Validation of a novel biomarker for acute axonal injury in experimental autoimmune encephalomyelitis.
In multiple sclerosis, inflammatory axonal injury is a key pathological mechanism responsible for the development of progressive neurological dysfunction. The injured axon represents a therapeutic target in this disease; however, therapeutic trials of neuroprotective candidates will initially require preclinical testing in an animal model of inflammatory axonal injury and subsequently the development of a reliable paraclinical measure of axonal degeneration in humans. In the present study, we demonstrate the validity of serum phosphorylated neurofilament H (pNF-H) as a marker of axonal injury in murine experimental autoimmune encephalomyelitis (EAE). At the time of maximum disease severity (EAE day 22), the average serum pNF-H level reached 5.7 ng/ml, correlating significantly with the EAE paraplegia score (r = 0.75, P < 0.001). On average, 40% of axons in the spinal cord were lost in EAE, and serum pNF-H levels were highly correlated with axon loss (r = 0.8, P < 0.001). Axonal injury was a severe and acute event, insofar as serum pNF-H levels were not significantly elevated at early (EAE day 12) or late (EAE days 35 and 50) disease time points. Our results demonstrate that acute inflammatory axonal injury is a pathological feature of murine MOG(35-55) EAE, indicating that this model may mirror the acute pathological events in active multiple sclerosis lesions. Furthermore, we have validated the serum pNF-H assay as an unbiased measurement of axonal injury in EAE, facilitating rapid screening of potential neuroprotective therapies in this model.
Gresle
Melissa M
MM
Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia. melissa.gresle@florey.edu.au
Shaw
Gerry
G
Jarrott
Bevyn
B
Alexandrou
Estella N
EN
Friedhuber
Anna
A
Kilpatrick
Trevor J
TJ
Butzkueven
Helmut
H
D000208:Acute Disease; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood* / Q000175:diagnosis* / Q000503:physiopathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D016900:Neurofilament Proteins / Q000032:analysis / Q000097:blood*; D010766:Phosphorylation; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014855:Wallerian Degeneration / Q000097:blood* / Q000175:diagnosis* / Q000503:physiopathology
D015415:Biomarkers; D016900:Neurofilament Proteins; C051774:neurofilament protein H