The nerve conditioning lesion: A strategy to enhance nerve regeneration

Abstract

By altering the intrinsic metabolism of the cell, including the upregulation of regeneration-associated genes (RAGs) and the production of structural proteins for axonal outgrowth, the conditioning lesion sets up an environment highly conducive to regeneration. In this review, we assess 40 years of research to provide a comprehensive overview of the conditioning lesion literature, directed at (1) discussing the mechanisms of and barriers to nerve regeneration that can be mitigated by the conditioning lesion, (2) describing the cellular and molecular pathways implicated in the conditioning lesion effect, and (3) deliberating on how these insights might be applied clinically. The consequential impact on regeneration is profound, with a conditioned nerve demonstrating longer neurite extensions in vitro, enhanced expression of RAGs within the dorsal root ganglia, early assembly and transportation of cytoskeletal elements, accelerated axonal growth, and improved functional recovery in vivo. Although this promising technique is not yet feasible to be performed in humans, there are potential strategies, such as conditioning electrical stimulation that may be explored to allow nerve conditioning in a clinically safe and well-tolerated manner. Ann Neurol 2018;83:691-702.

Axotomy Induces Phasic Alterations in Luman/CREB3 Expression and Nuclear Localization in Injured and Contralateral Uninjured Sensory Neurons: Correlation With Intrinsic Axon Growth Capacity

“…The increased Luman expression and significantly increased intrinsic axon growth competence that we observed in neurons contralateral to 1-week injury support previous work by the Ryoke et al (60) showing that a prior lesion can serve to condition contralateral DRG to express higher levels of protective and growth-promoting compounds, and to regenerate more robustly when subsequently injured (61). Interestingly, we found the mode of axon growth to be predominantly of the elongating form typically associated with the 1-week injuryconditioned neurons (31), as opposed to the highly arborized outgrowth we observed for contralateral neurons at the 2 earlier timepoints, which did not differ from that observed for naïve neurons and is in agreement with that which we previously reported for neurons contralateral to 1-day injury (12).…”

Macrophage biology in the peripheral nervous system after injury

“…As noted at the beginning of this review, although regeneration occurs in the PNS, it is slow and incomplete. It has been proposed recently that, if the molecular mechanism underlying the conditioning-lesion effect were understood, it might be possible to elicit this response via a non-destructive means and facilitate regeneration in patients soon after a peripheral nerve injury (Senger et al, 2018).…”

Peripheral Nerve Regeneration and Muscle Reinnervation

“…The majority of human nerve injuries, resulting from vehicle accidents, recreational activities and iatrogenic injuries during surgeries, occur in the upper extremity ( Figure 3A) [42]. Seminal studies in rodents in the Gordon and Brushart laboratories with Canadian and German collaborators [29,[43][44][45][46][47] (reviews [33,[48][49][50][51][52]), and in human patients in the Chan laboratory in Canada [53][54][55] (reviews [33,48,52,56]), demonstrated that brief low frequency, electrical stimulation of the nerve proximal to the site of transection and surgical repair, accelerated motor and sensory nerve regeneration. More recently, a positive conditioning effect of electrical stimulation of the intact nerve, prior to nerve transection and repair, has been pursued in rat studies in the laboratories of Chan and Webber [57][58][59][60].…”