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Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents
Author(s) -
Byrnes Kimberly R.,
Stoica Bogdan,
Riccio Angela,
PajooheshGanji Ahdeah,
Loane David J.,
Faden Alan I.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21673
Subject(s) - metabotropic glutamate receptor 5 , microglia , spinal cord injury , pharmacology , spinal cord , neuroprotection , glutamate receptor , metabotropic glutamate receptor , medicine , metabotropic receptor , agonist , neuroscience , anesthesia , biology , inflammation , receptor
Objective Activation of metabotropic glutamate receptor 5 (mGluR5) has neuroprotective properties in vitro and has been reported to limit postischemic lesion volume in vivo. Previously, mGluR5 has been identified on microglia in vitro, but the effects of mGluR5 activation on inflammation in vivo or on recovery after spinal cord injury is unknown. Methods Rats received intrathecal infusion of the selective mGluR5 agonist (RS)‐2‐chloro‐5‐hydroxyphenylglycine (CHPG) for 7 days after moderate impact spinal cord injury at T9. Complementary studies examined CHPG effects on activated spinal microglia cultures. Results Functional motor recovery was significantly increased by CHPG treatment up to 28 days after injury, with improvements in weight bearing, step taking, and coordination of stepping behavior. CHPG treatment significantly reduced lesion volume and increased white matter sparing at 28 days after injury. Administration of CHPG attenuated microglial‐associated inflammatory responses in a dose‐dependent fashion, including expression of ED1, Iba‐1, Galectin‐3, NADPH oxidase components, tumor necrosis factor‐α, and inducible nitric oxide synthase. Because mGluR5 is expressed by microglial cells in the rat spinal cord, such effects may be mediated by direct action on microglial cells. mGluR5 stimulation also reduced microglial activation and decreased microglial‐induced neurotoxicity in spinal cord microglia cultures; the latter effects were blocked by the selective mGluR5 antagonist MTEP. Interpretation These data demonstrate that mGluR5 activation can reduce microglial‐associated inflammation, suggesting that the protective effects of mGluR5 agonists may reflect this action. Ann Neurol 2009;66:63–74