Ca2+ blockers ameliorate disease in mouse model of multiple sclerosis (MS)

Abstract

Influx of extracellular Ca2+ is implicated in CNS white matter injury. We studied the effects of clinically used Ca2+ blockers on mouse adoptive‐transfer EAE (AT‐EAE), a model of MS, an inflammatory white matter disease. Lymph node cells (LNC) from donor mice, sensitized to a CNS antigen, MBP, and clonally expanded in vitro with the same antigen, were injected I.V. to recipient SJL/J mice. Mouse AT‐EAE presents an initial acute ascending paralysis (onset 8–10 days, remission 18–20 days after LNC transfer) and a relapsing–remitting disease course thereafter. Bepridil (BEP), a Ca2+ blocker (3 mg/kg/day), reduced average clinical score of AT‐EAE by 1.5–2 points (out of 5; p < 0.05) compared with vehicle control (VEH), when treatment started on day 0, as well as, on day 3 post‐LNC transfer. Nitrendipine, a selective voltage‐gated Ca2+‐channel blocker (2.5 mg/kg/day), started on day 0, ameliorated AT‐EAE (p < 0.05) compared with VEH, in a manner similar to BEP. That two different calcium antagonists provided similar benefits points at a common target, likely voltage gated Ca2+ channels. As to mechanism, BEP reduced white matter pathology but not peripheral monocyte infiltration, assessed by histochemistry, suggesting that BEP may have suppressed secondary damage that followed the initial immune attack. However, we can not rule out an effect of BEP on immune cell competence since LNC, treated with BEP before transfer to recipient mice, only induced a much delayed and weaker EAE compared with vehicle treated cells. Moreover, besides attenuating the acute phase of AT‐EAE, long‐term BEP treatment seems to decrease the number of relapses. Our data implicates Ca2+ influx in AT‐EAE and suggest Ca2+ blockers as potential therapeutics in MS.