Combination Treatment With Exogenous GDNF and Fetal Spinal Cord Cells Results in Better Motoneuron Survival and Functional Recovery After Avulsion Injury With Delayed Root Reimplantation

Abstract

When spinal roots are torn off from the spinal cord, both the peripheral and central nervous system get damaged. As the motoneurons lose their axons, they start to die rapidly, whereas target muscles atrophy due to the denervation. In this kind of complicated injury, different processes need to be targeted in the search for the best treatment strategy. In this study, we tested glial cell-derived neurotrophic factor (GDNF) treatment and fetal lumbar cell transplantation for their effectiveness to prevent motoneuron death and muscle atrophy after the spinal root avulsion and delayed reimplantation. Application of exogenous GDNF to injured spinal cord greatly prevented the motoneuron death and enhanced the regeneration and axonal sprouting, whereas no effect was seen on the functional recovery. In contrast, cell transplantation into the distal nerve did not affect the host motoneurons but instead mitigated the muscle atrophy. The combination of GDNF and cell graft reunited the positive effects resulting in better functional recovery and could therefore be considered as a promising strategy for nerve and spinal cord injuries that involve the avulsion of spinal roots.

Tissue Engineered Axon-Based “Living Scaffolds” Promote Survival of Spinal Cord Motor Neurons Following Peripheral Nerve Repair

“…70 Recent studies have developed biomimetic smart materials to offer a counter argument to acellular nerve guidance tubes by adding biological components and proteins, such as extracellular matrix, NGF, BDNF, and GDNF. [71][72][73][74][75][76][77][78] These boosted grafts, may prove effective in some instances of neural regeneration, including sustainment of host neurons during long distance gap repairs. 79,80 However, despite these novel engineering feats, even with the addition of biological fillers, acellular grafts remain unable to address overall shortcomings in nerve regeneration.…”

Nerve Root Reimplantation in Brachial Plexus Injuries

“…The timing of NR reimplantation is crucial, as a longer waiting period will correlate with a greater amount of MNs undergoing apoptosis [20,27,91,93,[101][102][103]. The percentage of dead MNs increases from 20% by 10-12 days post-avulsion [13,65,69] to 50% by 4 weeks [104,105], 85% by 6 weeks [106] and 90% by 20 weeks [27,83,93,107].…”

“…In animal models, NRA followed by immediate reimplantation in the same surgical procedure minimizes MN apoptosis and achieves muscle reinnervation with some limited functional recovery, which is better in the brachial plexus than in the lumbosacral plexus [27,69,83,110]. Ideally, the surgical repair must be performed no later than 10 days post-injury [65] as a delay over 2 weeks will lead to poor clinical results [20,26,27]. In clinical practice, patients suffering from brachial or lumbosacral plexus avulsions often experience other concomitant injuries, sometimes quite serious, that force delaying NR repair [111].…”

“…NFs enhance Schwann cell migration, axonal regeneration and myelination [8,16,69,93,105,[116][117][118][119][120] and delay MN apoptosis-by 6 weeks 80-90% of them are still alive [8,69,116,[118][119][120][121]. To be maximally effective, they must be administered locally at the SC-NR interface within the first 3 days and no later than 2 weeks post-avulsion [20,87,93,116]. NFs ought to be applied with Gelfoam or fibrin glue to avoid dilution in the CSF [72], but free intrathecal application by means of an injecting pump is not recommended [122].…”

“…Inside the avulsed NR itself, there is a Wallerian degeneration with axonal and myelin loss [18]. The muscles, devoid of nervous impulses, undergo atrophy and fibrous transformation [19,20]. At the SC, the neurons suffer loss of synapses with destruction of previous neuronal networks and creation of new anomalous ones that will lead to abnormal nerve impulses which might induce chronic neuropathic pain [21][22][23][24].…”