Neuromyelitis optica pathology in rats following intraperitoneal injection of NMO-IgG and intracerebral needle injury.
BACKGROUND
Animal models of neuromyelitis optica (NMO) are needed for drug testing and evaluation of NMO disease pathogenesis mechanisms.


RESULTS
We describe a novel passive-transfer model of NMO in which rats made seropositive for human anti-aquaporin-4 (AQP4) immunoglobulin G antibody (NMO-IgG) by intraperitoneal (IP) injections were subject to intracerebral needle injury. Following a single IP injection, NMO-IgG distributed rapidly to peripheral AQP4-expressing cells (kidney collecting duct, gastric glands, airways, skeletal muscle) and area postrema in brain, but not elsewhere in the central nervous system; however, no pathology was seen in brain, spinal cord, optic nerve or peripheral tissues. After testing various maneuvers to produce NMO-IgG-dependent pathology in brain, we found that transient puncture of brain parenchyma with a 28-gauge needle in NMO-IgG seropositive rats produced robust NMO pathology around the needle track, with loss of AQP4 and glial fibrillary acidic protein, granulocyte and macrophage infiltration, centrovascular deposition of activated complement, and blood-brain barrier disruption, with demyelination by 5 days. Pathology was not seen in rats receiving control (non-NMO) human IgG or in NMO-IgG-seropositive rats made complement-deficient by cobra venom factor. Interestingly, at 1 day a reversible, multifocal astrocytopathy was seen with loss of AQP4 and GFAP (but not myelin) in areas away from the needle track.


CONCLUSIONS
NMO-IgG-seropositivity alone is not sufficient to cause NMO pathology in rats, but a single intracerebral needle insertion, without pre-existing inflammation or infusion of pro-inflammatory factors, was sufficient to produce robust NMO pathology in seropositive rats.
Nithi
N
Asavapanumas
Departments of Medicine and Physiology, University of California, San Francisco, CA, USA. Alan.Verkman@ucsf.edu.
A S
AS
Verkman
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D051401:Aquaporin 4 / Q000235:genetics / Q000276:immunology*; D016466:CHO Cells; D002135:Calcium-Binding Proteins / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003412:Cricetulus; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008840:Microfilament Proteins / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009471:Neuromyelitis Optica / Q000150:complications* / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D014162:Transfection
C496030:AQP4 protein, human; C100745:Aif1 protein, rat; D015703:Antigens, CD; D000950:Antigens, Ly; D051401:Aquaporin 4; D002135:Calcium-Binding Proteins; D015938:Complement Membrane Attack Complex; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; D008840:Microfilament Proteins; D004676:Myelin Basic Protein