Identification of emetine as a therapeutic agent that targets pigment epithelium derived factor - mediated inflammation and improves hyperglycemia in murine models of type 1 diabetes (IRM9P.728)

Abstract

Abstract Pigment epithelium derived factor (PEDF) is a 50kDa secreted protein with inflammatory, antiangiogenic and neurotrophic properties. Elevated levels of PEDF are significantly associated with metabolic diseases including type 1 and type 2 diabetes, metabolic syndrome, and insulin resistance. PEDF administration to naïve animals result in the development of insulin resistance, and neutralization of PEDF with anti-PEDF antibodies improves the clinical outcome. Here we have identified a clinical drug candidate that attenuates PEDF mediated inflammation. Using a high-throughput screening approach, murine macrophages were stimulated with PEDF in the presence or absence of clinical drug candidates, and levels of secreted TNF analyzed. Following screening of 1,600 clinical candidate compounds, three lead compounds were identified, one being emetine, that dose dependently reduce PEDF induced macrophage activation without toxicity. Surface plasmon resonance analysis revealed that emetine binds to PEDF with high affinity (kD<25nM), and inhibits PEDF binding to its receptor adipose triglyceride lipase. Additionally, emetine reduces endocytosis of PEDF into macrophages. Administration of emetine to murine models of type 1 diabetes improves hyperglycemia, suppresses circulating levels of anti-insulin antibodies, and reduces pancreatic TNF and PEDF. Our studies suggest that emetine attenuates PEDF mediated inflammation, and has a therapeutic potential for treating type 1 diabetes.