Anti-inflammatory and neuroprotective effects of GILZ analogs. (THER7P.951)

Abstract

Abstract Increased activation of the p65 subunit of nuclear factor kappa-B (NF-κB) upregulate inflammatory and apoptotic factors that mediate neuroinflammation and neurodegeneration in chronic neurological diseases, suggesting that activated p65 is an excellent therapeutic target. Glucocorticoid induced leucine zipper (GILZ) is a p65 interacting protein, that sequesters activated p65 in the cytoplasm and suppresses NF-κB. The GILZ:p65 interaction is localized to the proline rich region at the carboxy terminus of GILZ. Previously we reported that a synthetic peptide (GILZ-P) derived from the p65 binding domain of GILZ ameliorated experimental encephalomyelitis. To determine the potential application of GILZ-P in humans, we evaluated the toxicity and efficacy of the peptide drug in mature human neuroblastoma cells, macrophage like THP-1 cells and fetal neuronal cells. Treatment with GILZ-P at a wide range of concentrations commonly used for peptide drugs was non-toxic as determined by the cell viability and apoptosis assays in THP-1 cells. Functionally GILZ-P suppressed pro-inflammatory cytokine secretion by proteolipid protein or amyloid-β (Aβ1-42) stimulated mature neuroblastoma cells and suppressed glutamate secretion by activated macrophages by inhibiting nuclear translocation of p65. Collectively, GILZ-P exhibits therapeutic potential for chronic diseases wherein persistent inflammation precipitates neurodegeneration such as progressive multiple sclerosis and Alzheimer’s disease.