The Mechanisms of Peripheral Nerve Preconditioning Injury on Promoting Axonal Regeneration

Abstract

Two major factors contribute to the failure of axonal regrowth in the central nervous system (CNS), namely, the neuronal intrinsic regenerative capacity and the extrinsic local inhibitory microenvironments. However, a preconditioning peripheral nerve lesion could substantially enhance the regeneration of central axons following a subsequent spinal cord injury. In the present review, we summarize the molecular mechanisms of the preconditioning injury effect on promoting axonal regeneration. The injury signal transduction resulting from preconditioning peripheral nerve injury regulates the RAG expression to enhance axonal regeneration. Importantly, preconditioning peripheral nerve injury triggers interactions between neurons and nonneuronal cells to amplify and maintain their effects. Additionally, the preconditioning injury impacts mitochondria, protein, and lipid synthesis. All these coordinated changes endow axonal regeneration.

Topoisomerase I inhibition and peripheral nerve injury induce DNA breaks and ATF3-associated axon regeneration in sensory neurons

“…One way to do this experimentally is to prime injured neurons for growth by a preconditioning nerve injury. The initial insult of the preconditioning injury induces the RAG network, resulting in an even greater further induction of these genes and faster growth of axons in response to a subsequent second nerve injury (Nix and Bastiani, 2012;van Kesteren et al, 2011;Yang et al, 2021).…”

Mitochondrial Behavior in Axon Degeneration and Regeneration

“…Miro overexpression enhances mitochondrial transport in proximal segments, whereas axon regeneration is significantly inhibited in individuals where Miro is suppressed (Han et al, 2016). In addition, by imaging axonal mitochondrial transport in vivo, and when the intercostal nerve is damaged, mitochondrial anterograde transport is increased (Misgeld et al, 2007), which may be associated with tyrosinated tubulin, and upregulated molecular motors (Yang et al, 2021). An in vivo sciatic nerve compression study indicates that enhanced mitochondrial transport, via SNPH knockout in mice, accelerates axon regeneration in the peripheral nervous system (Zhou et al, 2016).…”

Dorsal Root Injury—A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury

“…The potential of DRG neurons to mount an efficient regenerative response after dorsal root injury is shown by a so-called conditioning lesion, i.e., an injury to the peripheral sensory axons. This intervention, which is typically performed one to two weeks prior to injury to the central processes of the same sensory neurons induces RAGs in DRG neurons and stimulates growth supportive interactions between dorsal root axons and associated non-neuronal cells, thereby promoting elongation of injured dorsal root axons [ 45 ]. The conditioning lesion paradigm has made a significant contribution to our understanding of regeneration failure after injury to primary sensory axons.…”