2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Optic-Neuritis

The aim of this study was to investigate the role of voltage-dependent calcium channels (VDCCs) in axon degeneration during autoimmune optic neuritis.. 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 omega-conotoxin GVIA, an N-type specific blocker.. 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 alpha(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 omega-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.. 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.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Amlodipine; Amyloid beta-Protein Precursor; Animals; Autoimmune Diseases; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Cytokines; Disease Models, Animal; Drug Interactions; Ectodysplasins; Egtazic Acid; Excitatory Amino Acid Antagonists; Female; Glial Fibrillary Acidic Protein; Magnetic Resonance Imaging; Manganese; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Neoplasm Proteins; omega-Conotoxin GVIA; Optic Nerve; Optic Neuritis; Quinoxalines; Rats; RNA-Binding Proteins