounds have been performed using the site identification by ligand competitive saturation (SILCS) method. Binding affinities of the compounds to the transmembrane domain of mGluR5 have been evaluated using nitric oxide (NO) production assay, while the safety of the compounds is tested. One new compound found in this study, compound 22, showed promising activity with an IC50 value of 6.4μM, which is ∼20 fold more potent than that of DFB. Compound 22 represents a new lead for possible development as a treatment for TBI and related neurodegenerative conditions. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry 03/2015; 23(9). DOI:10.1016/j.bmc.2015.02.054 · 2.79 Impact Factor
  • David J Loane · Bogdan A Stoica · Alan I Faden ·
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    ABSTRACT: Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. To establish more effective neuroprotective treatments for TBI it is essential to better understand the complex cellular and molecular events that contribute to secondary injury. Here we critically review relevant research related to causes and modulation of delayed tissue damage, with particular emphasis on cell death mechanisms and post-traumatic neuroinflammation. We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific "laser"-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation. © 2015 Elsevier B.V. All rights reserved.
    Handbook of Clinical Neurology 02/2015; 127:343-66. DOI:10.1016/B978-0-444-52892-6.00022-2
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    S Liu · C Sarkar · M Dinizo · A I Faden · E Y Koh · M M Lipinski · J Wu ·
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    ABSTRACT: Autophagy is a catabolic mechanism facilitating degradation of cytoplasmic proteins and organelles in a lysosome-dependent manner. Autophagy flux is necessary for normal neuronal homeostasis and its dysfunction contributes to neuronal cell death in several neurodegenerative diseases. Elevated autophagy has been reported after spinal cord injury (SCI); however, its mechanism, cell type specificity and relationship to cell death are unknown. Using a rat model of contusive SCI, we observed accumulation of LC3-II-positive autophagosomes starting at posttrauma day 1. This was accompanied by a pronounced accumulation of autophagy substrate protein p62, indicating that early elevation of autophagy markers reflected disrupted autophagosome degradation. Levels of lysosomal protease cathepsin D and numbers of cathepsin-D-positive lysosomes were also decreased at this time, suggesting that lysosomal damage may contribute to the observed defect in autophagy flux. Normalization of p62 levels started by day 7 after SCI, and was associated with increased cathepsin D levels. At day 1 after SCI, accumulation of autophagosomes was pronounced in ventral horn motor neurons and dorsal column oligodendrocytes and microglia. In motor neurons, disruption of autophagy strongly correlated with evidence of endoplasmic reticulum (ER) stress. As autophagy is thought to protect against ER stress, its disruption after SCI could contribute to ER-stress-induced neuronal apoptosis. Consistently, motor neurons showing disrupted autophagy co-expressed ER-stress-associated initiator caspase 12 and cleaved executioner caspase 3. Together, these findings indicate that SCI causes lysosomal dysfunction that contributes to autophagy disruption and associated ER-stress-induced neuronal apoptosis.
    Cell Death & Disease 01/2015; 6(1):e1582. DOI:10.1038/cddis.2014.527 · 5.01 Impact Factor
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    Alan I Faden · David J Loane ·
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    ABSTRACT: It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).
    Journal of the American Society for Experimental NeuroTherapeutics 11/2014; 12(1). DOI:10.1007/s13311-014-0319-5 · 5.05 Impact Factor
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    ABSTRACT: Physical activity can attenuate neuronal loss, reduce neuroinflammation and facilitate recovery after brain injury. However, little is known about the mechanisms of exercise-induced neuroprotection after traumatic brain injury (TBI), or its modulation of posttraumatic neuronal cell death. Voluntary exercise using a running wheel was conducted for 4 weeks immediately preceding (preconditioning) moderate level controlled cortical impact (CCI), a well-established experimental TBI model in mice. Compared to non-exercised controls, exercise preconditioning (pre-exercise) improved recovery of sensorimotor performance in the beam walk task, and cognitive/affective functions in the Morris water maze, novel object recognition, and tail-suspension tests. Furthermore, pre-exercise reduced the lesion size; attenuated neuronal loss in the hippocampus, cortex and thalamus; and decreased microglial activation in the cortex. In addition, exercise preconditioning activated the BDNF pathway before trauma and amplified the injury-dependent increased in HSP70 expression, thus attenuating key apoptotic pathways. The latter include reduction in CCI-induced up-regulation of pro-apoptotic BH3-only Bcl-2 family molecules (Bid, Puma); decreased mitochondria permeabilization with attenuated release of cytochrome c and AIF; reduced AIF translocation to the nucleus and attenuated caspase activation. Given these neuroprotective actions, voluntary physical exercise may serve to limit the consequences of TBI.
