Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis. Issue 1 (27th June 2018)

• Record Type: Journal Article
• Authors: Ingwersen, Jens; De Santi, Lorenzo; Wingerath, Britta; Graf, Jonas; Koop, Barbara; Schneider, Reiner; Hecker, Christina; Schröter, Friederike; Bayer, Mary; Engelke, Anna Dorothee; Dietrich, Michael; Albrecht, Philipp; Hartung, Hans‐Peter; Annunziata, Pasquale; Aktas, Orhan; Prozorovski, Tim
• Is Part Of: Journal of neurochemistry. Volume 146:Issue 1(2018)
• Page Start: 86
• Page End: 98
• Publication Date: 2018-06-27
• Subjects: experimental autoimmune encephalomyelitis -- L‐type VGCC -- nimodipine; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14324
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Multiple sclerosis is characterised 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 Ca 2+ overload and subsequent activation of calcium‐dependent damage pathways. Thus, the inhibition of Ca 2+ influx by pharmacological modulation of Ca 2+ 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 blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE), an established experimental paradigm for multiple sclerosis. 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 immunised with encephalitic myelin peptide PLP139–151, specifically in late‐stage disease. Furthermore, supporting these data, administration of nimodipine to MOG35–55 ‐immunised 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‐amyloid precursor protein accumulation in the 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 voltage‐gated calcium channel blockade to inflammation‐induced neurodegeneration. Abstract : Accumulating data suggest an activation of calcium‐dependent damage pathways as a potential mechanism of neuronal and myelin injury in autoimmune CNS inflammation. Here, we show that nimodipine, an L‐type voltage‐gated calcium channel blocker, confers neuroprotective effects in different models of experimental autoimmune encephalomyelitis (EAE) by diminishing myelin loss and axonal degeneration and ameliorates disease progression. Particularly, we show that therapeutic application of nimodipine diminishes clinical EAE scores in pre‐established EAE induced in C57Bl/6 and SJL/J animal strains.