John Bethea - Academia.edu (original) (raw)

Papers by John Bethea

Research paper thumbnail of Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation

Research paper thumbnail of Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis

Journal of Neurochemistry, 2015

Although previous studies have shown that forced exercise modulates inflammation and is therapeut... more Although previous studies have shown that forced exercise modulates inflammation and is therapeutic acutely for experimental autoimmune encephalomyelitis (EAE), the long-term benefits have not been evaluated. In this study, we investigated the effects of preconditioning exercise on the clinical and pathological progression of EAE. Female C57BL/6 mice were randomly assigned to either an exercised (Ex) or unexercised (UEx) group and all of them were induced for EAE. Mice in the Ex group had an attenuated clinical score relative to UEx mice throughout the study. At 42 dpi, flow cytometry analysis showed a significant reduction in B cells, CD4(+) T cells, and CD8(+) T cells infiltrating into the spinal cord in the Ex group compared to UEx. Ex mice also had a significant reduction in myelin damage with a corresponding increase in proteolipid protein expression. Finally, Ex mice had a significant reduction in axonal damage. Collectively, our study demonstrates for the first time that a prolonged and forced preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease. In this study, we show that a program of 6 weeks of preconditioning exercise promoted a significant reduction of cells infiltrating into the spinal cord, a significant reduction in myelin damage and a significant reduction in axonal damage in experimental autoimmune encephalomyelitis (EAE) mice at 42 dpi. Collectively, our study demonstrates for the first time that a preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease.

Research paper thumbnail of Transgenic Inhibition of Astroglial NF-B Improves Functional Outcome in Experimental Autoimmune Encephalomyelitis by Suppressing Chronic Central Nervous System Inflammation 1

In the CNS, the transcription factor NF-B is a key regulator of inflammation and secondary injury... more In the CNS, the transcription factor NF-B is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-B-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-B (glial fibrillary acidic protein-IB-dominant-negative mice) resulted in reduced disease severity and improved functional recovery

Research paper thumbnail of IL7Rα Contributes to Experimental Autoimmune Encephalomyelitis through Altered T Cell Responses and Nonhematopoietic Cell Lineages

The Journal of Immunology

A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a... more A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7Rα has well documented roles in lymphocyte development and homeostasis, but its involvement in disease is largely understudied. In this study, we use the experimental autoimmune encephalomyelitis (EAE) model of MS to show that a less severe form of the disease results when IL7Rα expression is largely restricted to thymic tissue in IL7RTg(IL7R-/-) mice. Compared with wild-type (WT) mice, IL7RTg(IL7R-/-) mice exhibited reduced paralysis and myelin damage that correlated with dampened effector responses, namely decreased TNF production. Furthermore, treatment of diseased WT mice with neutralizing anti-IL7Rα Ab also resulted in significant improvement of EAE. In addition, chimeric mice were generated by bone marrow transplant to limit expression of IL7Rα to cells of either hematopoietic ...

Research paper thumbnail of Astroglial-NF-kB is a critical regulator of learning and memory and hippocampal neurogenesis in female mice

Frontiers in Behavioral Neuroscience, 2009

Research paper thumbnail of Central but not peripheral administration of XPro1595 is therapeutic following moderate spinal cord injury in mice

Journal of Neuroimmunology, 2014

Research paper thumbnail of Neural progenitors proliferation is inhibited by EphB3 in the developing subventricular zone

International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2011

The subventricular zone (SVZ) of the mammalian forebrain is a major source of multipotent stem ce... more The subventricular zone (SVZ) of the mammalian forebrain is a major source of multipotent stem cells during development, and contributes to neurogenesis throughout the lifespan of the organism. Several studies described molecules regulating adult neurogenesis, however, few of them have examined neurogenesis in the early postnatal period. Adult neurogenesis is regulated in part by ephrinB3 and its receptors, so we examined the role of EphB3 on neural stem/progenitor cell (NSPC) proliferation in early postnatal development in the SVZ. To examine NSPC proliferation, we used BrdU incorporation in both cultured NSPCs and neonatal gene-targeted knockout mice, as well as Ki67 immunostaining in EphB3(-/-) mice. We observed a significant increase in proliferation in cultured NSPCs derived from EphB3(-/-) mice and in the SVZ of EphB3(-/-) mice. These studies support an anti-proliferative role for EphB3 in regulating NSPC numbers in the developing SVZ.

