A novel and robust conditioning lesion induced by ethidium bromide

Abstract

Molecular and cellular mechanisms underlying the peripheral conditioning lesion remain unsolved. We show here that injection of a chemical demyelinating agent, ethidium bromide, into the sciatic nerve induces a similar set of regeneration-associated genes and promotes a 2.7-fold greater extent of sensory axon regeneration in the spinal cord than sciatic nerve crush. We found that more severe peripheral demyelination correlates with more severe functional and electrophysiological deficits, but more robust central regeneration. Ethidium bromide injection does not activate macrophages at the demyelinated sciatic nerve site, as observed after nerve crush, but briefly activates macrophages in the dorsal root ganglion. This study provides a new method for investigating the underlying mechanisms of the conditioning response and suggests that loss of the peripheral myelin may be a major signal to change the intrinsic growth state of adult sensory neurons and promote regeneration.

The nerve conditioning lesion: A strategy to enhance nerve regeneration

“…A CL is a purposeful peripheral nerve insult prior to definitive injury and repair, with the aim of enhancing axon regeneration. Parameters that appear to affect the CL response include the (1) method of conditioning, (2) location of the CL, (3) magnitude of the insult, (4) duration of conditioning effect, (5) CL interval, and (6) type of nerves suitable for conditioning . A summary of the findings is shown in Table .…”

“…Heightened inflammation induced by macrophages improves axon regeneration, and when macrophages are eliminated in the milieu, axon regeneration is significantly reduced. Hollis et al echoed the importance of macrophages by simulating a CL using ethidium bromide injected into the sciatic nerve . The increased number of macrophages in the DRGs was associated with a robust growth of the peripheral axons.…”

The Dorsal Column Lesion Model of Spinal Cord Injury and Its Use in Deciphering the Neuron‐Intrinsic Injury Response

“…The tape removal test showed deficits after C4 lesion (Bradbury et al, ) but only minor deficits in another study (Fagoe et al, ), and no effect on the similar adhesive dot removal task was found after C1 lesion (Ballermann et al, ). Significant deficits were found on the narrow beam (Bradbury et al, ; Hollis et al, ) and rotarod (Hollis et al, ), with cervical lesions. Skilled reaching tasks have also been assessed in cervical lesions.…”

“…Several other studies employ sensory tests that are primarily developed for nociceptive function and were used to investigate perceptual abnormalities in treatment groups or neuropathic pain states as a result of the lesion (Chan et al, ; Andrews et al, ; Hollis et al, ). For this aim, thermal and mechanical hyperalgesia can be assessed with Hargreaves and Von Frey tests.…”

Intrinsic Axonal Growth and the Drive for Regeneration

“…Interestingly, recent work from the Zou lab demonstrated a novel ethidium bromide-induced conditioning lesion (Hollis et al, 2015). Here, when injected into the sciatic nerve, ethidium bromide acted as a demyelinating agent and induced prototypical regeneration associated genes as well as robust central regeneration that surpassed that induced by traditional nerve crush.…”