Huijing Xu, Yushuang Gong, Yang Jiao, Jian Guo, Ling Zhao, Juechen Yang, Haibin Tong, Meiyan Sun* and Miao Li* Pages 793 - 802 ( 10 )
Background: Neuromyelitis optica (NMO) is a severe neurological demyelinating autoimmune disease affecting the optic nerves and spinal cord. The binding of neuromyelitis optica immunoglobulin G (NMO- IgG) and aquaporin-4 (AQP4) on the surface of astrocytes in the serum and cerebrospinal fluid is the main pathogenesis of NMO. Currently, therapeutic strategies for NMO include a reduction of the secondary inflammation response and the number of NMO-IgG, which can only alleviate clinical symptoms rather than fundamentally preventing a series of pathological processes caused by NMO-IgG binding to AQP4.
Objective: The purpose of this study was to investigate the blocking effect of melanthioidine on the binding of NMO-IgG to AQP4 and its potential cytotoxicity.
Methods: The current study developed a cell-based high-throughput screening approach to identify a molecular blocker of NMO-IgG binding to AQP4 using the Chinese hamster lung fibroblast (V79) cells expressing M23- AQP4. By screening ~400 small molecules, we identified melanthioidine with blocking effects without affecting AQP4 expression or its water permeability.
Results: Melanthioidine effectively blocked the binding of NMO-IgG to AQP4 in immunofluorescence assays and reduced complement-dependent cytotoxicity against both NMO-IgG/complement-treated Fischer rat thyroid- AQP4 cells and primary astrocytes. The docking computations identified the putative sites of blocker binding at the extracellular surface of AQP4.
Conclusion: This study serves as proof of a potential NMO therapy by using a small-molecule blocker to target NMO pathogenesis.
Neuromyelitis optica, autoimmune disease, aquaporin 4, high-throughput screening, melanthioidine, molecular blocker, NMOimmunoglobulin G.