Research paper thumbnail of Apoptotic and anti-apoptotic mechanisms following spinal cord injury

Journal of neuropathology and experimental neurology, 2001

A number of studies have provided evidence that cell death from moderate traumatic spinal cord in... more A number of studies have provided evidence that cell death from moderate traumatic spinal cord injury (SCI) is regulated, in part, by apoptosis that involves the caspase family of cysteine proteases. However, little or no information is available about anti-apoptotic mechanisms mediated by the inhibitors of apoptosis (IAP) family of proteins that inhibit cell death pathways. In the present study, we examined caspase and IAP expression in spinal cords of rats subjected to moderate traumatic injury. Within 6 h after injury, caspase-8 and-9 (2 initiators of apoptosis) were predominantly present in gray matter neurons within the lesion epicenter. By 3 days following spinal cord injury (SCI), caspase-8 and-9 immunoreactivity was localized to gray and white matter cells, and by 7 days following SCI, both upstream caspases were expressed in cells within white matter or within foamy macrophages in gray matter. Caspase-3, an effector caspase, was evident in a few fragmented cells in gray mat...

Research paper thumbnail of Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation

Blood, 2000

Tissue factor, which is expressed in vascular lesions, increases thrombin production, blood coagu... more Tissue factor, which is expressed in vascular lesions, increases thrombin production, blood coagulation, and smooth muscle cell proliferation. We demonstrate that oxidized low-density lipoprotein (LDL) induces surface tissue factor pathway activity (ie, activity of the tissue factor:factor VIIa complex) on human and rat smooth muscle cells. Tissue factor messenger RNA (mRNA) was induced by oxidized LDL or native LDL; however, native LDL did not markedly increase tissue factor activity. We hypothesized that oxidized LDL mediated the activation of the tissue factor pathway via an oxidant-dependent mechanism, because antioxidants blocked the enhanced tissue factor pathway activity by oxidized LDL, but not the increased mRNA or protein induction. We separated total lipid extracts of oxidized LDL using high-performance liquid chromatography (HPLC). This yielded 2 major peaks that induced tissue factor activity. Of the known oxysterols contained in the first peak, 7alpha- or 7beta-hydroxy...

Research paper thumbnail of Traumatic spinal cord injury induces nuclear factor-kappaB activation

The Journal of neuroscience : the official journal of the Society for Neuroscience, 1998

Inflammatory responses are a major component of secondary injury and play a central role in media... more Inflammatory responses are a major component of secondary injury and play a central role in mediating the pathogenesis of acute and chronic spinal cord injury (SCI). The nuclear factor-kappaB (NF-kappaB) family of transcription factors is required for the transcriptional activation of a variety of genes regulating inflammatory, proliferative, and cell death responses of cells. In this study we examined the temporal and cellular expression of activated NF-kappaB after traumatic SCI. We used a contusion model (N.Y.U. Impactor) to initiate the early biochemical and molecular changes that occur after traumatic injury to reproduce the pathological events associated with acute inflammation after SCI. The activation and cellular distribution of activated NF-kappaB was evaluated by using a monoclonal antibody that selectively recognizes activated p65 in a NF-kappaB dimer. Immunohistochemical and Western blot analyses demonstrated that NF-kappaB activation occurred as early as 0.5 hr postinj...

Research paper thumbnail of Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP): Nogo-interacting mitochondrial protein

Journal of Neurochemistry, 2002

Research paper thumbnail of Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP)

Nogo is a potent inhibitor of regeneration following spinal cord injury. To develop a better unde... more Nogo is a potent inhibitor of regeneration following spinal cord injury. To develop a better understanding of the mechanisms responsible for regenerative failure we used a yeast two- hybrid approach to try and identify proteins that interact with Nogo. We identified a novel mitochondrial protein designated Nogo-interacting mitochondrial protein (NIMP) in a screen of an adult human brain cDNA library.

Research paper thumbnail of Cytokines in Brain Trauma and Spinal Cord Injury

Cytokines and the CNS, 2005

Research paper thumbnail of Neuropathic pain-induced depressive-like behavior is associated with myelin remodeling and impaired neurogenesis

Journal of Neuroimmunology, 2014

Research paper thumbnail of Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling

Brain, behavior, and immunity, 2014

Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depres... more Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1(-/-) mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive ...

