Myelin-induced microglial neurotoxicity can be controlled by microglial metabotropic glutamate receptors.
Microglia are present in an activated state in multiple sclerosis lesions. Incubation of primary cultured rat microglia with rat-brain derived myelin (0.1-1 microg/mL) for 24 h induced microglial activation; cells displayed enhanced ED1 staining, expression of inducible nitric oxide synthase, production and release of the cytokine tumour necrosis factor-alpha and glutamate release. Exposure of microglia to myelin induced the expression of neuronal caspases and ultimately neuronal death in cultured cerebellar granule cell neurons; neurotoxicity was directly because of microglial-derived soluble toxins. Co-incubation of microglia with agonists or antagonists of different metabotropic glutamate receptor (mGluR) subtypes ameliorated microglial neurotoxicity by inhibiting soluble neurotoxin production. Activation of microglial mGluR2 exacerbated myelin-evoked neurotoxicity whilst activation of mGluR3 was protective as was activation of group III mGluRs. These data show that myelin-induced microglial neurotoxicity can be prevented by regulation of mGluRs and suggest these receptors on microglia may be promising targets for therapeutic intervention in multiple sclerosis.
Pinteaux-Jones
Fleur
F
Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, London, UK.
Sevastou
Ioanna G
IG
Fry
Victoria A H
VA
Heales
Simon
S
Baker
David
D
Pocock
Jennifer M
JM
D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005911:Gliosis / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009185:Myelin Proteins / Q000633:toxicity*; D009186:Myelin Sheath / Q000737:chemistry / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009185:Myelin Proteins; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; D014409:Tumor Necrosis Factor-alpha; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; D052248:Nitric Oxide Synthase Type I