A I Faden

University of Baltimore, Baltimore, Maryland, United States

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Publications (368)1691.63 Total impact

  • [Show abstract] [Hide abstract]
    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;
  • ChemInform 09/2014; 45(35).
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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.
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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.
    Journal of Neuroscience. 07/2014; 34(30):10055-71.
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    ABSTRACT: 1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea (5a), a key intermediate for the preparation of agonists of metabotropic glutamate receptor 5, in one-step when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-keto carboxylic acids.
    Tetrahedron Letters 07/2014; 55(4):842–844. · 2.40 Impact Factor
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    ABSTRACT: Cognitive dysfunction has been reported in patients with spinal cord injury (SCI), but it has been questioned whether such changes may reflect concurrent head injury, and the issue has not been addressed mechanistically or in a well-controlled experimental model. Our recent rodent studies examining SCI-induced hyperesthesia revealed neuroinflammatory changes not only in supratentorial pain-regulatory sites, but also in other brain regions, suggesting that additional brain functions may be impacted following SCI. Here we examined effects of isolated thoracic SCI in rats on cognition, brain inflammation, and neurodegeneration. We show for the first time that SCI causes widespread microglial activation in the brain, with increased expression of markers for activated microglia/macrophages, including translocator protein and chemokine ligand 21 (C-C motif). Stereological analysis demonstrated significant neuronal loss in the cortex, thalamus, and hippocampus. SCI caused chronic impairment in spatial, retention, contextual, and fear-related emotional memory-evidenced by poor performance in the Morris water maze, novel objective recognition, and passive avoidance tests. Based on our prior work implicating cell cycle activation (CCA) in chronic neuroinflammation after SCI or traumatic brain injury, we evaluated whether CCA contributed to the observed changes. Increased expression of cell cycle-related genes and proteins was found in hippocampus and cortex after SCI. Posttraumatic brain inflammation, neuronal loss, and cognitive changes were attenuated by systemic post-injury administration of a selective cyclin-dependent kinase inhibitor. These studies demonstrate that chronic brain neurodegeneration occurs after isolated SCI, likely related to sustained microglial activation mediated by cell cycle activation.
    Cell cycle (Georgetown, Tex.) 06/2014; 13(15). · 5.24 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) causes microglial activation and related neurotoxicity that contributes to chronic neurodegeneration and loss of neurological function. Selective activation of metabotropic glutamate receptor 5 (mGluR5) by the orthosteric agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), is neuroprotective in experimental models of TBI, and has potent anti-inflammatory effects in vitro. However, the therapeutic potential of CHPG is limited due to its relatively weak potency and brain permeability. Highly potent, selective and brain penetrant mGluR5 positive allosteric modulators (PAMs) have been developed and show promise as therapeutic agents. We evaluated the therapeutic potential of a novel mGluR5 PAM, VU0360172, after controlled cortical impact (CCI) in mice. Vehicle, VU0360172, or VU0360172 plus mGluR5 antagonist (MTEP), were administered systemically to CCI mice at 3 h post-injury; lesion volume, hippocampal neurodegeneration, microglial activation, and functional recovery were assessed through 28 days post-injury. Anti-inflammatory effects of VU0360172 were also examined in vitro using BV2 and primary microglia. VU0360172 treatment significantly reduced the lesion, attenuated hippocampal neurodegeneration, and improved motor function recovery after CCI. Effects were mediated by mGluR5 as co-administration of MTEP blocked the protective effects of VU0360172. VU0360172 significantly reduced CD68 and NOX2 expression in activated microglia in the cortex at 28 days post-injury, and also suppressed pro-inflammatory signaling pathways in BV2 and primary microglia. In addition, VU0360172 treatment shifted the balance between M1/M2 microglial activation states towards an M2 pro-repair phenotype. This study demonstrates that VU0360172 confers neuroprotection after experimental TBI, and suggests that mGluR5 PAMs may be promising therapeutic agents for head injury. © 2014 The American Society for Experimental NeuroTherapeutics, Inc.