Research paper thumbnail of Minimum information about a spinal cord injury experiment: a proposed reporting standard for spinal cord injury experiments

The lack of reproducibility in many areas of experimental science has a number of causes, includi... more The lack of reproducibility in many areas of experimental science has a number of causes, including a lack of transparency and precision in the description of experimental approaches. This has far-reaching consequences, including wasted resources and slowing of progress. Additionally, the large number of laboratories around the world publishing articles on a given topic make it difficult, if not impossible, for individual researchers to read all of the relevant literature. Consequently, centralized databases are needed to facilitate the generation of new hypotheses for testing. One strategy to improve transparency in experimental description, and to allow the development of frameworks for computer-readable knowledge repositories, is the adoption of uniform reporting standards, such as common data elements (data elements used in multiple clinical studies) and minimum information standards. This article describes a minimum information standard for spinal cord injury (SCI) experiments, its major elements, and the approaches used to develop it. Transparent reporting standards for experiments using animal models of human SCI aim to reduce inherent bias and increase experimental value.

Research paper thumbnail of Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice

Journal of Neuroinflammation, 2014

Background: Glial cell activation and overproduction of inflammatory mediators in the central ner... more Background: Glial cell activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in acute traumatic injuries to the CNS, including spinal cord injury (SCI). Elevated levels of the proinflammatory cytokine tumor necrosis factor (TNF), which exists in both a soluble (sol) and a transmembrane (tm) form, have been found in the lesioned cord early after injury. The contribution of solTNF versus tmTNF to the development of the lesion is, however, still unclear. Methods: We tested the effect of systemically or centrally blocking solTNF alone, using XPro1595, versus using the drug etanercept to block both solTNF and tmTNF compared to a placebo vehicle following moderate SCI in mice. Functional outcomes were evaluated using the Basso Mouse Scale, rung walk test, and thermal hyperalgesia analysis. The inflammatory response in the lesioned cord was investigated using immunohistochemistry and western blotting analyses.

Research paper thumbnail of Activation of NF- B in Schwann Cells Is Dispensable for Myelination In Vivo

Journal of Neuroscience, 2013

Research paper thumbnail of Ephb3 Inhibits the Expansion of Neural Progenitor Cells in the SVZ by Regulating p53 During Homeostasis and Following Traumatic Brain Injury

STEM CELLS, 2000

Ephrins and Eph receptor(s) have recently been implicated in regulating neurogenesis in the adult... more Ephrins and Eph receptor(s) have recently been implicated in regulating neurogenesis in the adult subventricular zone (SVZ) and rostral migratory stream (RMS). Here, we examined the role of ephrinB3-EphB3 signaling in mediating the SVZ response to traumatic brain injury (TBI). Analysis of EphB3 expression showed co-localization with glial fibrillary acidic protein (GFAP)positive neural stem progenitor cells (NSPCs) and doublecortin-positive neuroblasts, while ephrinB3 was expressed outside the neurogenic region. TBI resulted in a significant reduction in EphB3 expression, which coincided with enhanced NSPC survival and proliferation at 3 and 7 days post-injury. Analysis of mice lacking either ephrinB3 (ephrinB3 −/− ) or EphB3 (EphB3 −/− ) showed a significant increase in bromodeoxyuridine (BrdU) incorporation and Ki67 immunoreactivity in the SVZ. Interestingly, cell death was dissimilar between knockout mice, where cell death was reduced in EphB3 −/− but increased in ephrinB3 −/− mice. Lateral ventricle infusion of soluble pre-clustered ephrinB3-Fc reversed the proliferative and cell death defects in ephrinB3 −/− but not EphB3 −/− mice and prevented TBI-induced proliferation in wild type NSPCs. Coincidently, tumor suppressor p53 expression was increased following EphB3 stimulation and is reduced in the absence of either EphB3 or ephrinB3. Furthermore, pharmacological inhibition and siRNA knockdown of p53 attenuated ephrinB3-Fc mediated growth suppression while having no effect on cell death in cultured NSPCs. These data demonstrate that EphB3 signaling suppresses NSPC proliferation in a p53-dependent manner, induces cell death in the absence of ligand stimulation and is transiently reduced in the SVZ to initiate the expansion and survival of endogenous adult NSPCs following TBI.

