Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury

Journal of Neuroinflammation

Alan I Faden²  Jiangyang Zhang³  Bogdan A Stoica²  David J Loane²  Kimberly R Byrnes¹ 

[1] Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD, USA;Department of Radiology, Johns Hopkins University, Baltimore, MD, USA

关键词: neuroprotection;    delayed treatment;    metabotropic glutamate receptor 5;    microglia;    Traumatic brain injury;   

Others  :  1212764
DOI  :  10.1186/1742-2094-9-43

 received in 2011-11-21, accepted in 2012-02-28,  发布年份 2012

【 摘 要 】

Background

Traumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5) activation by (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) decreases microglial activation and release of associated pro-inflammatory factors in vitro, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice.

Methods

One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.

Results

Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field ex vivo diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.

Conclusion

Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.

【 授权许可】

   
2012 Byrnes et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Loane DJ, Faden AI: Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci 2010, 31:596-604.
• [2]Bramlett HM, Dietrich WD: Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies. Prog Brain Res 2007, 161:125-141.
• [3]Loane DJ, Byrnes KR: Role of microglia in neurotrauma. Neurotherapeutics 2010, 7:366-377.
• [4]Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB: ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005, 8:752-758.
• [5]Block ML, Zecca L, Hong JS: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007, 8:57-69.
• [6]Aloisi F: Immune function of microglia. Glia 2001, 36:165-179.
• [7]Block ML, Hong JS: Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 2005, 76:77-98.
• [8]Wilson S, Raghupathi R, Saatman KE, MacKinnon MA, McIntosh TK, Graham DI: Continued in situ DNA fragmentation of microglia/macrophages in white matter weeks and months after traumatic brain injury. J Neurotrauma 2004, 21:239-250.
• [9]Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, Gentleman S, Heckemann RA, Gunanayagam K, Gelosa G, Sharp DJ: Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 2011, 70:374-383.
• [10]Nagamoto-Combs K, McNeal DW, Morecraft RJ, Combs CK: Prolonged microgliosis in the rhesus monkey central nervous system after traumatic brain injury. J Neurotrauma 2007, 24:1719-1742.
• [11]Gentleman SM, Leclercq PD, Moyes L, Graham DI, Smith C, Griffin WS, Nicoll JA: Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Sci Int 2004, 146:97-104.
• [12]Smith DH, Chen XH, Pierce JE, Wolf JA, Trojanowski JQ, Graham DI, McIntosh TK: Progressive atrophy and neuron death for one year following brain trauma in the rat. J Neurotrauma 1997, 14:715-727.
• [13]Maxwell WL, MacKinnon MA, Smith DH, McIntosh TK, Graham DI: Thalamic nuclei after human blunt head injury. J Neuropathol Exp Neurol 2006, 65:478-488.
• [14]Bramlett HM, Dietrich WD: Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathol 2002, 103:607-614.
• [15]Bendlin BB, Ries ML, Lazar M, Alexander AL, Dempsey RJ, Rowley HA, Sherman JE, Johnson SC: Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging. NeuroImage 2008, 42:503-514.
• [16]Byrnes KR, Garay J, Di Giovanni S, De Biase A, Knoblach SM, Hoffman EP, Movsesyan V, Faden AI: Expression of two temporally distinct microglia-related gene clusters after spinal cord injury. Glia 2006, 53:420-433.
• [17]Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS: NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 2004, 279:1415-1421.
• [18]Gao HM, Hong JS: Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 2008, 29:357-365.
• [19]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, 284:15629-15639.
• [20]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.
• [21]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.
• [22]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.
• [23]Loane DJ, Pocivavsek A, Moussa CE, Thompson R, Matsuoka Y, Faden AI, Rebeck GW, Burns MP: Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med 2009, 15:377-379.
• [24]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.
• [25]Aggarwal M, Mori S, Shimogori T, Blackshaw S, Zhang J: Three-dimensional diffusion tensor microimaging for anatomical characterization of the mouse brain. Magn Reson Med 2010, 64:249-261.
• [26]Basser PJ, Mattiello J, LeBihan D: Estimation of the effective self-diffusion tensor from the NMR spin echo. J Magn Reson B 1994, 103:247-254.
• [27]Basser PJ, Pierpaoli C: A simplified method to measure the diffusion tensor from seven MR images. Magn Reson Med 1998, 39:928-934.
• [28]Jiang H, van Zijl PC, Kim J, Pearlson GD, Mori S: DtiStudio: resource program for diffusion tensor computation and fiber bundle tracking. Comput Methods Programs Biomed 2006, 81:106-116.
• [29]Aggarwal M, Zhang J, Miller MI, Sidman RL, Mori S: Magnetic resonance imaging and micro-computed tomography combined atlas of developing and adult mouse brains for stereotaxic surgery. Neuroscience 2009, 162:1339-1350.
