Novel mGluR5 Positive Allosteric Modulator Improves Functional Recovery,Attenuates Neurodegeneration,and Alters Microglial Polarization after Experimental Traumatic Brain Injury |
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| Authors: | David J. Loane Bogdan A. Stoica Flaubert Tchantchou Alok Kumar James P. Barrett Titilola Akintola Fengtian Xue P. Jeffrey Conn Alan I. Faden |
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| Affiliation: | Department of Anesthesiology and Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine, Health Sciences Facility II (HSFII), #S247, 20 Penn Street, Baltimore, MD 21201 USA ;Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD USA ;Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN USA |
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| Abstract: | Traumatic brain injury (TBI) causes microglial activation and related neurotoxicity that contributes to chronic neurodegeneration and loss of neurological function. Selective activation of metabotropic glutamate receptor 5 (mGluR5) by the orthosteric agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), is neuroprotective in experimental models of TBI, and has potent anti-inflammatory effects in vitro. However, the therapeutic potential of CHPG is limited due to its relatively weak potency and brain permeability. Highly potent, selective and brain penetrant mGluR5 positive allosteric modulators (PAMs) have been developed and show promise as therapeutic agents. We evaluated the therapeutic potential of a novel mGluR5 PAM, VU0360172, after controlled cortical impact (CCI) in mice. Vehicle, VU0360172, or VU0360172 plus mGluR5 antagonist (MTEP), were administered systemically to CCI mice at 3 h post-injury; lesion volume, hippocampal neurodegeneration, microglial activation, and functional recovery were assessed through 28 days post-injury. Anti-inflammatory effects of VU0360172 were also examined in vitro using BV2 and primary microglia. VU0360172 treatment significantly reduced the lesion, attenuated hippocampal neurodegeneration, and improved motor function recovery after CCI. Effects were mediated by mGluR5 as co-administration of MTEP blocked the protective effects of VU0360172. VU0360172 significantly reduced CD68 and NOX2 expression in activated microglia in the cortex at 28 days post-injury, and also suppressed pro-inflammatory signaling pathways in BV2 and primary microglia. In addition, VU0360172 treatment shifted the balance between M1/M2 microglial activation states towards an M2 pro-repair phenotype. This study demonstrates that VU0360172 confers neuroprotection after experimental TBI, and suggests that mGluR5 PAMs may be promising therapeutic agents for head injury.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-014-0298-6) contains supplementary material, which is available to authorized users. |
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| Keywords: | Traumatic brain injury Metabotropic glutamate receptor 5 Positive allosteric modulator Neuroprotection Functional recovery Microglial activation |
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