Research paper thumbnail of Inhibition of NADPH Oxidase Activation in Oligodendrocytes Reduces Cytotoxicity Following Trauma

PLoS ONE, 2013

Spinal cord injury is a debilitating neurological disorder that initiates a cascade of cellular e... more Spinal cord injury is a debilitating neurological disorder that initiates a cascade of cellular events that result in a period of secondary damage that can last for months after the initial trauma. The ensuing outcome of these prolonged cellular perturbations is the induction of neuronal and glial cell death through excitotoxic mechanisms and subsequent free radical production. We have previously shown that astrocytes can directly induce oligodendrocyte death following trauma, but the mechanisms regulating this process within the oligodendrocyte remain unclear. Here we provide evidence demonstrating that astrocytes directly regulate oligodendrocyte death after trauma by inducing activation of NADPH oxidase within oligodendrocytes. Spinal cord injury resulted in a significant increase in oxidative damage which correlated with elevated expression of the gp91 phox subunit of the NADPH oxidase enzyme. Immunohistochemical analysis confirmed the presence of gp91 phox in oligodendrocytes in vitro and at 1 week following spinal cord injury. Exposure of oligodendrocytes to media from injured astrocytes resulted in an increase in oligodendrocyte NADPH oxidase activity. Inhibition of NADPH oxidase activation was sufficient to attenuate oligodendrocyte death in vitro and at 1 week following spinal cord injury, suggesting that excitotoxicity of oligodendrocytes after trauma is dependent on the intrinsic activation of the NADPH oxidase enzyme. Acute administration of the NADPH oxidase inhibitor apocynin and the alpha-amino-3-hydroxy-5-methylisoxazole-4propionate channel blocker 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione significantly improved locomotor behavior and preserved descending axon fibers following spinal cord injury. These studies lead to a better understanding of oligodendrocyte death after trauma and identify potential therapeutic targets in disorders involving demyelination and oligodendrocyte death.

Research paper thumbnail of Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation

Research paper thumbnail of Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis

Journal of Neurochemistry, 2015

Although previous studies have shown that forced exercise modulates inflammation and is therapeut... more Although previous studies have shown that forced exercise modulates inflammation and is therapeutic acutely for experimental autoimmune encephalomyelitis (EAE), the long-term benefits have not been evaluated. In this study, we investigated the effects of preconditioning exercise on the clinical and pathological progression of EAE. Female C57BL/6 mice were randomly assigned to either an exercised (Ex) or unexercised (UEx) group and all of them were induced for EAE. Mice in the Ex group had an attenuated clinical score relative to UEx mice throughout the study. At 42 dpi, flow cytometry analysis showed a significant reduction in B cells, CD4(+) T cells, and CD8(+) T cells infiltrating into the spinal cord in the Ex group compared to UEx. Ex mice also had a significant reduction in myelin damage with a corresponding increase in proteolipid protein expression. Finally, Ex mice had a significant reduction in axonal damage. Collectively, our study demonstrates for the first time that a prolonged and forced preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease. In this study, we show that a program of 6 weeks of preconditioning exercise promoted a significant reduction of cells infiltrating into the spinal cord, a significant reduction in myelin damage and a significant reduction in axonal damage in experimental autoimmune encephalomyelitis (EAE) mice at 42 dpi. Collectively, our study demonstrates for the first time that a preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease.

Research paper thumbnail of Transgenic Inhibition of Astroglial NF-B Improves Functional Outcome in Experimental Autoimmune Encephalomyelitis by Suppressing Chronic Central Nervous System Inflammation 1

In the CNS, the transcription factor NF-B is a key regulator of inflammation and secondary injury... more In the CNS, the transcription factor NF-B is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-B-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-B (glial fibrillary acidic protein-IB-dominant-negative mice) resulted in reduced disease severity and improved functional recovery

Research paper thumbnail of IL7Rα Contributes to Experimental Autoimmune Encephalomyelitis through Altered T Cell Responses and Nonhematopoietic Cell Lineages

