Top

Published in:

01-10-2014 | Original Article

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

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

Published in: Neurotherapeutics | Issue 4/2014

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.

Available only for authorised users

Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 2009;8:41–54. doi:10.1038/nrd2760.PubMedCrossRefPubMedCentral

Nickols HH, Conn PJ. Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol Dis 2014;61:55–71. doi:10.1016/j.nbd.2013.09.013.PubMedCrossRef

Nicoletti F, Bockaert J, Collingridge GL, et al. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology. 2011;60:1017–1041. doi:10.1016/j.neuropharm.2010.10.022.PubMedCrossRefPubMedCentral

Byrnes KR, Loane DJ, Faden AI. Metabotropic glutamate receptors as targets for multipotential treatment of neurological disorders. Neurotherapeutics. 2009;6:94–107. doi:10.1016/j.nurt.2008.10.038.PubMedCrossRefPubMedCentral

Allen JW, Knoblach SM, Faden AI. Activation of group I metabotropic glutamate receptors reduces neuronal apoptosis but increases necrotic cell death in vitro. Cell Death Differ 2000;7:470–476. doi:10.1038/sj.cdd.4400678.PubMedCrossRef

Allen JW, Eldadah BA, Faden AI. Beta-amyloid-induced apoptosis of cerebellar granule cells and cortical neurons: exacerbation by selective inhibition of group I metabotropic glutamate receptors. Neuropharmacology 1999;38:1243–1252.PubMedCrossRef

Fei Z, Zhang X, Bai HM, Jiang XF, Wang XL. Metabotropic glutamate receptor antagonists and agonists: potential neuroprotectors in diffuse brain injury. J Clin Neurosci 2006;13:1023–1027.PubMedCrossRef

Szydlowska K, Kaminska B, Baude A, Parsons CG, Danysz W. Neuroprotective activity of selective mGlu1 and mGlu5 antagonists in vitro and in vivo. Eur J Pharmacol 2007;554:18–29.PubMedCrossRef

Movsesyan VA, Stoica BA, Faden AI. MGLuR5 activation reduces beta-amyloid-induced cell death in primary neuronal cultures and attenuates translocation of cytochrome c and apoptosis-inducing factor. J Neurochem 2004;89:1528–1536.PubMedCrossRef

10.

Vincent AM, TenBroeke M, Maiese K. Metabotropic glutamate receptors prevent programmed cell death through the modulation of neuronal endonuclease activity and intracellular pH. Exp Neurol 1999;155:79–94. doi:10.1006/exnr.1998.6966.PubMedCrossRef

11.

Zhu P, DeCoster MA, Bazan NG. Interplay among platelet-activating factor, oxidative stress, and group I metabotropic glutamate receptors modulates neuronal survival. J Neurosci Res 2004;77:525–531. doi:10.1002/jnr.20175.PubMedCrossRef

12.

Bao WL, Williams AJ, Faden AI, Tortella FC. Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischemia. Brain Res 2001;922:173–179.PubMedCrossRef

13.

Byrnes KR, Loane DJ, Stoica BA, Zhang J, Faden AI. Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury. J Neuroinflammation. 2012;9:43. doi:10.1186/1742-2094-9-43.PubMedCrossRefPubMedCentral

14.

Byrnes KR, Stoica B, Riccio A, Pajoohesh-Ganji A, Loane DJ, Faden AI. Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents. Ann Neurol 2009;66:63–74. doi:10.1002/ana.21673.PubMedCrossRefPubMedCentral

15.

Chen T, Zhang L, Qu Y, Huo K, Jiang X, Fei Z. The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway. Int J Mol Med 2012;29:630–636. doi:10.3892/ijmm.2011.870.PubMedPubMedCentral

16.

Loane DJ, Stoica BA, Byrnes KR, Jeong W, Faden AI. Activation of mGluR5 and inhibition of NADPH oxidase improves functional recovery after traumatic brain injury. J Neurotrauma 2013;30:403–412. doi:10.1089/neu.2012.2589.PubMedCrossRefPubMedCentral

17.