    Journal of Neurotrauma 11/2014; 32(17). DOI:10.1089/neu.2014.3739 · 3.71 Impact Factor
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    ABSTRACT: Dysregulation of autophagy contributes to neuronal cell death in several neurodegenerative and lysosomal storage diseases. Markers of autophagy are also increased after traumatic brain injury (TBI), but its mechanisms and function are not known. Following controlled cortical impact (CCI) brain injury in GFP-Lc3 (green fluorescent protein-LC3) transgenic mice, we observed accumulation of autophagosomes in ipsilateral cortex and hippocampus between 1 and 7 d. This accumulation was not due to increased initiation of autophagy but rather to a decrease in clearance of autophagosomes, as reflected by accumulation of the autophagic substrate SQSTM1/p62 (sequestosome 1). This was confirmed by ex vivo studies, which demonstrated impaired autophagic flux in brain slices from injured as compared to control animals. Increased SQSTM1 peaked at d 1-3 but resolved by d 7, suggesting that the defect in autophagy flux is temporary. The early impairment of autophagy is at least in part caused by lysosomal dysfunction, as evidenced by lower protein levels and enzymatic activity of CTSD (cathepsin D). Furthermore, immediately after injury both autophagosomes and SQSTM1 accumulated predominantly in neurons. This was accompanied by appearance of SQSTM1 and ubiquitin-positive puncta in the affected cells, suggesting that, similar to the situation observed in neurodegenerative diseases, impaired autophagy may contribute to neuronal injury. Consistently, GFP-LC3 and SQSTM1 colocalized with markers of both caspase-dependent and caspase-independent cell death in neuronal cells proximal to the injury site. Taken together, our data indicated for the first time that autophagic clearance is impaired early after TBI due to lysosomal dysfunction, and correlates with neuronal cell death.
    Autophagy 11/2014; 10(12). DOI:10.4161/15548627.2014.981787 · 11.75 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) can cause sleep-wake disturbances and excessive daytime sleepiness. However, the pathobiology of sleep disorders in TBI is not well understood and animal models have been underutilized in studying such changes and potential underlying mechanisms. Here we used the rat lateral fluid percussion (LFP) model to analyze sleep-wake patterns as a function of time after injury. Rapid-eye movement sleep (REM), non-REM sleep (NREM), and wake bouts during light and dark phases were measured with electroencephalography (EEG) and electromyography (EMG) at an early as well as chronic time points following LFP. Moderate TBI caused disturbances in ability to maintain consolidated wake bouts during the active phase and chronic loss of wakefulness. Furthermore, TBI resulted in cognitive impairments and depressive-like symptoms, and reduced the number of Orexin-A (ORX-A)-positive neurons in the lateral hypothalamus.
    Journal of Neurotrauma 09/2014; 32(5). DOI:10.1089/neu.2014.3664 · 3.71 Impact Factor

  • ChemInform 09/2014; 45(35). DOI:10.1002/chin.201435181
  • Shruti V. Kabadi · Alan I. Faden ·
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    ABSTRACT: Traumatic brain injury induces secondary injury that contributes to neuroinflammation, neuronal loss, and neurological dysfunction. One important injury mechanism is cell cycle activation which causes neuronal apoptosis and glial activation. The neuroprotective effects of both non-selective (Flavopiridol) and selective (Roscovitine and CR-8) cyclin-dependent kinase inhibitors have been shown across multiple experimental traumatic brain injury models and species. Cyclin-dependent kinaseinhibitors, administered as a single systemic dose up to 24 hours after traumatic brain injury, provide strong neuroprotection-reducing neuronal cell death, neuroinflammation and neurological dysfunction. Given their effectiveness and long therapeutic window, cyclin-dependent kinase inhibitors appear to be promising candidates for clinical traumatic brain injury trials.
