Research Article: Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis

Date Published: January 26, 2017

Publisher: Public Library of Science

Author(s): Tommaso Bonfiglio, Guendalina Olivero, Elisa Merega, Silvia Di Prisco, Cristina Padolecchia, Massimo Grilli, Marco Milanese, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Giambattista Bonanno, Mario Marchi, Anna Pittaluga, Jason R. Lees.

http://doi.org/10.1371/journal.pone.0170825

Abstract

Fingolimod, the first oral, disease-modifying therapy for MS, has been recently proposed to modulate glutamate transmission in the central nervous system (CNS) of mice suffering from Experimental Autoimmune Encephalomyelitis (EAE) and in MS patients. Our study aims at investigating whether oral fingolimod recovers presynaptic defects that occur at different stages of disease in the CNS of EAE mice. In vivo prophylactic (0.3 mg/kg for 14 days, from the 7th day post immunization, d.p.i, the drug dissolved in the drinking water) fingolimod significantly reduced the clinical symptoms and the anxiety-related behaviour in EAE mice. Spinal cord inflammation, demyelination and glial cell activation are markers of EAE progression. These signs were ameliorated following oral fingolimod administration. Glutamate exocytosis was shown to be impaired in cortical and spinal cord terminals isolated from EAE mice at 21 ± 1 d.p.i., while GABA alteration emerged only at the spinal cord level. Prophylactic fingolimod recovered these presynaptic defects, restoring altered glutamate and GABA release efficiency. The beneficial effect occurred in a dose-dependent, region-specific manner, since lower (0.1–0.03 mg/kg) doses restored, although to a different extent, synaptic defects in cortical but not spinal cord terminals. A delayed reduction of glutamate, but not of GABA, exocytosis was observed in hippocampal terminals of EAE mice at 35 d.p.i. Therapeutic (0.3 mg/kg, from 21 d.p.i. for 14 days) fingolimod restored glutamate exocytosis in the cortex and in the hippocampus of EAE mice at 35 ± 1 d.p.i. but not in the spinal cord, where also GABAergic defects remained unmodified. These results improve our knowledge of the molecular events accounting for the beneficial effects elicited by fingolimod in demyelinating disorders.

Partial Text

Multiple sclerosis (MS) is mediated by an immune attack directed at myelin, which leads to a progressively degenerating disorder of the central nervous system (CNS). Although immunological mechanisms are responsible for the majority of the cascade of events leading to MS, pathogenetic events involving neurons and astrocytes have been recently implicated in the pathogenesis of this disease [1–5].

Our study aimed to investigate the effect of in vivo oral fingolimod dissolved in the drinking water on the onset and during the course of EAE in mice. In particular, the study aimed at quantifying the effects of this drug on the presynaptic defects that occurs in selected CNS regions of EAE mice at different stages of disease.

 

Source:

http://doi.org/10.1371/journal.pone.0170825