Neurology Commons^™

Predictive Screening Of M1 And M2 Macrophages Reveals The Immunomodulatory Effectiveness Of Post Spinal Cord Injury Azithromycin Treatment, John C. Gensel, Timothy J. Kopper, Bei Zhang, Michael B. Orr, William M. Bailey

Spinal Cord and Brain Injury Research Center Faculty Publications

Spinal cord injury (SCI) triggers a heterogeneous macrophage response that when experimentally polarized toward alternative forms of activation (M2 macrophages) promotes tissue and functional recovery. There are limited pharmacological therapies that can drive this reparative inflammatory state. In the current study, we used in vitrosystems to comprehensively defined markers of macrophages with known pathological (M1) and reparative (M2) properties in SCI. We then used these markers to objectively define the macrophage activation states after SCI in response to delayed azithromycin treatment. Mice were subjected to moderate-severe thoracic contusion SCI. Azithromycin or vehicle was administered beginning 30 minutes post-SCI and …

Cellular And Subcellular Oxidative Stress Parameters Following Severe Spinal Cord Injury, Nishant P. Visavadiya, Samir P. Patel, Jenna L. Vanrooyen, Patrick G. Sullivan, Alexander G. Rabchevsky

Spinal Cord and Brain Injury Research Center Faculty Publications

The present study undertook a comprehensive assessment of the acute biochemical oxidative stress parameters in both cellular and, notably, mitochondrial isolates following severe upper lumbar contusion spinal cord injury (SCI) in adult female Sprague Dawley rats. At 24 h post-injury, spinal cord tissue homogenate and mitochondrial fractions were isolated concurrently and assessed for glutathione (GSH) content and production of nitric oxide (NO^•), in addition to the presence of oxidative stress markers 3-nitrotyrosine (3-NT), protein carbonyl (PC), 4-hydroxynonenal (4-HNE) and lipid peroxidation (LPO). Moreover, we assessed production of superoxide (O₂^•-) and hydrogen peroxide (H₂O …

Repeated Closed Head Injury In Mice Results In Sustained Motor And Memory Deficits And Chronic Cellular Changes, Amanda Nicholle Bolton Hall, Binoy Joseph, Jennifer M. Brelsfoard, Kathryn E. Saatman

Spinal Cord and Brain Injury Research Center Faculty Publications

Millions of mild traumatic brain injuries (TBIs) occur every year in the United States, with many people subject to multiple head injuries that can lead to chronic behavioral dysfunction. We previously reported that mild TBI induced using closed head injuries (CHI) repeated at 24h intervals produced more acute neuron death and glial reactivity than a single CHI, and increasing the length of time between injuries to 48h reduced the cumulative acute effects of repeated CHI. To determine whether repeated CHI is associated with behavioral dysfunction or persistent cellular damage, mice receiving either five CHI at 24h intervals, five CHI at …

Calpain-5 Expression In The Retina Localizes To Photoreceptor Synapses, Kellie A. Schaefer, Marcus A. Toral, Gabriel Velez, Allison J. Cox, Sheila A. Baker, Nicholas C. Borcherding, Diana F. Colgan, Vimala Bondada, Charles B. Mashburn, Chen Guang Yu, James W. Geddes, Stephen H. Tsang, Alexander G. Bassuk, Vinit B. Mahajan

Spinal Cord and Brain Injury Research Center Faculty Publications

Purpose: We characterize calpain-5 (CAPN5) expression in retinal and neuronal subcellular compartments.

Methods: CAPN5 gene variants were classified using the exome variant server, and RNA-sequencing was used to compare expression of CAPN5 mRNA in the mouse and human retina and in retinoblastoma cells. Expression of CAPN5 protein was ascertained in humans and mice in silico, in mouse retina by immunohistochemistry, and in neuronal cancer cell lines and fractionated central nervous system tissue extracts by Western analysis with eight antibodies targeting different CAPN5 regions.

