Motor Axonal Regeneration after Partial and Complete Spinal Cord Transection

Abstract

We subjected rats to either partial mid-cervical or complete upper thoracic spinal cord transections and examined whether combinatorial treatments support motor axonal regeneration into and beyond the lesion. Subjects received cAMP injections into brainstem reticular motor neurons to stimulate their endogenous growth state, bone marrow stromal cell grafts in lesion sites to provide permissive matrices for axonal growth, and brain-derived neurotrophic factor (BDNF) gradients beyond the lesion to stimulate distal growth of motor axons. Findings were compared to several control groups. Combinatorial treatment generated motor axon regeneration beyond both C5 hemisection and complete transection sites. Yet despite formation of synapses with neurons below the lesion, motor outcomes worsened after partial cervical lesions and spasticity worsened after complete transection. These findings highlight the complexity of spinal cord repair, and the need for additional control and shaping of axonal regeneration.

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

“…14 It is known that BDNF plays an important role in neuroplasticity following spinal cord injury, 1 and previous studies have shown that BDNF treatment after spinal cord injury increases survival of neurons, axonal sprouting, and/or recovery of function when delivered by intrathecal infusion, [66][67][68][69] intraspinal viral treatment, 28,29,70 or stem cell transplantation. 37,71 Unfortunately, nonlocalized administration of BDNF is associated with adverse effects in human studies.…”

“…23 Animal studies have additionally shown induction of muscle spasticity at 4 weeks after AAV-mediated delivery of BDNF. 28,29 The potential adverse effects of BDNF were not an outcome of the current study design; therefore, allodynia or spasticity was not systematically assessed. We did not observe behavioral manifestations suggestive of allodynia or spasticity following 14 days of MSCs-based BDNF delivery, in agreement with the lack of adverse effects of intrathecal BDNF treatment at C4.…”

“…Importantly, recovery of ipsilateral diaphragm activity after SH can be enhanced by intrathecal delivery of BDNF at the level of the phrenic motor nucleus. 14 Unfortunately, nonlocalized administration of BDNF by systemic, 22 or even intrathecal, treatment 23,24 in human studies is linked to adverse effects, mainly related to altered sensory processing and pain, [25][26][27] muscle spasticity, 28,29 and other behavioral effects 22 that prevent its therapeutic use.…”

Motor Axonal Regeneration following Cord Transection

“…Work by Lu and colleagues (2012) published in a recent issue of The Journal of Neuroscience yields evidence to suggest that more will be required to restore function after injury than simply promoting the regeneration of a given spinal tract. Lu et al (2012) used a rat lateral midcervical hemisection model and demonstrated that a combinatorial treatment strategy resulted in motor axon regeneration. This combinatorial strategy included administration of the cell-permeable dibutyryl cAMP in brainstem reticular motor nuclei, bone marrow stromal cell grafts in the lesion site, and brain-derived neurotrophic factor (BDNF) gradients beyond the lesion site.…”

“…To remove the contribution of the intact reticulospinal tract, which is spared following lateral hemisection, Lu et al (2012) also tested their optimal full combinatorial treatment in a rat upper thoracic full-transection model. Because the majority of motor assessments are inappropriate to use in fulltransection models, Lu et al (2012) used open-field locomotion, assessed with a Beattie-Basso-Bresnahan (BBB) score.…”