Infusion of anti-Nogo-A antibodies in adult rats increases growth and synapse related proteins in the absence of behavioral alterations.
Restricted structural re-growth in the adult CNS is a major limitation to fully functional recovery following extensive CNS trauma. This limitation is partly due to the presence of growth inhibitory proteins, in particular, Nogo-A. Pre-clinical studies have demonstrated that intrathecally infused anti-Nogo-A antibodies are readily distributed via the cerebrospinal fluid penetrating throughout the spinal cord and brain, where they promote sprouting, axonal regeneration and improved functional recovery after CNS injury. Whether anti-Nogo-A treatments of intact animals might induce behavioral alterations has not been systematically tested. This is addressed here in an adult rat model of chronic intrathecal infusion of function-blocking anti-Nogo-A antibodies for 2 to 4weeks. We observed by proteomic and immunohistochemical techniques that chronic Nogo-A neutralization in the intact CNS increased expression of cytoskeletal, fiber-growth-related, and synaptic proteins in the hippocampus, a brain region which might be particularly sensitive to Nogo-A depletion due to the high expression level of Nogo-A. Despite such molecular and proteomic changes, Nogo-A blockade was not associated with any pronounced cognitive-behavioral changes indicative of hippocampal functional deficiency across several critical tests. Our results suggest that the plastic changes induced by Nogo-A blockade in the adult hippocampus are counter-balanced by homeostatic mechanisms in the intact and the injured CNS. The data indicate that anti-Nogo-A therapy appears safe in the adult CNS over 4weeks of continuous administration.
Brain Research Institute, University of Zurich, Zurich, Switzerland; Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
Luis M
LM
Craveiro
Oliver
O
Weinmann
Bernd
B
Roschitzki
Roman R
RR
Gonzenbach
Björn
B
Zörner
Laura
L
Montani
Benjamin K
BK
Yee
Joram
J
Feldon
Roman
R
Willi
Martin E
ME
Schwab
D000375:Aging; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D007278:Injections, Spinal; D008297:Male; D009185:Myelin Proteins / Q000276:immunology*; D009473:Neuronal Plasticity / Q000187:drug effects*; D000070798:Nogo Proteins; D040901:Proteomics; D051381:Rats; D020318:Rats, Long-Evans; D013569:Synapses / Q000378:metabolism
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603197:Rtn4 protein, rat
Axonal growth; Behavior; Clinical; Hippocampus; Nogo-A; Plasticity; Proteomics