Nimodipine inhibits IL-1β release stimulated by amyloid β from microglia

BACKGROUND AND PURPOSE There is growing evidence that inflammation plays a major role in the pathogenesis of neural damage caused by deposition of amyloid beta (A beta) in the brain. Nimodipine has received attention as a drug that might improve learning and reduce cognitive deficits in Alzheimer's disease, but the mechanism of action is poorly known. In this study, we tested the hypothesis that nimodipine inhibited A beta-stimulated IL-1 beta release from microglia. EXPERIMENTAL APPROACH Cultures of N13 microglia cells or primary mouse microglia were treated with nimodipine, and intracellular accumulation and release of IL-1 beta in response to A beta or to the P2 receptor agonists ATP and benzoyl ATP (BzATP) were measured. Accumulation of IL-1 beta was measured in vivo after intrahippocampal inoculation of A beta in the absence or presence of nimodipine. The effect of nimodipine on A beta-triggered cytotoxicity was also investigated. KEY RESULTS We show here that nimodipine dose-dependently inhibited A beta-stimulated IL-1 beta synthesis and release from primary microglia and microglia cell lines. Furthermore, nimodipine also inhibited A beta-induced IL-1 beta in vivo accumulation at concentrations known to be reached in the CNS. Finally, nimodipine protected microglia from A beta-dependent cytotoxicity. CONCLUSION AND IMPLICATIONS These data suggest that alleviation of symptoms of Alzheimer's disease following nimodipine administration might be due to an anti-inflammatory effect and point to a novel role for nimodipine as a centrally acting anti-inflammatory drug.