Wang JW, Wang HD, Cong ZX, Zhang XS, Zhou XM, Zhang DD. Activation of metabotropic glutamate receptor 5 reduces the secondary brain injury after traumatic brain injury in rats. Biochem Biophys Res Commun 2013;430:1016–1021. doi:10.1016/j.bbrc.2012.12.046.PubMedCrossRef

18.

Loane DJ, Stoica BA, Faden AI. Metabotropic glutamate receptor-mediated signaling in neuroglia. Wiley Interdiscip Rev Membr Transp Signal 2012;1:136–150. doi:10.1002/wmts.30.PubMedCrossRefPubMedCentral

19.

Byrnes KR, Stoica B, Loane DJ, Riccio A, Davis MI, Faden AI. Metabotropic glutamate receptor 5 activation inhibits microglial associated inflammation and neurotoxicity. Glia 2009;57:550–560. doi:10.1002/glia.20783.PubMedCrossRefPubMedCentral

20.

Loane DJ, Stoica BA, Pajoohesh-Ganji A, Byrnes KR, Faden AI. Activation of metabotropic glutamate receptor 5 modulates microglial reactivity and neurotoxicity by inhibiting NADPH oxidase. J Biol Chem 2009;284:15629-39. doi:10.1074/jbc.M806139200.PubMedCrossRefPubMedCentral

21.

Loane DJ, Kumar A, Stoica BA, Cabatbat R, Faden AI. Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J Neuropathol Exp Neurol 2014;73:14–29. doi:10.1097/NEN.0000000000000021.PubMedCrossRef

22.

Homayoun H, Moghaddam B. Group 5 metabotropic glutamate receptors: role in modulating cortical activity and relevance to cognition. Eur J Pharmacol 2010;639:33–39. doi:10.1016/j.ejphar.2009.12.042.PubMedCrossRef

23.

Kinney GG, Burno M, Campbell UC, et al. Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther 2003;306:116–123. doi: 10.1124/jpet.103.048702.PubMedCrossRef

24.

Lecourtier L, Homayoun H, Tamagnan G, Moghaddam B. Positive allosteric modulation of metabotropic glutarnate 5 (rnGlu5) receptors reverses N-methyl-d-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex. Biol Psychiatry 2007;62:739–746. doi: 10.1016/j.biopsych.2006.12.003.PubMedCrossRefPubMedCentral

25.

Homayoun H, Stefani MR, Adams BW, Tamagan GD, Moghaddam B. Functional interaction between NMDA and mGlu5 receptors: effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology 2004;29:1259–1269. doi: 10.1038/sj.npp.1300417.PubMedCrossRef

26.

Kinney GG, O'Brien JA, Lemaire W, et al. A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J Pharmacol Exp Ther 2005;313:199–206. doi: 10.1124/jpet.104.079244.PubMedCrossRef

27.

Gravius A, Dekundy A, Nagel J, More L, Pietraszek M, Danysz W. Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats. J Neural Transm 2008;115:1609–1619. doi: 10.1007/s00702-008-0098-4.PubMedCrossRef

28.

Gass JT, Olive MF. Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory. Biol Psychiatry 2009;65:717–20. doi: 10.1016/j.biopsych.2008.11.001.PubMedCrossRefPubMedCentral

29.

Olive MF. Cognitive effects of Group I metabotropic glutamate receptor ligands in the context of drug addiction. Eur J Pharmacol 2010;639:47–58. doi:10.1016/j.ejphar.2010.01.029.PubMedCrossRefPubMedCentral

30.

Ayala JE, Chen YL, Banko JL, et al. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 2009;34:2057–2071. doi: 10.1038/Npp.2009.30.PubMedCrossRefPubMedCentral

31.

