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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Inhibition of Neuromyelitis Optica Immunoglobulin G Binding to Aquaporin-4 by the Small Molecule Blocker Melanthioidine

Author(s): Huijing Xu, Yushuang Gong, Yang Jiao, Jian Guo, Ling Zhao, Juechen Yang, Haibin Tong, Meiyan Sun* and Miao Li*

Volume 29, Issue 10, 2023

Published on: 05 April, 2023

Page: [793 - 802] Pages: 10

DOI: 10.2174/1381612829666230330090953

Price: $65

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.

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