Multiple sclerosis (MS) is characterized by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca2+overload and subsequent activation of calcium-dependent damage pathways. Thus, the inhibition of Ca2+influx by pharmacological modulation of Ca2+channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy. We therefore investigated the effects of the L-type voltage-gated calcium channel (VGCC) blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE), an established experimental paradigm for MS. We show that preventive application of nimodipine (10 mg/kg per day) starting on the day of induction had ameliorating effects on EAE in SJL/J mice immunized with encephalitic myelin peptide PLP139-151, specifically in late-stage disease. Furthermore, supporting these data, administration of nimodipine to MOG35-55-immunized C57BL/6 mice starting at the peak of pre-established disease, also led to a significant decrease in disease score, indicating a protective effect on secondary CNS damage. Histological analysis confirmed that nimodipine attenuated demyelination, axonal loss and pathological axonal β-APP accumulation in cerebellum and spinal cord in the chronic phase of disease. Of note, we observed no effects of nimodipine on the peripheral immune response in EAE mice with regard to distribution, antigen-specific proliferation or activation patterns of lymphocytes. Taken together, our data suggest a CNS-specific effect of L-type VGCC blockade to inflammation-induced neurodegeneration. This article is protected by copyright. All rights reserved.
|Titolo:||Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis|
|Citazione:||Ingwersen, J., De Santi, L., Wingerath, B., Graf, J., Koop, B., Schneider, R., et al. (2018). Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis. JOURNAL OF NEUROCHEMISTRY.|
|Appare nelle tipologie:||1.1 Articolo in rivista|
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