Release of glutamate and activation of ionotropic glutamate receptors have been strongly implicated in the pathobiology of post-traumatic CNS injury. The role of metabotropic glutamate receptors (mGluR) has been less well studied. Using both in vivo and in vitro trauma models, we have acquired strong evidence that activation of group I mGluR contributes to neuronal necrosis. We have also demonstrated that among group I mGIuR, mGluRl but not mGluR5 activation, exacerbates post-traumatic neuronal injury. Moreover, recent data indicate that activation of both mGluRl and mGIuR5 may attenuate neuronal apoptosis in vitro. Elucidation of the mechanisms involved in these modulatory actions can provide a better understanding of glutamatergic processes involved in secondary neuronal injury, as well as a potential basis for novel treatment strategies. The proposed studies are intended to extend our initial findings by addressing the following hypotheses: (1) activation of mGluR1 contributes to post-traumatic neuronal necrosis by multiple mechanisms that include enhancing the activity of NMDA receptors, modulating Ca2+ channels in a direction favoring necrosis, potentiating the release of arachidonic acid, upregulating cyclic AMP, and stimulating the activation of calpain; (2) activation of either mGluR1 or mGluR5 attenuates neuronal apoptosis, both post-traumatic and biochemically induced, by inhibiting the intrinsic caspase cascade; (3) injury alters expression of mGluR1 and mGluR5 in a cell type specific fashion; and (4) activation of group I mGluR alters cellular bioenergetic state and associated magnesium homeostasis after traumatic brain injury (TBI), in part by modulating NMDA receptors.
The Specific Aims propose to address these hypotheses by: (1) delineating potential mechanisms of group I mGluR mediated neurotoxicity, including assessment of the relative contributions of modulation of NMDA receptors, Ca2+ channels, arachidonic acid release, cAMP, and calpain activation; and comparing the relative roles of mGluRl and mGluR5 in this process; (2) examining mechanisms by which activation of group I mGluR inhibits neuronal cell death, and comparing the relative effects of mGluR1 and mGluR5 in this regard; (3) evaluating the effects of injury on cell type-specific alterations in mGluR1 and mGluR5 expression, receptor activity, and cell-cell interactions after neuronal injury; (4) determining the effects of group I mGluR modulation on cellular bioenergetics and intracellular free magnesium concentration after TBI, their relationship to subsequent cell death, and the extent to which this is mediated through modulation of NMDA receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037313-08
Application #
7098038
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Hicks, Ramona R
Project Start
1999-02-03
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
8
Fiscal Year
2006
Total Cost
$287,950
Indirect Cost
Name
Georgetown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Henry, Rebecca J; Doran, Sarah J; Barrett, James P et al. (2018) Inhibition of miR-155 Limits Neuroinflammation and Improves Functional Recovery After Experimental Traumatic Brain Injury in Mice. Neurotherapeutics :
Ritzel, Rodney M; Doran, Sarah J; Barrett, James P et al. (2018) Chronic Alterations in Systemic Immune Function after Traumatic Brain Injury. J Neurotrauma 35:1419-1436
Ma, Elise L; Smith, Allen D; Desai, Neemesh et al. (2017) Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice. Brain Behav Immun 66:56-69
Kumar, Alok; Stoica, Bogdan A; Loane, David J et al. (2017) Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury. J Neuroinflammation 14:47
Barrett, James P; Henry, Rebecca J; Villapol, Sonia et al. (2017) NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury. J Neuroinflammation 14:65
Kumar, Alok; Alvarez-Croda, Dulce-Mariely; Stoica, Bogdan A et al. (2016) Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury. J Neurotrauma 33:1732-1750
Kumar, Alok; Barrett, James P; Alvarez-Croda, Dulce-Mariely et al. (2016) NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury. Brain Behav Immun 58:291-309
Faden, Alan I; Wu, Junfang; Stoica, Bogdan A et al. (2016) Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury. Br J Pharmacol 173:681-91
Zhao, Zaorui; Sabirzhanov, Boris; Wu, Junfang et al. (2015) Voluntary Exercise Preconditioning Activates Multiple Antiapoptotic Mechanisms and Improves Neurological Recovery after Experimental Traumatic Brain Injury. J Neurotrauma 32:1347-60
Kabadi, Shruti V; Stoica, Bogdan A; Zimmer, Danna B et al. (2015) S100B inhibition reduces behavioral and pathologic changes in experimental traumatic brain injury. J Cereb Blood Flow Metab 35:2010-20

Showing the most recent 10 out of 36 publications