Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis Andrea Schampela, Oleg Volovitchb, Tobias Koenigera, Claus-Jürgen Scholzc,d, Stefanie Jörge, Ralf A. Linkere, Erhard Wischmeyerf, Marie Wunscha, Johannes W. Hellg, Süleyman Ergüna, and Stefanie Kuerrtena,1 Author Affiliations aDepartment of Anatomy and Cell Biology, University of Würzburg, 97070 Wuerzburg, Germany; bDepartment of Anatomy and Cell Biology, University of Cologne, 50931 Cologne, Germany; cCore Unit Systems Medicine, University Hospital of Würzburg, 97080 Wuerzburg, Germany; dThe Life & Medical Sciences Institute, University of Bonn, 53113 Bonn, Germany; eDepartment of Neurology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany; fInstitute of Physiology, Molecular Electrophysiology, University of Würzburg, 97070 Wuerzburg, Germany; gDepartment of Pharmacology, University of California, Davis, CA 95616 Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved March 14, 2017 (received for review December 6, 2016) Significance Multiple sclerosis (MS) is the most frequent neurological disease that leads to premature retirement in young adults. Progressive MS currently is not only incurable, but also untreatable. Here we show that the calcium channel antagonist nimodipine significantly attenuated clinical disease and central nervous system degeneration and also fostered remyelination in a mouse model of MS. The effect of nimodipine was microglia specific, inducing apoptosis and decreasing the production of neurotoxic molecules such as nitric oxide and reactive oxygen species both in vitro and in vivo. These results introduce a treatment option for MS and also may have broad therapeutic implications for chronic neuroinflammatory diseases in general. Abstract Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2+APC+ oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.