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    Inhibition of Traumatic Brain Injury (TBI)-Induced Neuroinflammation Using Pharmacological Modulators of Metabotropic Glutamate Receptors

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    Author
    Vinueza, Gelareh
    0000-0002-1036-6378
    Advisor
    Faden, A. I.
    Date
    2020
    Type
    dissertation
    
    Metadata
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    Abstract
    Chronic dysregulated microglial activation is a major hallmark of persistent inflammation and progressive neurodegeneration following traumatic brain injury (TBI). Thus, research has focused on strategies to inhibit chronically activated microglial responses following TBI. Metabotropic glutamate receptors (mGluRs) 4 and 5 are expressed on microglia and can modulate microglial activity; therefore, they may serve as potential therapeutic targets for inhibition of microglial-dependent neuroinflammation. In the first of these studies, based on its reported neuroprotective roles, we examined the effects of the mGluR5 positive allosteric modulator (PAM) VU0360172 in an established fluid percussion injury (FPI) rat model of TBI plus hypobaria (HB). Systemic administration of VU0360172 significantly reduced pro-inflammatory cytokines, chemokines and microRNAs (miRs) at 1- and 7- days following FP+HB. However, VU0360172 did not alter injury-induced behavioral deficits examined over the following 28 days. In order to assess potential mechanisms underlying the inflammatory changes, we used Nanostring analysis to identify miRs that modulate neuroinflammation and compared plasma changes for selected miRs with brain tissue changes. The pro-inflammatory miR-223 showed the strongest correlation between plasma and brain tissue expression levels at the 7d time-point in TBI+HB experimental rodent models. An additional series of studies addressed the purported anti-inflammatory effects of mGluR4 PAMs. We employed in vitro models of immortalized microglia cell lines and primary microglia to elucidate the molecular mechanisms responsible for the modulation of inflammation by ADX88178 and other mGluR4 PAMs. ADX88178 downregulated lipopolysaccharide (LPS)-induced expression of pro-inflammatory mediators in BV2 cells and primary microglia. However, ADX88178 anti-inflammatory effects appeared to be mGluR4-independent as mGluR4 expression in our in vitro models was very low and its actions were not altered by pharmacological or molecular inhibition of mGluR4. Moreover, we showed that putative mGluR4 PAMs attenuate pro-inflammatory pathways in BV2 microglia through mGluR4/Gi-independent mechanisms involving activation of cAMP-response element binding protein (CREB) and inhibition of NFkB. Overall, these studies show that mGluR4 and mGluR5 PAMs can significantly attenuate microglial activation. Therefore, further studies should examine their potential therapeutic effectiveness after TBI.
    Description
    2020
    Molecular Medicine
    University of Maryland, Baltimore
    Ph.D.
    Keyword
    fluid percussion injury
    neuroinflammation
    Brain Injuries, Traumatic
    Microglia
    Neuropharmacology
    Receptors, Metabotropic Glutamate
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13523
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    Theses and Dissertations School of Medicine
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