Xue F, Stoica BA, Hanscom M, Kabadi SV, Faden AI. Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGluR5) attenuate microglial activation. CNS Neurol Disord Drug Targets 2013;13:558–566CrossRef

32.

Rodriguez AL, Grier MD, Jones CK, et al. Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol Pharmacol 2010;78:1105–1123. doi:10.1124/mol.110.067207.PubMedCrossRefPubMedCentral

33.

Fox GB, Fan L, Levasseur RA, Faden AI. Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse. J Neurotrauma 1998;15:599–614.PubMedCrossRef

34.

Zhao Z, Loane DJ, Murray MG 2nd, Stoica BA, Faden AI. Comparing the predictive value of multiple cognitive, affective, and motor tasks after rodent traumatic brain injury. J Neurotrauma 2012;29:2475–2489. doi:10.1089/neu.2012.2511.PubMedCrossRefPubMedCentral

35.

Kumar A, Stoica BA, Sabirzhanov B, Burns MP, Faden AI, Loane DJ. Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol Aging 2013;34:1397–1411. doi:10.1016/j.neurobiolaging.2012.11.013.PubMedCrossRefPubMedCentral

36.

Loane DJ, Pocivavsek A, Moussa CE, et al. Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nature Med 2009;15:377–379. doi:10.1038/nm.1940.PubMedCrossRefPubMedCentral

37.

Colton CA. Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 2009;4:399–418. doi:10.1007/s11481-009-9164-4.PubMedCrossRefPubMedCentral

38.

Lynch MA. The multifaceted profile of activated microglia. Mol Neurobiol 2009;40:139–156. doi:10.1007/s12035-009-8077-9.PubMedCrossRef

39.

de Paulis T, Hemstapat K, Chen Y, et al. Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes. J Med Chem 2006;49:3332–3344. doi:10.1021/jm051252j.PubMedCrossRef

40.

Noetzel MJ, Rook JM, Vinson PN, et al. Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function. Mol Pharmacol 2012;81:120–133. doi:10.1124/mol.111.075184.PubMedCrossRefPubMedCentral

41.

Lull ME, Block ML. Microglial activation and chronic neurodegeneration. Neurotherapeutics 2010;7:354–365.PubMedCrossRefPubMedCentral

42.

Piers TM, Heales SJ, Pocock JM. Positive allosteric modulation of metabotropic glutamate receptor 5 down-regulates fibrinogen-activated microglia providing neuronal protection. Neurosci Lett 2011;505:140–145. doi:10.1016/j.neulet.2011.10.007.PubMedCrossRef

43.

Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003;3:23–35. doi:10.1038/nri978nri978.PubMedCrossRef

44.

Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004;25:677–686.PubMedCrossRef

45.

Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 2006;3:27. doi:10.1186/1742-2094-3-27.PubMedCrossRefPubMedCentral

46.

Ponomarev ED, Maresz K, Tan Y, Dittel BN. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 2007;27:10714–10721. doi:10.1523/JNEUROSCI.1922-07.2007.PubMedCrossRef

Title: Novel mGluR5 Positive Allosteric Modulator Improves Functional Recovery, Attenuates Neurodegeneration, and Alters Microglial Polarization after Experimental Traumatic Brain Injury
Authors: David J. Loane
Bogdan A. Stoica
Flaubert Tchantchou
Alok Kumar
James P. Barrett
Titilola Akintola
Fengtian Xue
P. Jeffrey Conn
Alan I. Faden
Publication date: 01-10-2014
Publisher: Springer US
Published in: Neurotherapeutics / Issue 4/2014
Print ISSN: 1933-7213
Electronic ISSN: 1878-7479
DOI: https://doi.org/10.1007/s13311-014-0298-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2014

Neurogenetic Disease: Genes, Mechanisms, and Future Promise

Spinal Muscular Atrophy: Journeying From Bench to Bedside

Epigenetic Mechanisms Underlying the Pathogenesis of Neurogenetic Diseases

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

Next Generation Sequencing and the Future of Genetic Diagnosis

A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy