Novel mGluR5 Positive Allosteric Modulator Improves Functional Recovery, Attenuates Neurodegeneration, and Alters Microglial Polarization after Experimental Traumatic Brain Injury

Loane, David J.; Stoica, Bogdan A.; Tchantchou, Flaubert; Kumar, Alok; Barrett, James W.; Akintola, Titilola; Xue, Fengtian; Conn, P. Jeffrey; Faden, Alan I.

doi:10.1007/s13311-014-0298-6

Cited by 74 publications

(67 citation statements)

References 46 publications

(92 reference statements)

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“…In the injured brain, recruitment of CD68+ microglia/macrophages and sustained GFAP reactivity at the site of injury are known mechanisms of persistent, cytotoxic neuroinflammation that contributes to long-term secondary injury and related neurodegeneration 61 . In experimental models of chronic TBI, these neurodegenerative and neuroinflammatory processes are linked to alterations in cognitive and behavioral functions 62,63 . In the present study, neuronal densities in the hippocampus were not reduced further in the TBI+ Cr group, indicating that the exacerbation of brain injury was confined to the cortical lesion.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Elise

Smith

Desai

et al. 2017

Brain, Behavior, and Immunity

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123

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Objectives Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related morbidity and mortality. We examined changes in mucosal barrier properties and enteric glial cell response in the gut after experimental TBI in mice, as well as effects of the enteric pathogen Citrobacter rodentium (Cr) on both gut and brain after injury. Methods Moderate-level TBI was induced in C57BL/6 mice by controlled cortical impact (CCI). Mucosal barrier function was assessed by transepithelial resistance, fluorescent-labelled dextran flux, and quantification of tight junction proteins. Enteric glial cell number and activation were measured by Sox10 expression and GFAP reactivity, respectively. Separate groups of mice were challenged with Cr infection during the chronic phase of TBI, and host immune response, barrier integrity, enteric glial cell reactivity, and progression of brain injury and inflammation were assessed. Results Chronic CCI induced changes in colon morphology, including increased mucosal depth and smooth muscle thickening. At day 28 post-CCI, increased paracellular permeability and decreased claudin-1 mRNA and protein expression were observed in the absence of inflammation in the colon. Colonic glial cell GFAP and Sox10 expression were significantly increased 28 days after brain injury. Clearance of Cr and upregulation of Th1/Th17 cytokines in the colon were unaffected by CCI; however, colonic paracellular flux and enteric glial cell GFAP expression were significantly increased. Importantly, Cr infection in chronically-injured mice worsened the brain lesion injury and increased astrocyte- and microglial-mediated inflammation. Conclusion These experimental studies demonstrate chronic and bidirectional brain-gut interactions after TBI, which may negatively impact late outcomes after brain injury.

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Section: Discussionmentioning

confidence: 99%

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Elise

Smith

Desai

et al. 2017

Brain, Behavior, and Immunity

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123

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“…Control and LPS-stimulated MP (total 8 × 10 5 MP) were co-cultured with BV2 microglia (2 × 10 4 /96 well) or primary microglia (1 × 10 5 /96 well) that were obtained from postnatal day 1 C57BL/6 mouse pups as previously described [31] for 24 h at 37 °C and at 5% CO 2 prior to cell extraction using TRIzol reagent (Invitrogen) to assess markers of microglial activation.…”

Section: Methodsmentioning

confidence: 99%

Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury

Kumar

Stoica

Loane

et al. 2017

J Neuroinflammation

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BackgroundLocal and systemic inflammatory responses are initiated early after traumatic brain injury (TBI), and may play a key role in the secondary injury processes resulting in neuronal loss and neurological deficits. However, the mechanisms responsible for the rapid expansion of neuroinflammation and its long-term progression have yet to be elucidated. Here, we investigate the role of microparticles (MP), a member of the extracellular vesicle family, in the exchange of pro-inflammatory molecules between brain immune cells, as well as their transfer to the systemic circulation, as key pathways of inflammation propagation following brain trauma.MethodsAdult male C57BL/6 mice were subjected to controlled cortical impact TBI for 24 h, and enriched MP were isolated in the blood, while neuroinflammation was assessed in the TBI cortex. MP were characterized by flow cytometry, and MP content was assayed using gene and protein markers for pro-inflammatory mediators. Enriched MP co-cultured with BV2 or primary microglial cells were used for immune propagation assays. Enriched MP from BV2 microglia or CD11b-positive microglia from the TBI brain were stereotactically injected into the cortex of uninjured mice to evaluate MP-related seeding of neuroinflammation in vivo.ResultsAs the neuroinflammatory response is developing in the brain after TBI, microglial-derived MP are released into the circulation. Circulating enriched MP from the TBI animals can activate microglia in vitro. Lipopolysaccharide stimulation increases MP release from microglia in vitro and enhances their content of pro-inflammatory mediators, interleukin-1β and microRNA-155. Enriched MP from activated microglia in vitro or CD11b-isolated microglia/macrophage from the TBI brain ex vivo are sufficient to initiate neuroinflammation following their injection into the cortex of naïve (uninjured) animals.ConclusionsThese data provide further insights into the mechanisms underlying the development and dissemination of neuroinflammation after TBI. MP loaded with pro-inflammatory molecules initially released by microglia following trauma can activate additional microglia that may contribute to progressive neuroinflammatory response in the injured brain, as well as stimulate systemic immune responses. Due to their ability to independently initiate inflammatory responses, MP derived from activated microglia may provide a potential therapeutic target for other neurological disorders in which neuroinflammation may be a contributing factor.

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“…Positive allosteric activation of mGluR5 has powerful neuroprotective effects in experimental models of CNS injury (Loane et al, 2014b). …”

Section: Anti-inflammatory Treatments Targeting Microglia Activation mentioning

confidence: 99%

Microglial Activation in Traumatic Brain Injury

Donat

Scott

Gentleman

et al. 2017

Front. Aging Neurosci.

343

279

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Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.

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Novel mGluR5 Positive Allosteric Modulator Improves Functional Recovery, Attenuates Neurodegeneration, and Alters Microglial Polarization after Experimental Traumatic Brain Injury

Cited by 74 publications

References 46 publications

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury

Microglial Activation in Traumatic Brain Injury

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