Positive allosteric modulation of metabotropic glutamate receptor 5 down-regulates fibrinogen-activated microglia providing neuronal protection.
Microglial activation and blood brain barrier dysfunction are significant hallmarks in an array of neurodegenerative disorders. A leaky blood brain barrier potentially allows infiltration of blood-borne proteins into the CNS parenchyma, and previous studies have shown that the blood borne protein fibrinogen (FG) can activate microglia to produce a neurotoxic phenotype. Here we show that FG-mediated neurotoxicity and ERK1/2 phosphorylation in neuronal cultures is significantly attenuated by activation of metabotropic glutamate receptor 5 (mGluR5) but not mGluR2. Furthermore, FG-mediated microglial activation was down-regulated by direct mGluR5 activation on these cells but not by mGluR2, suggesting that targeting microglial mGluR5 provides neuronal protection against blood protein-triggered innate inflammatory responses.
Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, London WC1N 1PJ, UK.
Thomas M
TM
Piers
Simon J
SJ
Heales
Jennifer M
JM
Pocock
D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000502:physiology; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005340:Fibrinogen / Q000037:antagonists & inhibitors* / Q000502:physiology* / Q000633:toxicity; D005911:Gliosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000633:toxicity; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism* / Q000502:physiology
C578937:Grm5 protein, rat; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D005340:Fibrinogen