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.