Proton Pump Inhibitors Reduce Interferon-γ-Induced Neurotoxicity and STAT3 Phosphorylation of Human Astrocytes

Proton pump inhibitors (PPIs) are known to possess anti-inflammatory properties. Inflammatory processes, including astrocytic activation, are implicated in the pathogenesis of different neurodegenerative diseases. Our recent study has indicated that interferon (IFN)-gamma-induced astrocytic neurotoxicity is mediated, at least in part, by phosphorylation of signal transducer and activator of transcription (STAT) 3. We therefore studied the effects of PPIs on IFN-gamma-induced neurotoxicity and STAT3 activation of human astrocytes. Both lansoprazole (LPZ) and omeprazole (OPZ) significantly attenuated IFN-gamma-induced neurotoxicity of human astrocytes and astrocytoma cells. These drugs inhibited IFN-gamma-induced phosphorylation of STAT 3, but not STAT1. We found that LPZ significantly reduced secretion of IFN-gamma-inducible T cell a chemoattractant from IFN-gamma-activated astrocytes. Neither LPZ nor OPZ suppressed expression of intercellular adhesion molecule-1 by IFN-gamma-activated astrocytes. These results suggest that PPIs attenuate IFN-gamma-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. PPIs that possess antineurotoxic properties may be a useful treatment option for Alzheimer's disease and other neuroinflammatory disorders associated with activated astrocytes. (c) 2011 Wiley-Liss, Inc.