Inhibition of human astrocyte and microglia neurotoxicity by calcium channel blockers

We examined the effects of L-type calcium channel blockers (CCBs) on toxicity exerted by activated human astrocytes and microglia towards SH-SY5Y human neuronal cells. The CCBs nimodipine (NDP) and verapamil (VPM) both significantly suppressed toxic secretions from human astrocytes and astrocytoma U-373 MG cells that were induced by interferon (IFN)-γ. NDP also inhibited neurotoxic secretions of human microglia and monocytic THP-1 cells that were induced by the combination of lipopolysaccharide and IFN-γ. In human astrocytes, both NDP and VPM reduced IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 3. They also inhibited the astrocytic production of IFN-γ-inducible T cell α chemoattractant (I-TAC). These results suggest that CCBs attenuate IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. L-type CCBs, especially NDP, might be a useful treatment option for a broad spectrum of neurodegenerative diseases, including Alzheimer disease, where the pathology is believed to be exacerbated by neurotoxic glial activation.

► Nimodipine (NDP) and verapamil (VPM) reduced the interferon (IFN)-γ-induced neurotoxicity of human astrocytes. ► NDP attenuated lipopolysaccharide plus IFN-γ-induced neurotoxicity of human microglia. ► NDP and VPM inhibited the IFN-γ-induced phosphorylation of STAT3 in human astrocytes. ► Both drugs decreased the secretion of IFN-γ-inducible T cell α chemoattractant from human astrocytes.