Anti‐Nogo‐A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey

Abstract

After injury, regrowth of axons in mammalian adult central nervous system is highly limited. However, in monkeys subjected to unilateral cervical lesion (C7-C8 level), neutralization of an important neurite outgrowth inhibitor, Nogo-A, stimulated axonal sprouting caudal to the lesion, accompanied by enhanced functional recovery of manual dexterity, compared with lesioned monkeys treated with a control antibody (Freund et al. [2006] Nat. Med. 12:790 -792). The present study aimed at comparing the same two groups of monkeys for axonal sprouting rostral to the cervical lesion. The corticospinal tract was labeled by injecting the anterograde tracer biotinylated dextran amine into the contralesional motor cortex. The corticospinal axons were interrupted at the level of the lesion, accompanied by retrograde axonal degeneration (axon dieback), reflected by the presence of terminal retraction bulbs. The number of terminal retraction bulbs was lower in anti-Nogo-A antibody treated monkeys, and, when present, they were found closer to the lesion than in controlantibody treated monkeys. Compared with control antibody treated monkeys, the antiNogo-A antibody treated monkeys exhibited an increased cumulated axon arbor length and a higher number of axon arbors going in the medial direction from the white to the gray matter. Higher in the cervical cord (at C5 level), the anti-Nogo-A treatment enhanced the number of corticospinal fibers crossing the midline, suggesting axonal sprouting. Thus, the anti-Nogo-A antibody treatment enhanced axonal sprouting rostral to the cervical lesion; some of these fibers grew around the lesion and into the caudal spinal segments. These processes paralleled the observed improved functional recovery.

Fate of rubrospinal neurons after unilateral section of the cervical spinal cord in adult macaque monkeys: Effects of an antibody treatment neutralizing Nogo-A

“…The manual dexterity performances were assessed for several months post-lesion, until the animals reached a plateau reflecting a stable level of manual dexterity. The behavioural, electrophysiological and neuroanatomical tracing data related to the CS tract derived from these animals were described in previous reports (Freund et al, , 2007Schmidlin et al, 2005Schmidlin et al, , 2004Wannier et al, 2005). The present report is focussed on anatomical aspects dealing specifically with the issue of fate of RS neurons after unilateral cervical section.…”

“…For the same lesion, the treatment with an antibody neutralizing the neurite growth inhibitor Nogo-A induced sprouting of CS axons (Freund et al, , 2007. In parallel to these morphological changes, the antiNogo-A treatment also enhanced functional recovery .…”

“…All animals included in the present study belong to a long-term research project on spinal cord lesion from which post-lesion changes in the CS system were described earlier (Freund et al, , 2007Schmidlin et al, 2005Schmidlin et al, , 2004Wannier et al, 2005). To assess the number of RS neurons in this model, midbrain sections including the red nucleus were obtained from 15 adult (3-8 years old) macaque monkeys (Macaca mulatta or Macaca fascicularis).…”

“…This view is however rather unlikely, because no effect on the number or volume of SMI-32 neurons was observed for axotomized CS neurons (Beaud et al, 2006). For these neurons, the mechanisms mentioned above should have then entered in action, as the neutralization of Nogo-A has been shown to promote CS axonal sprouting after cervical spinal cord lesion in rats (Bregman et al, 1995;Liebscher et al, 2005;Schwab, 2004), marmoset monkeys (Fouad et al, 2004) and macaque monkeys (Freund et al, , 2007. Nevertheless, the issue of whether anti-Nogo-A antibody treatment enhances sprouting of the RS tract in non-human primates remains an open question that will require future attention.…”

“…The surgical procedures for the unilateral spinal cord lesion at C7/C8 level have been described in detail in previous reports; (Freund et al, , 2007Schmidlin et al, 2004;Wannier et al, 2005). Briefly, the animal was anesthetized by intramuscular (i.m.)…”