Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors

Abstract

After lesions in the differentiated central nervous system (CNS) of higher vertebrates, interrupted fibre tracts do not regrow and elongate by more than an initial sprout of approximately 1 mm. Transplantations of pieces of peripheral nerves into various parts of the CNS demonstrate the widespread capability of CNS neurons to regenerate lesioned axons over long distances in a peripheral nerve environment. CNS white matter, cultured oligodendrocytes (the myelin-producing cells of the CNS), and CNS myelin itself, are strong inhibitors of neuron growth in culture, a property associated with defined myelin membrane proteins of relative molecular mass (Mr) 35,000 (NI-35) and 250,000 (NI-250). We have now intracerebrally applied the monoclonal antibody IN-1, which neutralizes the inhibitory effect of both these proteins, to young rats by implanting antibody-producing tumours. In 2-6-week-old rats we made complete transections of the cortico-spinal tract, a major fibre tract of the spinal cord, the axons of which originate in the motor and sensory neocortex. Previous studies have shown a complete absence of cortico-spinal tract regeneration after the first postnatal week in rats, and in adult hamsters and cats. In IN-1-treated rats, massive sprouting occurred at the lesion site, and fine axons and fascicles could be observed up to 7-11 mm caudal to the lesion within 2-3 weeks. In control rats, a similar sprouting reaction occurred, but the maximal distance of elongation rarely exceeded 1 mm. These results demonstrate the capacity for CNS axons to regenerate and elongate within differentiated CNS tissue after the neutralization of myelin-associated neurite growth inhibitors.

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…After SCI, myelin-derived molecules take the stage in a new light, as critical inhibitors of axonal growth/ regeneration. The role of myelin in suppressing plasticity after SCI was first illustrated in landmark experiments employing the Nogo-blocking antibody (IN-1): 33,34 antagonizing Nogo, the now notorious inhibitory constituent of central myelin, permitted extensive growth of cut corticospinal axons in young rats. In fact, Nogo -now known to exist in three isoforms 35,36 -is but one of a number of myelin-derived inhibitory proteins.…”

International spinal research trust research strategy. III: A discussion document

“…The idea that the presence of inhibitory molecules causes regeneration failure was proposed by Schwab and collaborators, first in culture 12 and then in the injured spinal cord, 13 on the basis of a molecule present on the surface of oligodendrocytic myelin. 14 This molecule is now known as Nogo.…”

“…14 This molecule is now known as Nogo. Blocking Nogo promotes either regeneration 13 or beneficial sprouting. 15 Nogo is one of several inhibitory molecules that are associated with CNS myelin, with other candidates including myelin-associated glycoprotein and oligoden- [16][17][18][19][20] and a common pathway for the effects of these various inhibitory molecules has been described.…”

Repair of spinal cord injuries: where are we, where are we going?

“…This antibody was applied to rat spinal cord injuries by implanting antibodysecreting hybridoma cells into the brain. The corticospinal tract was labelled, and axons were seen regenerating for distances of over 1 cm 43 (Figure 1a). Behavioural assessment showed that some spinal cord functions that rely on corticospinal function returned in these animals.…”