    Neural Regeneration Research 09/2014; 9(17):1578-1580. DOI:10.4103/1673-5374.141779 · 0.22 Impact Factor
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    ABSTRACT: Experimental spinal cord injury (SCI) causes chronic neuropathic pain associated with inflammatory changes in thalamic pain regulatory sites. Our recent studies examining chronic pain mechanisms after rodent SCI showed chronic inflammatory changes not only in thalamus, but also in other regions including hippocampus and cerebral cortex. Because changes appeared similar to those in our rodent TBI models that are associated with neurodegeneration and neurobehavioral dysfunction, we examined effects of mouse SCI on cognition, depressive-like behavior, and brain inflammation. SCI caused spatial and retention memory impairment and depressive-like behavior, as evidenced by poor performance in the Morris water maze, Y-maze, novel objective recognition, step-down passive avoidance, tail suspension, and sucrose preference tests. SCI caused chronic microglial activation in the hippocampus and cerebral cortex, where microglia with hypertrophic morphologies and M1 phenotype predominated. Stereological analyses showed significant neuronal loss in the hippocampus at 12 weeks but not 8 d after injury. Increased cell-cycle-related gene (cyclins A1, A2, D1, E2F1, and PCNA) and protein (cyclin D1 and CDK4) expression were found chronically in hippocampus and cerebral cortex. Systemic administration of the selective cyclin-dependent kinase inhibitor CR8 after SCI significantly reduced cell cycle gene and protein expression, microglial activation and neurodegeneration in the brain, cognitive decline, and depression. These studies indicate that SCI can initiate a chronic brain neurodegenerative response, likely related to delayed, sustained induction of M1-type microglia and related cell cycle activation, which result in cognitive deficits and physiological depression.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2014; 34(33):10989-11006. DOI:10.1523/JNEUROSCI.5110-13.2014 · 6.34 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression at the post-transcriptional level. To identify miRs that may regulate neuronal cell death after experimental traumatic brain injury (TBI), we profiled miR expression changes during the first several days after controlled cortical impact (CCI) in mice. miR-23a and miR-27a were rapidly downregulated in the injured cortex in the first hour after TBI. These changes coincided with increased expression of the proapoptotic Bcl-2 family members Noxa, Puma, and Bax. In an etoposide-induced in vitro model of apoptosis in primary cortical neurons, miR-23a and miR-27a were markedly downregulated as early as 1 h after exposure, before the upregulation of proapoptotic Bcl-2 family molecules. Administration of miR-23a and miR-27a mimics attenuated etoposide-induced changes in Noxa, Puma, and Bax, reduced downstream markers of caspase-dependent (cyto-chrome c release and caspase activation) and caspase-independent (apoptosis-inducing factor release) pathways, and limited neuronal cell death. In contrast, miRs hairpin inhibitors enhanced etoposide-induced neuronal apoptosis and caspase activation. Importantly, administration of miR-23a and miR-27a mimics significantly reduced activation of Puma, Noxa, and Bax as well as attenuated markers of caspase-dependent and -independent apoptosis after TBI. Furthermore, miR-23a and miR-27a mimics significantly attenuated cortical lesion volume and neuronal cell loss in the hippocampus after TBI. These findings indicate that post-traumatic decreases in miR-23a and miR-27a contribute to neuronal cell death after TBI by upregulating proapoptotic Bcl-2 family members, thus providing a novel thera-peutic target.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2014; 34(30):10055-71. DOI:10.1523/JNEUROSCI.1260-14.2014. · 6.34 Impact Factor

Publication Stats

19k Citations
1,952.19 Total Impact Points


  • 2010-2015
    • University of Maryland, Baltimore
      • • Department of Anatomy and Neurobiology
      • • Department of Anesthesiology
      • • Shock, Trauma and Anesthesiology Research Organized Research Center (STAR-ORC)
      Baltimore, Maryland, United States
    • Loyola University Maryland
      Baltimore, Maryland, United States
  • 2014
    • University of Baltimore
      Baltimore, Maryland, United States
  • 1992-2011
    • Georgetown University
      • • Department of Neuroscience
      • • Division of Neurology
      • • Institute for Cognitive and Computational Sciences
      Washington, D. C., DC, United States
  • 1998-2008
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 1981-2006
    • Uniformed Services University of the Health Sciences
      • Department of Neurology
      Maryland, United States
  • 2004
    • University of Adelaide
      Tarndarnya, South Australia, Australia
  • 1995
    • Chiba University
      Tiba, Chiba, Japan
  • 1985-1995
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Department of Neurology
      San Francisco, California, United States
  • 1994
    • University of Pennsylvania
      • Department of Neurosurgery
      Filadelfia, Pennsylvania, United States
  • 1989-1994
    • James Cook University
      • School of Pharmacy and Molecular Sciences
      Townsville, Queensland, Australia
    • CSU Mentor
      Long Beach, California, United States
  • 1990
    • University of California, Berkeley
      • Division of Neurobiology
      Berkeley, California, United States
  • 1985-1988
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 1984
    • Eli Lilly
      Indianapolis, Indiana, United States
  • 1983
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
    • Adventist University of Health Sciences
      Orlando, Florida, United States
  • 1978-1983
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States
  • 1980
    • Walter Reed National Military Medical Center
      Washington, Washington, D.C., United States