Results: Most CAPN5 genetic variation occurs outside its protease core; and searches …

Dietary Supplementation With Organoselenium Accelerates Recovery Of Bladder Expression, But Does Not Improve Locomotor Function, Following Spinal Cord Injury, Carolyn A. Meyer, Ranjana Singh, Mackenzie T. Jones, Chen-Guang Yu, Ronan F. Power, James W. Geddes

Spinal Cord and Brain Injury Research Center Faculty Publications

Selenium is an essential element required for activity of several antioxidant enzymes, including glutathione peroxidase. Because of the critical role of the antioxidant system in responding to traumatic events, we hypothesized that dietary selenium supplementation would enhance neuroprotection in a rodent model of spinal cord injury. Rats were maintained on either a control or selenium-enriched diet prior to, and following, injury. Dietary selenium supplementation, provided as selenized yeast added to normal rat chow, resulted in a doubling of selenium levels in the spinal cord. Dietary selenium reduced the time required for recovery of bladder function following thoracic spinal cord injury. …

Cns Plasticity In Injury And Disease, Brandon A. Miller, John C. Gensel, Michael S. Beattie

Spinal Cord and Brain Injury Research Center Faculty Publications

No abstract provided.

Azithromycin Drives Alternative Macrophage Activation And Improves Recovery And Tissue Sparing In Contusion Spinal Cord Injury, Bei Zhang, William M. Bailey, Timothy J. Kopper, Michael B. Orr, David J. Feola, John C. Gensel

Spinal Cord and Brain Injury Research Center Faculty Publications

BACKGROUND: Macrophages persist indefinitely at sites of spinal cord injury (SCI) and contribute to both pathological and reparative processes. While the alternative, anti-inflammatory (M2) phenotype is believed to promote cell protection, regeneration, and plasticity, pro-inflammatory (M1) macrophages persist after SCI and contribute to protracted cell and tissue loss. Thus, identifying non-invasive, clinically viable, pharmacological therapies for altering macrophage phenotype is a challenging, yet promising, approach for treating SCI. Azithromycin (AZM), a commonly used macrolide antibiotic, drives anti-inflammatory macrophage activation in rodent models of inflammation and in humans with cystic fibrosis.

METHODS: We hypothesized that AZM treatment can alter …

Toll-Like Receptors And Dectin-1, A C-Type Lectin Receptor, Trigger Divergent Functions In Cns Macrophages, John C. Gensel, Yan Wang, Zhen Guan, Kyle A. Beckwith, Kaitlyn J. Braun, Ping Wei, Dana M. Mctigue, Phillip G. Popovich

Spinal Cord and Brain Injury Research Center Faculty Publications

Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid …

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective P38Αmapk Inhibitor That Attenuates Disease Progression In Alzheimer's Disease Mouse Models, Saktimayee M. Roy, Valerie L. Grum-Tokars, James P. Schavocky, Faisal Saeed, Agnieszka Staniszewski, Andrew F. Teich, Ottavio Arancio, Adam D. Bachstetter, Scott J. Webster, Linda J. Van Eldik, George Minasov, Wayne F. Anderson, Jeffrey C. Pelletier, D. Martin Watterson

Spinal Cord and Brain Injury Research Center Faculty Publications

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, …

Ketones Prevent Oxidative Impairment Of Hippocampal Synaptic Integrity Through KAtp Channels, Do Young Kim, Mohammed G. Abdelwahab, Soo Han Lee, Derek O'Neill, Roger J. Thompson, Henry J. Duff, Patrick G. Sullivan, Jong M. Rho

Spinal Cord and Brain Injury Research Center Faculty Publications

Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent studies have shown that ketones may modulate neuronal firing through interactions with ATP-sensitive potassium (K_ATP) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of K_ATP channel activation. Ketones dose-dependently …

Il-4 Signaling Drives A Unique Arginase+/Il-1Β+ Microglia Phenotype And Recruits Macrophages To The Inflammatory Cns: Consequences Of Age-Related Deficits In Il-4rα After Traumatic Spinal Cord Injury, Ashley M. Fenn, Jodie C.E. Hall, John C. Gensel, Phillip G. Popovich, Jonathan P. Godbout

Spinal Cord and Brain Injury Research Center Faculty Publications

Alternative activation of microglia/macrophages (M2a) by interleukin (IL)-4 is purported to support intrinsic growth and repair processes after CNS injury. Nonetheless, alternative activation of microglia is poorly understood in vivo, particularly in the context of inflammation, injury, and aging. Here, we show that aged mice (18-19 months) had reduced functional recovery after spinal cord injury (SCI) associated with impaired induction of IL-4 receptor α (IL-4Rα) on microglia. The failure to successfully promote an IL-4/IL-4Rα response in aged mice resulted in attenuated arginase (M2a associated), IL-1β, and chemokine ligand 2 (CCL2) expression, and diminished recruitment of IL-4Rα⁺ macrophages to …

