Spatio-temporal development of axonopathy in canine intervertebral disc disease as a translational large animal model for nonexperimental spinal cord injury.
Spinal cord injury (SCI) represents a devastating central nervous system disease that still lacks sufficient therapies. Here, dogs are increasingly recognized as a preclinical animal model for the development of future therapies. The aim of this study was a detailed characterization of axonopathy in canine intervertebral disc disease, which produces a mixed contusive and compressive injury and functions as a spontaneous translational animal model for human SCI. The results revealed an early occurrence of ultrastructurally distinct axonal swelling. Immunohistochemically, enhanced axonal expression of β-amyloid precursor protein, non-phosphorylated neurofilament (n-NF) and growth-associated protein-43 was detected in the epicenter during acute canine SCI. Indicative of a progressive axonopathy, these changes showed a cranial and caudally accentuated spatial progression in the subacute disease phase. In canine spinal cord slice cultures, immunoreactivity of axons was confined to n-NF. Real-time quantitative polymerase chain reaction of naturally traumatized tissue and slice cultures revealed a temporally distinct dysregulation of the matrix metalloproteinases (MMP)-2 and MMP-9 with a dominating expression of the latter. Contrasting to early axonopathy, diminished myelin basic protein immunoreactivity and phagocytosis were delayed. The results present a basis for assessing new therapies in the canine animal model for translational research that might allow partial extrapolation to human SCI.
Department of Pathology, University of Veterinary Medicine, Hannover, Germany.
Patricia
P
Bock
Ingo
I
Spitzbarth
Verena
V
Haist
Veronika M
VM
Stein
Andrea
A
Tipold
Christina
C
Puff
Andreas
A
Beineke
Wolfgang
W
Baumgärtner
D000818:Animals; D001369:Axons / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000502:physiology; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D055959:Intervertebral Disc Degeneration / Q000473:pathology*; D007405:Intervertebral Disc Displacement / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D016253:Microscopy, Immunoelectron; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism; D010586:Phagocytes / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000662:veterinary; D018709:Statistics, Nonparametric
D019922:GAP-43 Protein; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D020648:Peptide Elongation Factor 1; D012333:RNA, Messenger; D007041:Hypoxanthine Phosphoribosyltransferase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9