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.
Kinsmen Laboratory of Neurological Research, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C., V6T 2A1 Canada. hashioka@f2.dion.ne.jp
Sadayuki
S
Hashioka
Andis
A
Klegeris
Patrick L
PL
McGeer
D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D054371:Chemokine CXCL11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D009474:Neurons / Q000276:immunology; D009553:Nimodipine / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology* / Q000627:therapeutic use
C515202:CXCL11 protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D054371:Chemokine CXCL11; C573415:IFNG protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009553:Nimodipine; D007371:Interferon-gamma; D014700:Verapamil