Glatiramer acetate protects against inflammatory synaptopathy in experimental autoimmune encephalomyelitis.
Glutamate-mediated excitotoxicity is supposed to induce neurodegeneration in multiple sclerosis (MS). Glatiramer acetate (GA) is an immunomodulatory agent used in MS treatment with potential neuroprotective action. Aim of the present study was to investigate whether GA has effects on glutamate transmission alterations occurring in experimental autoimmune encephalomyelitis (EAE), to disclose a possible mechanism of GA-induced neuroprotection in this mouse model of MS. Single neuron electrophysiological recordings and immunofluorescence analysis of microglia activation were performed in the striatum of EAE mice, treated or not with GA, at different stages of the disease. GA treatment was able to reverse the tumor necrosis factor-α (TNF-α)-induced alterations of striatal glutamate-mediated excitatory postsynaptic currents (EPSCs) of EAE mice. Incubation of striatal slices of control animals with lymphocytes taken from EAE mice treated with GA failed to replicate such an anti-glutamatergic effect, while activated microglial cells stimulated with GA in vitro mimicked the effect of GA treatment of EAE mice. Consistently, EAE mice treated with GA had less microglial activation and less TNF-α expression than untreated EAE animals. Furthermore, direct application of GA to EAE slices replicated the in vivo protective activity of GA. Our results show that GA is neuroprotective against glutamate toxicity independently of its peripheral immunodulatory action, and through direct modulation of microglial activation and TNF-α release in the grey matter of EAE and possibly of MS brains.
Fondazione Santa Lucia/Centro Europeo per la Ricerca sul Cervello, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
Antonietta
A
Gentile
Silvia
S
Rossi
Valeria
V
Studer
Caterina
C
Motta
Valentina
V
De Chiara
Alessandra
A
Musella
Helena
H
Sepman
Diego
D
Fresegna
Gabriele
G
Musumeci
Giorgio
G
Grasselli
Nabila
N
Haji
Sagit
S
Weiss
Liat
L
Hayardeny
Georgia
G
Mandolesi
Diego
D
Centonze
D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology* / Q000517:prevention & control*; D005260:Female; D000068717:Glatiramer Acetate; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D013569:Synapses / Q000187:drug effects / Q000473:pathology*
D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D010455:Peptides; D000068717:Glatiramer Acetate