Abstract

Inflammation and excitoxicity appear to be pivotal in CNS trauma, but effective strategies for targeting these aspects of secondary injury have been elusive. Proinflammatory cytokines appear to have complex and sometimes contradictory roles in CNS injury and repair. Similarly, glutamate receptors are responsible for excitotoxic death of neurons and glia in injury, but are also essential for normal CNS function, and have been implicated in recovery after injury. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNFa) has recently been shown to have a unique and critical role in the modulation of normal neuronal glutamate synaptic transmission (Beattie et ai, 2002;Stellwagen and Malenka, 2006;Aizenman and Pratt, 2008), and also to exacerbate excitotoxic cell death (Hermann et ai, 2001;Beattie, 2004). We have identified TN Fa-mediated trafficking of GluR2-lacking, Ca++-permeable AMPA receptors (CP-AMPARs) as a novel and perhaps 'nodal'link between injury-induced inflammation and excitotoxicity. TN Fa increases excitotoxic cell death in vitro, and enhances neuronal death after spinal cord injury (SCI). Further, reducing GluR2- lacking AMPAR-insertion into neuronal membranes by blocking TNFa after SCI, results in reduced neuronal death, reduced white matter damage, and better outcomes in a cervical injury model of SCI.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS038079-11
Application #
7782898
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
1999-02-10
Project End
2011-08-14
Budget Start
2010-03-01
Budget End
2011-08-14
Support Year
11
Fiscal Year
2010
Total Cost
$889,321
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Lee, Sangmi; Mattingly, Aaron; Lin, Amity et al. (2016) A novel antagonist of p75NTR reduces peripheral expansion and CNS trafficking of pro-inflammatory monocytes and spares function after traumatic brain injury. J Neuroinflammation 13:88
Miller, Brandon A; Gensel, John C; Beattie, Michael S (2016) CNS Plasticity in Injury and Disease. Neural Plast 2016:1923950
Delbary-Gossart, Sandrine; Lee, Sangmi; Baroni, Marco et al. (2016) A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury. Brain 139:1762-82
Talbott, Jason F; Nout-Lomas, Yvette S; Wendland, Michael F et al. (2016) Diffusion-Weighted Magnetic Resonance Imaging Characterization of White Matter Injury Produced by Axon-Sparing Demyelination and Severe Contusion Spinal Cord Injury in Rats. J Neurotrauma 33:929-42
Song, Yuanquan; Sretavan, David; Salegio, Ernesto A et al. (2015) Regulation of axon regeneration by the RNA repair and splicing pathway. Nat Neurosci 18:817-25
Nielson, Jessica L; Haefeli, Jenny; Salegio, Ernesto A et al. (2015) Leveraging biomedical informatics for assessing plasticity and repair in primate spinal cord injury. Brain Res 1619:124-38
Huie, J Russell; Stuck, Ellen D; Lee, Kuan H et al. (2015) AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury. eNeuro 2:
Wang, Aijun; Brown, Erin G; Lankford, Lee et al. (2015) Placental mesenchymal stromal cells rescue ambulation in ovine myelomeningocele. Stem Cells Transl Med 4:659-69
Irvine, Karen-Amanda; Ferguson, Adam R; Mitchell, Kathleen D et al. (2014) The Irvine, Beatties, and Bresnahan (IBB) Forelimb Recovery Scale: An Assessment of Reliability and Validity. Front Neurol 5:116
Nielson, Jessica L; Guandique, Cristian F; Liu, Aiwen W et al. (2014) Development of a database for translational spinal cord injury research. J Neurotrauma 31:1789-99

Showing the most recent 10 out of 26 publications