Epub: Gentile et al. Glatiramer Acetate Protects Against Inflammatory Synaptopathy in Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol. 2013 Jan 31.
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 (brains) 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 post-synaptic 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.
During it long history in MS, Glaterimer acetate has inhibited EAE by more mechanisms than we have had hot dinners. If delivered in certain ways the drug is immunosuppressive, so it will be secondarily neuroprotectective, others have found it to be neuroprotective in non-autoimmune models. In this study GA stops glutamine (major nerve transmitter)-induced nerve damage through effect on microglia. whilst this may be encouraging one has to wonder what is the significance, as GA has not yet been found to have a neuroprotective effect in progressive MS.