Neuronal Growth Cones And Regeneration: Gridlock Within The Extracellular Matrix, Diane M. Snow

Spinal Cord and Brain Injury Research Center Faculty Publications

The extracellular matrix is a diverse composition of glycoproteins and proteoglycans found in all cellular systems. The extracellular matrix, abundant in the mammalian central nervous system, is temporally and spatially regulated and is a dynamic "living" entity that is reshaped and redesigned on a continuous basis in response to changing needs. Some modifications are adaptive and some are maladaptive. It is the maladaptive responses that pose a significant threat to successful axonal regeneration and/or sprouting following traumatic and spinal cord injuries, and has been the focus of a myriad of research laboratories for many years. This review focuses largely on …

Proteoglycans: Road Signs For Neurite Outgrowth, Justin A. Beller, Diane M. Snow

Spinal Cord and Brain Injury Research Center Faculty Publications

Proteoglycans in the central nervous system play integral roles as "traffic signals" for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and …

Commentary On: "Facilitating Transparency In Spinal Cord Injury Studies Using Data Standards And Ontologies", Diane M. Snow

Spinal Cord and Brain Injury Research Center Faculty Publications

No abstract provided.

Astrocyte-Specific Overexpression Of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons And Reduces Behavioral Deficits Following Traumatic Brain Injury In Mice, Sindhu K. Madathil, Shaun W. Carlson, Jennifer M. Brelsfoard, Ping Ye, A Joseph D'Ercole, Kathryn E. Saatman

Spinal Cord and Brain Injury Research Center Faculty Publications

Traumatic brain injury (TBI) survivors often suffer from long-lasting cognitive impairment that stems from hippocampal injury. Systemic administration of insulin-like growth factor-1 (IGF-1), a polypeptide growth factor known to play vital roles in neuronal survival, has been shown to attenuate posttraumatic cognitive and motor dysfunction. However, its neuroprotective effects in TBI have not been examined. To this end, moderate or severe contusion brain injury was induced in mice with conditional (postnatal) overexpression of IGF-1 using the controlled cortical impact (CCI) injury model. CCI brain injury produces robust reactive astrocytosis in regions of neuronal damage such as the hippocampus. We exploited …

Calpain 1 Knockdown Improves Tissue Sparing And Functional Outcomes After Spinal Cord Injury In Rats, Chen Guang Yu, Yanzhang Li, Kashif Raza, Xin Xin Yu, Sarbani Ghoshal, James W. Geddes

Spinal Cord and Brain Injury Research Center Faculty Publications

To evaluate the hypothesis that calpain 1 knockdown would reduce pathological damage and functional deficits after spinal cord injury (SCI), we developed lentiviral vectors encoding calpain 1 shRNA and eGFP as a reporter (LV-CAPN1 shRNA). The ability of LV-CAPN1 shRNA to knockdown calpain 1 was confirmed in rat NRK cells using Northern and Western blot analysis. To investigate the effects on spinal cord injury, LV-CAPN1shRNA or LV-mismatch control shRNA (LV-control shRNA) were administered by convection enhanced diffusion at spinal cord level T10 in Long-Evans female rats (200–250 g) 1 week before contusion SCI, 180 kdyn force, or sham surgery at …

Mitochondria, Amyloid Β, And Alzheimer's Disease, Ryan Douglas Readnower, Andrew David Sauerbeck, Patrick G. Sullivan

Spinal Cord and Brain Injury Research Center Faculty Publications

Hypometabolism is a hallmark of Alzheimer's disease (AD) and implicates a mitochondrial role in the neuropathology associated with AD. Mitochondrial amyloid-beta (Aβ) accumulation precedes extracellular Aβ deposition. In addition to increasing oxidative stress, Aβ has been shown to directly inhibit mitochondrial enzymes. Inhibition of mitochondrial enzymes as a result of oxidative damage or Aβ interaction perpetuates oxidative stress and leads to a hypometabolic state. Additionally, Aβ has also been shown to interact with cyclophilin D, a component of the mitochondrial permeability transition pore, which may promote cell death. Therefore, ample evidence exists indicating that …