Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats.
Intense training is the most clinically successful treatment modality following incomplete spinal cord injuries (SCIs). With the advent of plasticity enhancing treatments, understanding how treatments might interact when delivered in combination becomes critical. Here, we investigated a rational approach to sequentially combine treadmill locomotor training with antibody mediated suppression of the fiber growth inhibitory protein Nogo-A. Following a large but incomplete thoracic lesion, rats were immediately treated with either anti-Nogo-A or control antibody (2weeks) and then either left untrained or step-trained starting 3weeks after injury for 8weeks. It was found that sequentially combined therapy improved step consistency and reduced toe dragging and climbing errors, as seen with training and anti-Nogo-A individually. Animals with sequential therapy also adopted a more parallel paw position during bipedal walking and showed greater overall quadrupedal locomotor recovery than individual treatments. Histologically, sequential therapy induced the greatest corticospinal tract sprouting caudally into the lumbar region and increased the number of serotonergic synapses onto lumbar motoneurons. Increased primary afferent sprouting and synapse formation onto lumbar motoneurons observed with anti-Nogo-A antibody were reduced by training. Animals with sequential therapy also showed the highest reduction of lumbar interneuronal activity associated with walking (c-fos expression). No treatment effects for thermal nociception, mechanical allodynia, or lesion volume were observed. The results demonstrate that sequential administration of anti-Nogo-A antibody followed in time with intensive locomotor training leads to superior recovery of lost locomotor functions, which is probably mediated by changes in the interaction between descending sprouting and local segmental networks after SCI.
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom; School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.
Kinon
K
Chen
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Barnaby C
BC
Marsh
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Matthew
M
Cowan
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Yazi D
YD
Al'Joboori
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Sylvain
S
Gigout
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Calvin C
CC
Smith
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Neil
N
Messenger
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Nikita
N
Gamper
Brain Research Institute, University of Zurich, CH-8057 Zurich, Switzerland.
Martin E
ME
Schwab
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom. Electronic address: R.M.Ichiyama@leeds.ac.uk.
Ronaldo M
RM
Ichiyama
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D005260:Female; D008124:Locomotion / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009185:Myelin Proteins / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D000070798:Nogo Proteins / Q000276:immunology / Q000378:metabolism; D010805:Physical Conditioning, Animal; D011712:Pyramidal Tracts / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D000906:Antibodies; D009185:Myelin Proteins; D000070798:Nogo Proteins
5-HT; Axonal sprouting; Corticospinal; Exercise; Ia afferents; Kinematics; Locomotor training; c-Fos