    Neurotherapeutics 06/2014; · 5.90 Impact Factor
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    ABSTRACT: Repeated mild traumatic brain injury (mTBI) can cause sustained cognitive and psychiatric changes, as well as neurodegeneration, but the underlying mechanisms remain unclear. We examined histologic, neurophysiological, and cognitive changes after single or repeated (three injuries) mTBI using the rat lateral fluid percussion (LFP) model. Repeated mTBI caused substantial neuronal cell loss and significantly increased numbers of activated microglia in both ipsilateral and contralateral hippocampus on post-injury day (PID) 28. Long-term potentiation (LTP) could not be induced on PID 28 after repeated mTBI in ex vivo hippocampal slices from either hemisphere. N-Methyl-D-aspartate (NMDA) receptor-mediated responses were significantly attenuated after repeated mTBI, with no significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated responses. Long-term potentiation was elicited in slices after single mTBI, with potentiation significantly increased in ipsilateral versus contralateral hippocampus. After repeated mTBI, rats displayed cognitive impairments in the Morris water maze (MWM) and novel object recognition (NOR) tests. Thus, repeated mTBI causes deficits in the hippocampal function and changes in excitatory synaptic neurotransmission, which are associated with chronic neuroinflammation and neurodegeneration.Journal of Cerebral Blood Flow & Metabolism advance online publication, 23 April 2014; doi:10.1038/jcbfm.2014.75.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2014; · 5.46 Impact Factor
  • Tetrahedron Letters 03/2014; · 2.40 Impact Factor
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    ABSTRACT: Abstract Traumatic brain injury (TBI) causes neuronal cell death as well as microglial activation and related neurotoxicity that contribute to subsequent neurological dysfunction. Poly (ADP-ribose) polymerase (PARP-1) induces neuronal cell death through activation of caspase-independent mechanisms, including release of apoptosis inducing factor (AIF), and microglial activation. Administration of PJ34, a selective PARP-1 inhibitor, reduced cell death of primary cortical neurons exposed to N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG), a potent inducer of AIF-dependent cell death. PJ34 also attenuated lipopolysaccharide and interferon-γ-induced activation of BV2 or primary microglia, limiting NF-κB activity and iNOS expression as well as decreasing generation of reactive oxygen species and TNFα. Systemic administration of PJ34 starting as late as 24 h after controlled cortical impact resulted in improved motor function recovery in mice with TBI. Stereological analysis demonstrated that PJ34 treatment reduced the lesion volume, attenuated neuronal cell loss in the cortex and thalamus, and reduced microglial activation in the TBI cortex. PJ34 treatment did not improve cognitive performance in a Morris water maze test or reduce neuronal cell loss in the hippocampus. Overall, our data indicate that PJ34 has a significant, albeit selective, neuroprotective effect after experimental TBI, and its therapeutic effect may be from multipotential actions on neuronal cell death and neuroinflammatory pathways.
