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Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS
- Source :
- Acta Neuropathologica, Acta neuropathologica 130 (2015): 279–295. doi:10.1007/s00401-015-1422-3, info:cnr-pdr/source/autori:Parodi B.; Rossi S.; Morando S.; Cordano C.; Bragoni A.; Motta C.; Usai C.; Wipke B.T.; Scannevin R.H.; Mancardi G.L.; Centonze D.; Kerlero de Rosbo N.; Uccelli A./titolo:Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS/doi:10.1007%2Fs00401-015-1422-3/rivista:Acta neuropathologica/anno:2015/pagina_da:279/pagina_a:295/intervallo_pagine:279–295/volume:130
- Publication Year :
- 2015
-
Abstract
- Dimethyl fumarate (DMF), recently approved as an oral immunomodulatory treatment for relapsing-remitting multiple sclerosis (MS), metabolizes to monomethyl fumarate (MMF) which crosses the blood–brain barrier and has demonstrated neuroprotective effects in experimental studies. We postulated that MMF exerts neuroprotective effects through modulation of microglia activation, a critical component of the neuroinflammatory cascade that occurs in neurodegenerative diseases such as MS. To ascertain our hypothesis and define the mechanistic pathways involved in the modulating effect of fumarates, we used real-time PCR and biochemical assays to assess changes in the molecular and functional phenotype of microglia, quantitative Western blotting to monitor activation of postulated pathway components, and ex vivo whole-cell patch clamp recording of excitatory post-synaptic currents in corticostriatal slices from mice with experimental autoimmune encephalomyelitis (EAE), a model for MS, to study synaptic transmission. We show that exposure to MMF switches the molecular and functional phenotype of activated microglia from classically activated, pro-inflammatory type to alternatively activated, neuroprotective one, through activation of the hydroxycarboxylic acid receptor 2 (HCAR2). We validate a downstream pathway mediated through the AMPK–Sirt1 axis resulting in deacetylation, and thereby inhibition, of NF-κB and, consequently, of secretion of pro-inflammatory molecules. We demonstrate through ex vivo monitoring of spontaneous glutamate-mediated excitatory post-synaptic currents of single neurons in corticostriatal slices from EAE mice that the neuroprotective effect of DMF was exerted on neurons at pre-synaptic terminals by modulating glutamate release. By exposing control slices to untreated and MMF-treated activated microglia, we confirm the modulating effect of MMF on microglia function and, thereby, its indirect neuroprotective effect at post-synaptic level. These findings, whereby DMF-induced activation of a new HCAR2-dependent pathway on microglia leads to the modulation of neuroinflammation and restores synaptic alterations occurring in EAE, represent a possible novel mechanism of action for DMF in MS. Electronic supplementary material The online version of this article (doi:10.1007/s00401-015-1422-3) contains supplementary material, which is available to authorized users.
- Subjects :
- AMP-Activated Protein Kinases
Receptors, Nicotinic
Receptors, G-Protein-Coupled
Tissue Culture Techniques
chemistry.chemical_compound
0302 clinical medicine
Fumarates
Sirtuin 1
Neuroinflammation
0303 health sciences
Experimental autoimmune encephalomyelitis
Multiple sclerosis
Microglia
Hydroxycarboxylic acid receptor 2
Synaptopathy
Neuroprotection
Dimethyl fumarate
NF-kappa B
Glutamate receptor
Brain
3. Good health
Cell biology
Neuroprotective Agents
medicine.anatomical_structure
Biochemistry
Female
Settore MED/26 - Neurologia
medicine.symptom
Signal Transduction
Encephalomyelitis, Autoimmune, Experimental
Clinical Neurology
Glutamic Acid
Biology
Neurotransmission
Cell Line
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Animals
030304 developmental biology
Original Paper
Dose-Response Relationship, Drug
Excitatory Postsynaptic Potentials
medicine.disease
Mice, Inbred C57BL
chemistry
Mechanism of action
Synapses
Neurology (clinical)
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica, Acta neuropathologica 130 (2015): 279–295. doi:10.1007/s00401-015-1422-3, info:cnr-pdr/source/autori:Parodi B.; Rossi S.; Morando S.; Cordano C.; Bragoni A.; Motta C.; Usai C.; Wipke B.T.; Scannevin R.H.; Mancardi G.L.; Centonze D.; Kerlero de Rosbo N.; Uccelli A./titolo:Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS/doi:10.1007%2Fs00401-015-1422-3/rivista:Acta neuropathologica/anno:2015/pagina_da:279/pagina_a:295/intervallo_pagine:279–295/volume:130
- Accession number :
- edsair.doi.dedup.....93b7cd4f7fd444a5c9904fd90ef84858