Title:Inhibition of Neuromyelitis Optica Immunoglobulin G Binding to Aquaporin-4
by the Small Molecule Blocker Melanthioidine
Volume: 29
Issue: 10
Author(s): Huijing Xu, Yushuang Gong, Yang Jiao, Jian Guo, Ling Zhao, Juechen Yang, Haibin Tong, Meiyan Sun*Miao Li*
Affiliation:
- College of Laboratory Medicine, Jilin Medical University, Jilin, 132013, China
- Department of Neurosurgery, The China-Japan
Union Hospital, Jilin University, Changchun, 130033, China
Keywords:
Neuromyelitis optica, autoimmune disease, aquaporin 4, high-throughput screening, melanthioidine, molecular blocker, NMOimmunoglobulin G.
Abstract:
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.
