Role of n-type voltage-dependent calcium channels in autoimmune optic neuritis.
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 omega-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 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.


CONCLUSIONS
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.
Gadjanski
Ivana
I
Department of Neurology, Georg-August University, Göttingen, Germany.
Boretius
Susann
S
Williams
Sarah K
SK
Lingor
Paul
P
Knöferle
Johanna
J
Sättler
Muriel B
MB
Fairless
Richard
R
Hochmeister
Sonja
S
Sühs
Kurt-Wolfram
KW
Michaelis
Thomas
T
Frahm
Jens
J
Storch
Maria K
MK
Bähr
Mathias
M
Diem
Ricarda
R
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D017311:Amlodipine / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D053331:Ectodysplasins / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008345:Manganese / Q000378:metabolism; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009363:Neoplasm Proteins / Q000378:metabolism; D009900:Optic Nerve / Q000187:drug effects / Q000378:metabolism; D009902:Optic Neuritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011810:Quinoxalines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D016207:Cytokines; D053331:Ectodysplasins; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009363:Neoplasm Proteins; D011810:Quinoxalines; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D017311:Amlodipine; D008345:Manganese; D004533:Egtazic Acid; D020866:omega-Conotoxin GVIA; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D002118:Calcium