The Journal of Immunology

A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a... more A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7Rα has well documented roles in lymphocyte development and homeostasis, but its involvement in disease is largely understudied. In this study, we use the experimental autoimmune encephalomyelitis (EAE) model of MS to show that a less severe form of the disease results when IL7Rα expression is largely restricted to thymic tissue in IL7RTg(IL7R-/-) mice. Compared with wild-type (WT) mice, IL7RTg(IL7R-/-) mice exhibited reduced paralysis and myelin damage that correlated with dampened effector responses, namely decreased TNF production. Furthermore, treatment of diseased WT mice with neutralizing anti-IL7Rα Ab also resulted in significant improvement of EAE. In addition, chimeric mice were generated by bone marrow transplant to limit expression of IL7Rα to cells of either hematopoietic ...

Research paper thumbnail of Astroglial-NF-kB is a critical regulator of learning and memory and hippocampal neurogenesis in female mice

Frontiers in Behavioral Neuroscience, 2009

Research paper thumbnail of Central but not peripheral administration of XPro1595 is therapeutic following moderate spinal cord injury in mice

Journal of Neuroimmunology, 2014

Research paper thumbnail of Neural progenitors proliferation is inhibited by EphB3 in the developing subventricular zone

International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2011

The subventricular zone (SVZ) of the mammalian forebrain is a major source of multipotent stem ce... more The subventricular zone (SVZ) of the mammalian forebrain is a major source of multipotent stem cells during development, and contributes to neurogenesis throughout the lifespan of the organism. Several studies described molecules regulating adult neurogenesis, however, few of them have examined neurogenesis in the early postnatal period. Adult neurogenesis is regulated in part by ephrinB3 and its receptors, so we examined the role of EphB3 on neural stem/progenitor cell (NSPC) proliferation in early postnatal development in the SVZ. To examine NSPC proliferation, we used BrdU incorporation in both cultured NSPCs and neonatal gene-targeted knockout mice, as well as Ki67 immunostaining in EphB3(-/-) mice. We observed a significant increase in proliferation in cultured NSPCs derived from EphB3(-/-) mice and in the SVZ of EphB3(-/-) mice. These studies support an anti-proliferative role for EphB3 in regulating NSPC numbers in the developing SVZ.

Research paper thumbnail of Apoptotic and anti-apoptotic mechanisms following spinal cord injury

Journal of neuropathology and experimental neurology, 2001

A number of studies have provided evidence that cell death from moderate traumatic spinal cord in... more A number of studies have provided evidence that cell death from moderate traumatic spinal cord injury (SCI) is regulated, in part, by apoptosis that involves the caspase family of cysteine proteases. However, little or no information is available about anti-apoptotic mechanisms mediated by the inhibitors of apoptosis (IAP) family of proteins that inhibit cell death pathways. In the present study, we examined caspase and IAP expression in spinal cords of rats subjected to moderate traumatic injury. Within 6 h after injury, caspase-8 and-9 (2 initiators of apoptosis) were predominantly present in gray matter neurons within the lesion epicenter. By 3 days following spinal cord injury (SCI), caspase-8 and-9 immunoreactivity was localized to gray and white matter cells, and by 7 days following SCI, both upstream caspases were expressed in cells within white matter or within foamy macrophages in gray matter. Caspase-3, an effector caspase, was evident in a few fragmented cells in gray mat...

Research paper thumbnail of Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation

Blood, 2000

Tissue factor, which is expressed in vascular lesions, increases thrombin production, blood coagu... more Tissue factor, which is expressed in vascular lesions, increases thrombin production, blood coagulation, and smooth muscle cell proliferation. We demonstrate that oxidized low-density lipoprotein (LDL) induces surface tissue factor pathway activity (ie, activity of the tissue factor:factor VIIa complex) on human and rat smooth muscle cells. Tissue factor messenger RNA (mRNA) was induced by oxidized LDL or native LDL; however, native LDL did not markedly increase tissue factor activity. We hypothesized that oxidized LDL mediated the activation of the tissue factor pathway via an oxidant-dependent mechanism, because antioxidants blocked the enhanced tissue factor pathway activity by oxidized LDL, but not the increased mRNA or protein induction. We separated total lipid extracts of oxidized LDL using high-performance liquid chromatography (HPLC). This yielded 2 major peaks that induced tissue factor activity. Of the known oxysterols contained in the first peak, 7alpha- or 7beta-hydroxy...

