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Role of n‐type voltage‐dependent calcium channels in autoimmune optic neuritis
Author(s) -
Gadjanski Ivana,
Boretius Susann,
Williams Sarah K.,
Lingor Paul,
Knöferle Johanna,
Sättler Muriel B.,
Fairless Richard,
Hochmeister Sonja,
Sühs KurtWolfram,
Michaelis Thomas,
Frahm Jens,
Storch Maria K.,
Bähr Mathias,
Diem Ricarda
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21668
Subject(s) - optic neuritis , axon , medicine , optic nerve , voltage dependent calcium channel , microglia , multiple sclerosis , inflammation , calcium channel , neuroprotection , pathology , calcium , immunology , pharmacology , anatomy
Objective The aim of this study was to investigate the role of voltage‐dependent calcium channels (VDCCs) in axon degeneration during autoimmune optic neuritis. Methods Calcium ion (Ca 2+ ) influx into the optic nerve (ON) through VDCCs was investigated in a rat model of optic neuritis using manganese‐enhanced magnetic resonance imaging and in vivo calcium imaging. After having identified the most relevant channel subtype (N‐type VDCCs), we correlated immunohistochemistry of channel expression with ON histopathology. In the confirmatory part of this work, we performed a treatment study using ω‐conotoxin GVIA, an N‐type specific blocker. Results We observed that pathological Ca 2+ influx into ONs during optic neuritis is mediated via N‐type VDCCs. By analyzing the expression of VDCCs in the inflamed ONs, we detected an upregulation of α 1B , the pore‐forming subunit of N‐type VDCCs, in demyelinated axons. However, high expression levels were also found on macrophages/activated microglia, and lower levels were detected on astrocytes. The relevance of N‐type VDCCs for inflammation‐induced axonal degeneration and the severity of optic neuritis was corroborated by treatment with ω‐conotoxin GVIA. This blocker led to decreased axon and myelin degeneration in the ONs together with a reduced number of macrophages/activated microglia. These protective effects were confirmed by analyzing the spinal cords of the same animals. Interpretation We conclude that N‐type VDCCs play an important role in inflammation‐induced axon degeneration via two mechanisms: First, they directly mediate toxic Ca 2+ influx into the axons; and second, they contribute to macrophage/microglia function, thereby promoting secondary axonal damage. Ann Neurol 2009;66:81–93