title: Novel mGluR5 positive allosteric modulator improves functional recovery, attenuates neurodegeneration, and alters microglial polarization after experimental traumatic brain injury.
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.
authors.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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Loane
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.forename: Flaubert
authors.initials: F
authors.lastname: Tchantchou
authors.forename: Alok
authors.initials: A
authors.lastname: Kumar
authors.forename: James P
authors.initials: JP
authors.lastname: Barrett
authors.forename: Titilola
authors.initials: T
authors.lastname: Akintola
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism / Q000517:prevention & control*; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists* / Q000037:antagonists & inhibitors; D020127:Recovery of Function; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C107349:2-chloro-5-hydroxyphenylglycine; C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C578936:Grm5 protein, mouse; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D010648:Phenylacetates; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D005998:Glycine
references.citation: Biol Psychiatry. 2007 Oct 1;62(7):739-46
references.pmid: 17511968
references.citation: Wiley Interdiscip Rev Membr Transp Signal. 2012 Mar;1(2):136-150
references.pmid: 22662309
references.citation: J Med Chem. 2006 Jun 1;49(11):3332-44
references.pmid: 16722652
references.citation: J Neurosci. 2007 Oct 3;27(40):10714-21
references.pmid: 17913905
references.citation: CNS Neurol Disord Drug Targets. 2014;13(4):558-66
references.pmid: 24168364
references.citation: J Clin Neurosci. 2006 Dec;13(10):1023-7
references.pmid: 17113985
references.citation: Nat Rev Immunol. 2003 Jan;3(1):23-35
references.pmid: 12511873
references.citation: Neurobiol Dis. 2014 Jan;61:55-71
references.pmid: 24076101
references.citation: J Neuropathol Exp Neurol. 2014 Jan;73(1):14-29
references.pmid: 24335533
references.citation: Cell Death Differ. 2000 May;7(5):470-6
references.pmid: 10800080
references.citation: Eur J Pharmacol. 2010 Aug 10;639(1-3):47-58
references.pmid: 20371237
references.citation: Ann Neurol. 2009 Jul;66(1):63-74
references.pmid: 19670441
references.citation: Exp Neurol. 1999 Jan;155(1):79-94
references.pmid: 9918707
references.citation: Eur J Pharmacol. 2007 Jan 5;554(1):18-29
references.pmid: 17109843
references.citation: J Neurotrauma. 1998 Aug;15(8):599-614
references.pmid: 9726259
references.citation: J Pharmacol Exp Ther. 2005 Apr;313(1):199-206
references.pmid: 15608073
references.citation: Neuropharmacology. 2011 Jun;60(7-8):1017-41
references.pmid: 21036182
references.citation: J Neurotrauma. 2013 Mar 1;30(5):403-12
references.pmid: 23199080
references.citation: Biochem Biophys Res Commun. 2013 Jan 18;430(3):1016-21
references.pmid: 23261470
references.citation: J Neuroinflammation. 2012 Feb 28;9:43
references.pmid: 22373400
references.citation: Eur J Pharmacol. 2010 Aug 10;639(1-3):33-9
references.pmid: 20371231
references.citation: J Neuroinflammation. 2006 Sep 27;3:27
references.pmid: 17005052
references.citation: Biol Psychiatry. 2009 Apr 15;65(8):717-20
references.pmid: 19100966
references.citation: Mol Pharmacol. 2012 Feb;81(2):120-33
references.pmid: 22021324
references.citation: Neuropsychopharmacology. 2004 Jul;29(7):1259-69
references.pmid: 15010696
references.citation: Trends Immunol. 2004 Dec;25(12):677-86
references.pmid: 15530839
references.citation: Neurosci Lett. 2011 Nov 14;505(2):140-5
references.pmid: 22015768
references.citation: Neurobiol Aging. 2013 May;34(5):1397-411
references.pmid: 23273602
references.citation: Neurotherapeutics. 2010 Oct;7(4):354-65
references.pmid: 20880500
references.citation: Nat Med. 2009 Apr;15(4):377-9
references.pmid: 19287391
references.citation: Neurotherapeutics. 2009 Jan;6(1):94-107
references.pmid: 19110202
references.citation: Neuropsychopharmacology. 2009 Aug;34(9):2057-71
references.pmid: 19295507
references.citation: J Neurosci Res. 2004 Aug 15;77(4):525-31
references.pmid: 15264222
references.citation: Brain Res. 2001 Dec 20;922(2):173-9
references.pmid: 11743947
references.citation: Nat Rev Drug Discov. 2009 Jan;8(1):41-54
references.pmid: 19116626
references.citation: Mol Neurobiol. 2009 Oct;40(2):139-56
references.pmid: 19629762
references.citation: J Biol Chem. 2009 Jun 5;284(23):15629-39
references.pmid: 19364772
references.citation: Int J Mol Med. 2012 Apr;29(4):630-6
references.pmid: 22211238
references.citation: Mol Pharmacol. 2010 Dec;78(6):1105-23
references.pmid: 20923853
references.citation: Glia. 2009 Apr 1;57(5):550-60
references.pmid: 18816644
references.citation: J Neuroimmune Pharmacol. 2009 Dec;4(4):399-418
references.pmid: 19655259
references.citation: J Neurotrauma. 2012 Oct 10;29(15):2475-89
references.pmid: 22924665
references.citation: Neuropharmacology. 1999 Aug;38(8):1243-52
references.pmid: 10462136
references.citation: J Neural Transm (Vienna). 2008 Dec;115(12):1609-19
references.pmid: 18690408
references.citation: J Neurochem. 2004 Jun;89(6):1528-36
references.pmid: 15189356
references.citation: J Pharmacol Exp Ther. 2003 Jul;306(1):116-23
references.pmid: 12660307