    Journal of neurotrauma 01/2014; · 4.25 Impact Factor
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    ABSTRACT: Central nervous system injury causes a marked increase in the expression of cell cycle-related proteins. In this study, we show that cell cycle activation (CCA) is detected in mature neurons at 24 hours after rat lateral fluid percussion (LFP)-induced traumatic brain injury (TBI), as reflected by increased expression of cyclin G1, phosphorylated retinoblastoma (phospho-Rb), E2F1 and proliferating cell nuclear antigen (PCNA). These changes were associated with progressive cortical, hippocampal, and thalamic neuronal loss and microglial and astrocyte activation. Notably, we detected 5-bromo-2'-deoxyuridine (BrdU)-positive neurons, microglia, and astrocytes at 7 days, but not at 24 hours, suggesting that cell cycle reaches the S phase in these cell types at the latter time point. A delayed systemic post-LFP administration at 3 hours of CR8-a potent second-generation cyclin-dependent kinase (CDK) inhibitor-reduced CCA; cortical, hippocampal, and thalamic neuronal loss; and cortical microglial and astrocyte activation. Furthermore, CR8 treatment attenuated sensorimotor and cognitive deficits, alleviated depressive-like symptoms, and decreased lesion volume. These findings underscore the contribution of CCA to progressive neurodegeneration and chronic neuroinflammation following TBI, and demonstrate the neuroprotective potential of cell cycle inhibition in a clinically relevant experimental TBI model.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 January 2014; doi:10.1038/jcbfm.2013.228.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2014; · 5.46 Impact Factor
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    ABSTRACT: Amyloid-β (Aβ) is produced through the enzymatic cleavage of amyloid precursor protein (APP) by β (Bace1) and γ -secretases. The accumulation and aggregation of Aβ as amyloid plaques is the hallmark pathology of Alzheimer’s disease and has been found in other neurological disorders, such as traumatic brain injury and multiple sclerosis. Although the role of Aβ after injury is not well understood, several studies have reported a negative correlation between Aβ formation and functional outcome. In this study we show that levels of APP, the enzymes cleaving APP (Bace1 and γ-secretase), and Aβ are significantly increased from 1 to 3 days after impact spinal cord injury (SCI) in mice. To determine the role of Aβ after SCI, we reduced or inhibited Aβ in vivo through pharmacological (using DAPT) or genetic (Bace1 knockout mice) approaches. We found that these interventions significantly impaired functional recovery as evaluated by white matter sparing and behavioral testing. These data are consistent with a beneficial role for Aβ after SCI.
    Brain research 01/2014; · 2.46 Impact Factor
  • Shruti V Kabadi, Alan I Faden
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    ABSTRACT: Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI.
    International Journal of Molecular Sciences 01/2014; 15(1):1216-1236. · 2.46 Impact Factor
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    ABSTRACT: Recent clinical studies indicate that traumatic brain injury (TBI) produces chronic and progressive neurodegenerative changes leading to late neurologic dysfunction, but little is known about the mechanisms underlying such changes. Microglial-mediated neuroinflammation is an important secondary injury mechanism after TBI. In human studies, microglial activation has been found to persist for many years after the initial brain trauma, particularly after moderate to severe TBI. In the present study, adult C57Bl/6 mice were subjected to single moderate-level controlled cortical impact and were followed up by longitudinal T2-weighted magnetic resonance imaging in combination with stereologic histologic assessment of lesion volume expansion, neuronal loss, and microglial activation for up to 1 year after TBI. Persistent microglial activation was observed in the injured cortex through 1 year after injury and was associated with progressive lesion expansion, hippocampal neurodegeneration, and loss of myelin. Notably, highly activated microglia that expressed major histocompatibility complex class II (CR3/43), CD68, and NADPH oxidase (NOX2) were detected at the margins of the expanding lesion at 1 year after injury; biochemical markers of neuroinflammation and oxidative stress were significantly elevated at this time point. These data support emerging clinical TBI findings and provide a mechanistic link between TBI-induced chronic microglial activation and progressive neurodegeneration.
    Journal of neuropathology and experimental neurology. 12/2013;
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    ABSTRACT: Traumatic brain injury causes progressive neurodegeneration associated with chronic microglial activation. Recent studies show that neurodegeneration and neuroinflammation after traumatic brain injury can be inhibited as late as one month in animals by the activation of the metabotropic glutamate receptor 5 in microglia using (RS)-2-chloro-5-hydroxy-phenylglycine. However, the therapeutic potential of this agonist is limited due to its relatively weak potency and brain permeability. To address such concerns, we evaluated the anti-inflammatory activities of several positive allosteric modulators using various in vitro assays, and found that 3,3'-difluorobenzaldazine, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide and 4-nitro-N-(1-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5-yl)benzamide showed significantly improved potency which makes them potential lead compounds for further development of positive allosteric modulators for the treatment of traumatic brain injury.