Research paper thumbnail of Traumatic spinal cord injury induces nuclear factor-kappaB activation

The Journal of neuroscience : the official journal of the Society for Neuroscience, 1998

Inflammatory responses are a major component of secondary injury and play a central role in media... more Inflammatory responses are a major component of secondary injury and play a central role in mediating the pathogenesis of acute and chronic spinal cord injury (SCI). The nuclear factor-kappaB (NF-kappaB) family of transcription factors is required for the transcriptional activation of a variety of genes regulating inflammatory, proliferative, and cell death responses of cells. In this study we examined the temporal and cellular expression of activated NF-kappaB after traumatic SCI. We used a contusion model (N.Y.U. Impactor) to initiate the early biochemical and molecular changes that occur after traumatic injury to reproduce the pathological events associated with acute inflammation after SCI. The activation and cellular distribution of activated NF-kappaB was evaluated by using a monoclonal antibody that selectively recognizes activated p65 in a NF-kappaB dimer. Immunohistochemical and Western blot analyses demonstrated that NF-kappaB activation occurred as early as 0.5 hr postinj...

Research paper thumbnail of Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP): Nogo-interacting mitochondrial protein

Journal of Neurochemistry, 2002

Research paper thumbnail of Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP)

Nogo is a potent inhibitor of regeneration following spinal cord injury. To develop a better unde... more Nogo is a potent inhibitor of regeneration following spinal cord injury. To develop a better understanding of the mechanisms responsible for regenerative failure we used a yeast two- hybrid approach to try and identify proteins that interact with Nogo. We identified a novel mitochondrial protein designated Nogo-interacting mitochondrial protein (NIMP) in a screen of an adult human brain cDNA library.

Research paper thumbnail of Cytokines in Brain Trauma and Spinal Cord Injury

Cytokines and the CNS, 2005

Research paper thumbnail of Neuropathic pain-induced depressive-like behavior is associated with myelin remodeling and impaired neurogenesis

Journal of Neuroimmunology, 2014

Research paper thumbnail of Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling

Brain, behavior, and immunity, 2014

Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depres... more Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1(-/-) mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive ...

Research paper thumbnail of Minimum information about a spinal cord injury experiment: a proposed reporting standard for spinal cord injury experiments

The lack of reproducibility in many areas of experimental science has a number of causes, includi... more The lack of reproducibility in many areas of experimental science has a number of causes, including a lack of transparency and precision in the description of experimental approaches. This has far-reaching consequences, including wasted resources and slowing of progress. Additionally, the large number of laboratories around the world publishing articles on a given topic make it difficult, if not impossible, for individual researchers to read all of the relevant literature. Consequently, centralized databases are needed to facilitate the generation of new hypotheses for testing. One strategy to improve transparency in experimental description, and to allow the development of frameworks for computer-readable knowledge repositories, is the adoption of uniform reporting standards, such as common data elements (data elements used in multiple clinical studies) and minimum information standards. This article describes a minimum information standard for spinal cord injury (SCI) experiments, its major elements, and the approaches used to develop it. Transparent reporting standards for experiments using animal models of human SCI aim to reduce inherent bias and increase experimental value.

Research paper thumbnail of Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice

Journal of Neuroinflammation, 2014

Background: Glial cell activation and overproduction of inflammatory mediators in the central ner... more Background: Glial cell activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in acute traumatic injuries to the CNS, including spinal cord injury (SCI). Elevated levels of the proinflammatory cytokine tumor necrosis factor (TNF), which exists in both a soluble (sol) and a transmembrane (tm) form, have been found in the lesioned cord early after injury. The contribution of solTNF versus tmTNF to the development of the lesion is, however, still unclear. Methods: We tested the effect of systemically or centrally blocking solTNF alone, using XPro1595, versus using the drug etanercept to block both solTNF and tmTNF compared to a placebo vehicle following moderate SCI in mice. Functional outcomes were evaluated using the Basso Mouse Scale, rung walk test, and thermal hyperalgesia analysis. The inflammatory response in the lesioned cord was investigated using immunohistochemistry and western blotting analyses.

