Survival and regeneration of rubrospinal neurons 1 year after spinal cord injury

Abstract

Scientific interest to find a treatment for spinal cord injuries has led to the development of numerous experimental strategies to promote axonal regeneration across the spinal cord injury site. Although these strategies have been developed in acute injury paradigms and hold promise for individuals with spinal cord injuries in the future, little is known about their applicability for the vast majority of paralyzed individuals whose injury occurred long ago and who are considered to have a chronic injury. Some studies have shown that the effectiveness of these approaches diminishes dramatically within weeks after injury. Here we investigated the regenerative capacity of rat rubrospinal neurons whose axons were cut in the cervical spinal cord 1 year before. Contrary to earlier reports, we found that rubrospinal neurons do not die after axotomy but, rather, they undergo massive atrophy that can be reversed by applying brain-derived neurotrophic factor to the cell bodies in the midbrain. This administration of neurotrophic factor to the cell body resulted in increased expression of growthassociated protein-43 and T␣1 tubulin, genes thought to be related to axonal regeneration. This treatment promoted the regeneration of these chronically injured rubrospinal axons into peripheral nerve transplants engrafted at the spinal cord injury site. This outcome is a demonstration of the regenerative capacity of spinal cord projection neurons a full year after axotomy.

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

“…Despite this capacity to sprout, the neurotrophic requirements of neonatal rubrospinal neurons lead to massive cell loss following rubrospinal tract lesion, which can be rescued with BDNF administration [91][92][93]. In contrast, rubrospinal tract lesion in the adult results in significant atrophy of motor neurons in the red nucleus but limited cell death; this atrophy is fully reversible with BDNF delivery even for as much as 1 year after SCI [94][95][96][97]. In addition, BDNF administration to either the red nucleus or the spinal cord following rubrospinal tract lesion results in up-regulation of growth associated genes and promotes axonal growth [67, 94-96, 98, 99].…”

“…NGF promotes the sprouting and regeneration of cholinergic local motor axons, primary nociceptive sensory axons, and cerulospinal axons [104,105]. BDNF-secreting bone marrow stromal cell grafts promote regeneration of a number of neuronal populations including raphaespinal, cerulospinal, rubrospinal, local motor and propprioceptive sensory axons [63,67,94,96]. NT-3 expression, similar to BDNF, promotes the regeneration of ascending sensory neurons across the dorsal root entry zone and within the dorsal columns [60,64,[106][107][108][109].…”

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

“…In the adult rat, some reports have suggested that SCI leads to the death of a sizable proportion of RS neurons (Houle and Ye, 1999;Mori et al, 1997;Novikova et al, 2000), while some other reports have brought evidence that the axotomized RS shrink but survive in an atrophic state (Kwon et al, 2002;Prendergast and Stelzner, 1976). These discrepancies of interpretation may result from methodological differences; in particular they may reflect the inherent difficulty to detect shrunken neurons.…”

“…In the rat, after a spinal cord lesion at cervical levels, axotomized reticulospinal (RS) neurons shrink and display modification in the expression of various molecules (Egan et al, 1977;Kwon et al, 2002Kwon et al, , 2004Novikova et al, 2000;Tetzlaff et al, 1991). In this species, the RNm regains a normal aspect if brain derived neurotrophic factor (BDNF) is provided (Kwon et al, 2002;Liu et al, 1999;Novikova et al, 2000). Because neurotrophic substances are uptaken at synapses, the amount of neurotrophic factors accessible to a neuron relates ultimately to the number of synapses that this neuron possesses.…”

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

“…Even 1 year after a cervical SCI, the cell bodies of severed descending rubrospinal axons, which were previously thought to have perished, regained normal neuronal morphology when BDNF was administered in the vicinity of the red nucleus. 23 Rather than being generated de novo, these rubrospinal neurons had atrophied to the point where they were easily missed during previous histological screens, leading to an underestimation of their numbers and resulting in the premature declaration of their death. Recently, adeno-associated viral (AAV) vectormediated BDNF gene transfer into the red nucleus similarly counteracted atrophy of chronically lesioned rubrospinal neurons.…”