    CNS & neurological disorders drug targets 10/2013; · 3.57 Impact Factor
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    ABSTRACT: Microglial activation is implicated in delayed tissue damage after traumatic brain injury (TBI). Activation of microglia causes up-regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, with the release of reactive oxygen species and cytotoxicity. Propofol appears to have antiinflammatory actions. The authors evaluated the neuroprotective effects of propofol after TBI and examined in vivo and in vitro whether such actions reflected modulation of NADPH oxidase. Adult male rats were subjected to moderate lateral fluid percussion TBI. Effect of propofol on brain microglial activation and functional recovery was assessed up to 28 days postinjury. By using primary microglial and BV2 cell cultures, the authors examined propofol modulation of lipopolysaccharide and interferon-γ-induced microglial reactivity and neurotoxicity. Propofol improved cognitive recovery after TBI in novel object recognition test (48 ± 6% for propofol [n = 15] vs. 30 ± 4% for isoflurane [n = 14]; P = 0.005). The functional improvement with propofol was associated with limited microglial activation and decreased cortical lesion volume and neuronal loss. Propofol also attenuated lipopolysaccharide- and interferon-γ-induced microglial activation in vitro, with reduced expression of inducible nitric oxide synthase, nitric oxide, tumor necrosis factor-α, interlukin-1β, reactive oxygen species, and NADPH oxidase. Microglial-induced neurotoxicity in vitro was also markedly reduced by propofol. The protective effect of propofol was attenuated when the NADPH oxidase subunit p22 was knocked down by small interfering RNA. Moreover, propofol reduced the expression of p22 and gp91, two key components of NADPH oxidase, after TBI. The neuroprotective effects of propofol after TBI appear to be mediated, in part, through the inhibition of NADPH oxidase.
    Anesthesiology 10/2013; · 5.16 Impact Factor
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    ABSTRACT: Geranylgeranylacetone (GGA) is an inducer of heat-shock protein 70 (HSP70) that has been used clinically for many years as an antiulcer treatment. It is centrally active after oral administration and is neuroprotective in experimental brain ischemia/stroke models. We examined the effects of single oral GGA before treatment (800 mg/kg, 48 hours before trauma) or after treatment (800 mg/kg, 3 hours after trauma) on long-term functional recovery and histologic outcomes after moderate-level controlled cortical impact, an experimental traumatic brain injury (TBI) model in mice. The GGA pretreatment increased the number of HSP70(+) cells and attenuated posttraumatic α-fodrin cleavage, a marker of apoptotic cell death. It also improved sensorimotor performance on a beam walk task; enhanced recovery of cognitive/affective function in the Morris water maze, novel object recognition, and tail-suspension tests; and improved outcomes using a composite neuroscore. Furthermore, GGA pretreatment reduced the lesion size and neuronal loss in the hippocampus, cortex, and thalamus, and decreased microglial activation in the cortex when compared with vehicle-treated TBI controls. Notably, GGA was also effective in a posttreatment paradigm, showing significant improvements in sensorimotor function, and reducing cortical neuronal loss. Given these neuroprotective actions and considering its longstanding clinical use, GGA should be considered for the clinical treatment of TBI.Journal of Cerebral Blood Flow & Metabolism advance online publication, 14 August 2013; doi:10.1038/jcbfm.2013.144.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 08/2013; · 5.46 Impact Factor
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    ABSTRACT: Spinal cord injury (SCI) frequently causes severe, persistent central neuropathic pain that responds poorly to conventional pain treatments. Brain-derived neurotrophic factor (BDNF) signaling appears to contribute to central sensitization and nocifensive behaviors in certain animal models of chronic pain through effects mediated in part by the alternatively spliced truncated isoform of the BDNF receptor tropomyosin-related kinase B.T1 (trkB.T1). Mechanisms linking trkB.T1 to SCI-induced chronic central pain are unknown. Here, we examined the role of trkB.T1 in central neuropathic pain after spinal cord contusion. Genetic deletion of trkB.T1 in mice significantly reduced post-SCI mechanical hyperesthesia, locomotor dysfunction, lesion volumes, and white matter loss. Whole genome analysis, confirmed at the protein level, revealed that cell cycle genes were upregulated in trkB.T1(+/+) but not trkB.T1(-/-) spinal cord after SCI. TGFβ-induced reactive astrocytes from WT mice showed increased cell cycle protein expression that was significantly reduced in astrocytes from trkB.T1(-/-) mice that express neither full-length trkB nor trkB.T1. Administration of CR8, which selectively inhibits cyclin-dependent kinases, reduced hyperesthesia, locomotor deficits, and dorsal horn (SDH) glial changes after SCI, similar to trkB.T1 deletion, without altering trkB.T1 protein expression. In trkB.T1(-/-) mice, CR8 had no effect. These data indicate that trkB.T1 contributes to the pathobiology of SCI and SCI pain through modulation of cell cycle pathways and suggest new therapeutic targets.
