On FTY720: Fingolimod/FTY720 abstracts from ECTRIMS
Oral fingolimod maintains and restores neuronal function in demyelinating models of multiple sclerosis, as assessed by somatosensory and visual evoked potentials
B. Balatoni, M.K. Storch, R. Weissert, C.A. Foster (Vienna, Graz, A; Tubingen, D)
Background: Fingolimod (FTY720) is an orally-active sphingosine 1-phosphate (S1P) receptor modulator under development for the treatment of multiple sclerosis (MS). During a phase II trial in relapsing MS, it reduced clinical relapse rate by more than 50% and inflammatory lesion activity on magnetic resonance imaging by up to 80%. Phase III studies are ongoing.
Aim: To elucidate how FTY720 exerts its beneficial effects in the central nervous system (CNS), we compared functional parameters of nerve conductance with morphological features in the DA rat model of experimental autoimmune encephalomyelitis (EAE) under prophylactic and therapeutic settings.
Methods: EAE was induced with myelin oligodendrocyte glycoprotein (MOG) or syngeneic neuroantigen. Prophylactic oral treatment with FTY720 (0.3 to 0.4 mg/kg) or vehicle started on day 0 and continued for 3 weeks, while therapeutic treatment was initiated on day 25 or 40 post-immunization.
Clinical scores were assessed daily; visual and somatosensory evoked potentials (VEP, SEP) were recorded prior to perfusion-fixation; histological and immunocytochemical analyses were performed on the brain, optic nerves and spinal cord to assess inflammation, demyelination, axonal loss and blood-brain-barrier (BBB) integrity.
Results: FTY720 prophylaxis completely protected against the emergence of EAE symptoms, electrophysiological disturbances and pathology in the CNS. Therapeutic treatment reversed severe neurological deficits in established EAE induced by syngeneic myelin proteins as well as MOG.
In parallel to these clinical benefits, FTY720 restored and normalized the functional responses to SEP and VEP stimulation. Neuronal function and clinical efficacy correlated with a reversal of BBB leakiness and a reduction of inflammatory infiltrates, actively demyelinating lesions and axonal loss.
Conclusions: The effectiveness of FTY720 in reversing clinical disease and restoring nerve conductance is likely due to several contributing factors. Evidence thus far support its role in the reduction of inflammation and preservation of BBB integrity. FTY720 may also act via S1P receptors expressed by glial cells and/or neurons in the CNS to promote endogenous repair mechanisms that complement its immunomodulatory action.
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