Research paper thumbnail of Activation of NF- B in Schwann Cells Is Dispensable for Myelination In Vivo

Journal of Neuroscience, 2013

Research paper thumbnail of Ephb3 Inhibits the Expansion of Neural Progenitor Cells in the SVZ by Regulating p53 During Homeostasis and Following Traumatic Brain Injury

STEM CELLS, 2000

Ephrins and Eph receptor(s) have recently been implicated in regulating neurogenesis in the adult... more Ephrins and Eph receptor(s) have recently been implicated in regulating neurogenesis in the adult subventricular zone (SVZ) and rostral migratory stream (RMS). Here, we examined the role of ephrinB3-EphB3 signaling in mediating the SVZ response to traumatic brain injury (TBI). Analysis of EphB3 expression showed co-localization with glial fibrillary acidic protein (GFAP)positive neural stem progenitor cells (NSPCs) and doublecortin-positive neuroblasts, while ephrinB3 was expressed outside the neurogenic region. TBI resulted in a significant reduction in EphB3 expression, which coincided with enhanced NSPC survival and proliferation at 3 and 7 days post-injury. Analysis of mice lacking either ephrinB3 (ephrinB3 −/− ) or EphB3 (EphB3 −/− ) showed a significant increase in bromodeoxyuridine (BrdU) incorporation and Ki67 immunoreactivity in the SVZ. Interestingly, cell death was dissimilar between knockout mice, where cell death was reduced in EphB3 −/− but increased in ephrinB3 −/− mice. Lateral ventricle infusion of soluble pre-clustered ephrinB3-Fc reversed the proliferative and cell death defects in ephrinB3 −/− but not EphB3 −/− mice and prevented TBI-induced proliferation in wild type NSPCs. Coincidently, tumor suppressor p53 expression was increased following EphB3 stimulation and is reduced in the absence of either EphB3 or ephrinB3. Furthermore, pharmacological inhibition and siRNA knockdown of p53 attenuated ephrinB3-Fc mediated growth suppression while having no effect on cell death in cultured NSPCs. These data demonstrate that EphB3 signaling suppresses NSPC proliferation in a p53-dependent manner, induces cell death in the absence of ligand stimulation and is transiently reduced in the SVZ to initiate the expansion and survival of endogenous adult NSPCs following TBI.

Research paper thumbnail of Inhibition of NADPH Oxidase Activation in Oligodendrocytes Reduces Cytotoxicity Following Trauma

PLoS ONE, 2013

Spinal cord injury is a debilitating neurological disorder that initiates a cascade of cellular e... more Spinal cord injury is a debilitating neurological disorder that initiates a cascade of cellular events that result in a period of secondary damage that can last for months after the initial trauma. The ensuing outcome of these prolonged cellular perturbations is the induction of neuronal and glial cell death through excitotoxic mechanisms and subsequent free radical production. We have previously shown that astrocytes can directly induce oligodendrocyte death following trauma, but the mechanisms regulating this process within the oligodendrocyte remain unclear. Here we provide evidence demonstrating that astrocytes directly regulate oligodendrocyte death after trauma by inducing activation of NADPH oxidase within oligodendrocytes. Spinal cord injury resulted in a significant increase in oxidative damage which correlated with elevated expression of the gp91 phox subunit of the NADPH oxidase enzyme. Immunohistochemical analysis confirmed the presence of gp91 phox in oligodendrocytes in vitro and at 1 week following spinal cord injury. Exposure of oligodendrocytes to media from injured astrocytes resulted in an increase in oligodendrocyte NADPH oxidase activity. Inhibition of NADPH oxidase activation was sufficient to attenuate oligodendrocyte death in vitro and at 1 week following spinal cord injury, suggesting that excitotoxicity of oligodendrocytes after trauma is dependent on the intrinsic activation of the NADPH oxidase enzyme. Acute administration of the NADPH oxidase inhibitor apocynin and the alpha-amino-3-hydroxy-5-methylisoxazole-4propionate channel blocker 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione significantly improved locomotor behavior and preserved descending axon fibers following spinal cord injury. These studies lead to a better understanding of oligodendrocyte death after trauma and identify potential therapeutic targets in disorders involving demyelination and oligodendrocyte death.