    Journal of Neuroscience 07/2013; 33(30):12447-63. · 6.91 Impact Factor
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    ABSTRACT: Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.
    Journal of the American Society for Experimental NeuroTherapeutics 06/2013; · 5.38 Impact Factor
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    ABSTRACT: Group 1 metabotropic glutamate receptors (mGluR) are G-protein coupled receptors with a large bilobate extracellular ligand binding region (LBR) that resembles a Venus fly trap. Closing of this LBR in the presence of a ligand is associated with the activation of the receptor. From conformational sampling of the LBR-ligand complexes using all-atom molecular dynamics (MD) simulations, we characterized the conformational minima related to the hinge like motion associated with the LBR closing/opening in the presence of known agonists and antagonists. By applying a harmonic restraint on the LBR, we also determined the conformational forces generated by the different ligands. The change in the location of the minima and the conformational forces were used to quantify the efficacies of the ligands. This analysis shows that efficacies can be estimated from the forces of a single conformation of the receptor, indicating the potential of MD simulations as an efficient and useful technique to quantify efficacies, thereby facilitating the rational design of mGluR agonists and antagonists.
    Journal of Chemical Information and Modeling 05/2013; · 4.30 Impact Factor

Publication Stats

12k Citations
1,691.63 Total Impact Points


  • 2014
    • University of Baltimore
      Baltimore, Maryland, United States
  • 2010–2014
    • Loyola University Maryland
      Baltimore, Maryland, United States
    • University of Maryland, Baltimore
      • • Department of Anesthesiology
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 2012–2013
    • University of Maryland Medical Center
      • Department of Medicine
      Baltimore, Maryland, United States
  • 1992–2012
    • Georgetown University
      • • Department of Neuroscience
      • • Institute for Cognitive and Computational Sciences
      • • Department of Neurology
      Washington, D. C., DC, United States
  • 2007
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2006
    • Hertie-Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 1981–2006
    • Uniformed Services University of the Health Sciences
      • Department of Neurology
      Maryland, United States
  • 2003–2005
    • Children's National Medical Center
      • Center for Genetic Medicine Research
      Washington, D. C., DC, United States
  • 1995
    • Chiba University
      Tiba, Chiba, Japan
  • 1990–1995
    • James Cook University
      • School of Pharmacy and Molecular Sciences
      Townsville, Queensland, Australia
    • University of California, Berkeley
      • Division of Neurobiology
      Berkeley, MO, United States
  • 1985–1995
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Department of Neurology
      • • Department of Neurological Surgery
      San Francisco, California, United States
    • San Francisco VA Medical Center
      San Francisco, California, United States
    • Morehouse School of Medicine
      Atlanta, Georgia, United States
  • 1994
    • University of Pennsylvania
      • Department of Surgery
      Philadelphia, PA, United States
  • 1989
    • CSU Mentor
      Long Beach, California, United States
  • 1978–1983
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States