Shock Wave Treatment Protects From Neuronal Degeneration via a Toll-Like Receptor 3 Dependent Mechanism: Implications of a First-Ever Causal Treatment for Ischemic Spinal Cord Injury.
BACKGROUND
Paraplegia following spinal cord ischemia represents a devastating complication of both aortic surgery and endovascular aortic repair. Shock wave treatment was shown to induce angiogenesis and regeneration in ischemic tissue by modulation of early inflammatory response via Toll-like receptor (TLR) 3 signaling. In preclinical and clinical studies, shock wave treatment had a favorable effect on ischemic myocardium. We hypothesized that shock wave treatment also may have a beneficial effect on spinal cord ischemia.


RESULTS
A spinal cord ischemia model in mice and spinal slice cultures ex vivo were performed. Treatment groups received immediate shock wave therapy, which resulted in decreased neuronal degeneration and improved motor function. In spinal slice cultures, the activation of TLR3 could be observed. Shock wave effects were abolished in spinal slice cultures from TLR3(-/-) mice, whereas the effect was still present in TLR4(-/-) mice. TLR4 protein was found to be downregulated parallel to TLR3 signaling. Shock wave-treated animals showed significantly better functional outcome and survival. The protective effect on neurons could be reproduced in human spinal slices.


CONCLUSIONS
Shock wave treatment protects from neuronal degeneration via TLR3 signaling and subsequent TLR4 downregulation. Consequently, it represents a promising treatment option for the devastating complication of spinal cord ischemia after aortic repair.
University Hospital for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria (D.L., C.T., R.K., E.J.P., M.G., S.S., M.G., J.H.).
Daniela
D
Lobenwein
University Hospital for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria (D.L., C.T., R.K., E.J.P., M.G., S.S., M.G., J.H.).
Can
C
Tepeköylü
University Hospital for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria (D.L., C.T., R.K., E.J.P., M.G., S.S., M.G., J.H.).
Radoslaw
R
Kozaryn
University Hospital for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria (D.L., C.T., R.K., E.J.P., M.G., S.S., M.G., J.H.) Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria (E.J.P., M.B., H.F.).
Elisabeth J
EJ
Pechriggl
Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria (E.J.P., M.B., H.F.).
Mario
M
Bitsche
University Hospital for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria (D.L., C.T., R.K., E.J.P., M.G., S.S., M.G., J.H.).
Michael
M
Graber
Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria (E.J.P., M.B., H.F.).
Helga
H
Fritsch
University Hospital for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria (D.L., C.T., R.K., E.J.P., M.G., S.S., M.G., J.H.).
Severin
S
Semsroth
Division of Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria (N.S.).
Nadia
N
Stefanova
Department of Anesthesiology and Operative Intensive Care Medicine, Kepler University Hospital Linz, Linz, Austria (P.P.).
Patrick
P
Paulus
Department for Cardiovascular Surgery, University Hospital Freiburg, Freiburg, Germany (M.C.).
Martin
M
Czerny
University Hospital for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria (D.L., C.T., R.K., E.J.P., M.G., S.S., M.G., J.H.).
Michael
M
Grimm
University Hospital for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria (D.L., C.T., R.K., E.J.P., M.G., S.S., M.G., J.H.).
Johannes
J
Holfeld
D000818:Animals; D002102:Cadaver; D004195:Disease Models, Animal; D019220:High-Energy Shock Waves; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D018919:Neovascularization, Physiologic; D009410:Nerve Degeneration; D012039:Regional Blood Flow; D015398:Signal Transduction; D013116:Spinal Cord / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D020760:Spinal Cord Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics
C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4
Toll‐like receptors; neuronal degeneration; shock wave therapy; spinal cord ischemia