• [30]Woods RP, Grafton ST, Holmes CJ, Cherry SR, Mazziotta JC: Automated image registration: I. General methods and intrasubject, intramodality validation. J Comput Assist Tomogr 1998, 22:139-152.
• [31]Woods RP, Grafton ST, Watson JD, Sicotte NL, Mazziotta JC: Automated image registration: II. Intersubject validation of linear and nonlinear models. J Comput Assist Tomogr 1998, 22:153-165.
• [32]Frick KM, Stillner ET, Berger-Sweeney J: Mice are not little rats: species differences in a one-day water maze task. NeuroReport 2000, 11:3461-3465.
• [33]Brody DL, Holtzman DM: Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury. Exp Neurol 2006, 197:330-340.
• [34]Soltys Z, Ziaja M, Pawlinski R, Setkowicz Z, Janeczko K: Morphology of reactive microglia in the injured cerebral cortex Fractal analysis and complementary quantitative methods. J Neurosci Res 2001, 63:90-97.
• [35]Kabadi SV, Stoica BA, Byrnes KR, Hanscom M, Loane DJ, Faden AI: Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma. J Cereb Blood Flow Metab 2011, 32:137-149.
• [36]Davis E, Foster T, Thomas W: Cellular forms and functions of brain microglia. Brain Res Bull 1994, 34:73-78.
• [37]Zhan X, Kim C, Sharp F: Very brief focal ischemia simulating transient ischemic attacks (TIAs) can injure brain and induce Hsp70 protein. Brain Res 2008, 1234:184-197.
• [38]Nonaka M, Chen XH, Pierce JE, Leoni MJ, McIntosh TK, Wolf JA, Smith DH: Prolonged activation of NF-kappaB following traumatic brain injury in rats. J Neurotrauma 1999, 16:1023-1034.
• [39]Rodriguez-Paez AC, Brunschwig JP, Bramlett HM: Light and electron microscopic assessment of progressive atrophy following moderate traumatic brain injury in the rat. Acta Neuropathol 2005, 109:603-616.
• [40]Drouin-Ouellet J, Brownell AL, Saint-Pierre M, Fasano C, Emond V, Trudeau LE, Levesque D, Cicchetti F: Neuroinflammation is associated with changes in glial mGluR5 expression and the development of neonatal excitotoxic lesions. Glia 2011, 59:188-199.
• [41]Nimmerjahn A, Kirchhoff F, Helmchen F: Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308:1314-1318.
• [42]Vilhardt F: Microglia: phagocyte and glia cell. Int J Biochem Cell Biol 2005, 37:17-21.
• [43]Lynch MA: The multifaceted profile of activated microglia. Mol Neurobiol 2009, 40:139-156.
• [44]Kabadi SV, Stoica BA, Loane DJ, Byrnes KR, Hanscom M, Cabatbat RM, Tan MT, Faden AI: Cyclin D1 gene ablation confers neuroprotection in traumatic brain injury. J Neurotrauma 2012, in press.
• [45]Wang H, Lynch JR, Song P, Yang HJ, Yates RB, Mace B, Warner DS, Guyton JR, Laskowitz DT: Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury. Exp Neurol 2007, 206:59-69.
• [46]Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A: Neuroinflammation in Alzheimer's disease and prion disease. Glia 2002, 40:232-239.
• [47]Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG: Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 2009, 29:13435-13444.
• [48]Chen H, Kim GS, Okami N, Narasimhan P, Chan PH: NADPH oxidase is involved in post-ischemic brain inflammation. Neurobiol Dis 2011, 42:341-348.
• [49]Byrnes KR, Loane DJ, Faden AI: Metabotropic glutamate receptors as targets for multipotential treatment of neurological disorders. Neurotherapeutics 2009, 6:94-107.
• [50]Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP: Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 2010, 60:1017-1041.
• [51]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.
• [52]Deng W, Wang H, Rosenberg PA, Volpe JJ, Jensen FE: Role of metabotropic glutamate receptors in oligodendrocyte excitotoxicity and oxidative stress. Proc Natl Acad Sci USA 2004, 101:7751-7756.
• [53]Menon DK: Unique challenges in clinical trials in traumatic brain injury. Crit Care Med 2009, 37:S129-135.
• [54]Stoica BA, Faden AI: Cell death mechanisms and modulation in traumatic brain injury. Neurotherapeutics 2010, 7:3-12.
• [55]Faden AI: Neuroprotection and traumatic brain injury: theoretical option or realistic proposition. Curr Opin Neurol 2002, 15:707-712.
• [56]Trivedi MA, Ward MA, Hess TM, Gale SD, Dempsey RJ, Rowley HA, Johnson SC: Longitudinal changes in global brain volume between 79 and 409 days after traumatic brain injury: relationship with duration of coma. J Neurotrauma 2007, 24:766-771.
• [57]Sidaros A, Skimminge A, Liptrot MG, Sidaros K, Engberg AW, Herning M, Paulson OB, Jernigan TL, Rostrup E: Long-term global and regional brain volume changes following severe traumatic brain injury: a longitudinal study with clinical correlates. NeuroImage 2009, 44:1-8.
• [58]Mac Donald CL, Dikranian K, Bayly P, Holtzman D, Brody D: Diffusion tensor imaging reliably detects experimental traumatic axonal injury and indicates approximate time of injury. J Neurosci 2007, 27:11869-11876.
• [59]Niogi SN, Mukherjee P, Ghajar J, Johnson CE, Kolster R, Lee H, Suh M, Zimmerman RD, Manley GT, McCandliss BD: Structural dissociation of attentional control and memory in adults with and without mild traumatic brain injury. Brain 2008, 131:3209-3221.
• [60]Lowenstein DH, Thomas MJ, Smith DH, McIntosh TK: Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci 1992, 12:4846-4853.
• [61]Smith DH, Soares HD, Pierce JS, Perlman KG, Saatman KE, Meaney DF, Dixon CE, McIntosh TK: A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. J Neurotrauma 1995, 12:169-178.