Inhibition of human astrocyte and microglia neurotoxicity by calcium channel blockers.

Abstract

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.

• Authors: Sadayuki Hashioka, Andis Klegeris, Patrick L McGeer
• Journal: Neuropharmacology (Neuropharmacology) Vol. 63 Issue 4 Pg. 685-91 (Sep 2012) ISSN: 1873-7064 [Electronic] England
• PMID: 22659089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• CXCL11 protein, human
• Calcium Channel Blockers
• Calcium Channels, L-Type
• Chemokine CXCL11
• IFNG protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• Nimodipine
• Interferon-gamma
• Verapamil

Topics

• Astrocytes (drug effects, immunology, metabolism)
• Calcium Channel Blockers (pharmacology, therapeutic use)
• Calcium Channels, L-Type (chemistry, metabolism)
• Cell Line
• Cells, Cultured
• Chemokine CXCL11 (antagonists & inhibitors, metabolism)
• Cytotoxicity, Immunologic (drug effects)
• Down-Regulation (drug effects)
• Humans
• Interferon-gamma (metabolism)
• Microglia (cytology, drug effects, immunology, metabolism)
• Molecular Targeted Therapy
• Monocytes (drug effects, immunology, metabolism)
• Neurodegenerative Diseases (drug therapy)
• Neurons (immunology)
• Nimodipine (pharmacology, therapeutic use)
• Phosphorylation (drug effects)
• Protein Processing, Post-Translational (drug effects)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Verapamil (pharmacology, therapeutic use)