Abstract
The primary sensory neurons of dorsal root ganglia (DRG) are a very useful model to study the neuronal regenerative program that is a prerequisite for successful axon regeneration after peripheral nerve injury. Seven days after a unilateral sciatic nerve injury by compression or transection, we detected a bilateral increase in growth-associated protein-43 (GAP-43) and superior cervical ganglion-10 (SCG-10) mRNA and protein levels not only in DRG neurons of lumbar spinal cord segments (L4-L5) associated with injured nerve, but also in remote cervical segments (C6-C8). The increase in regeneration-associated proteins in the cervical DRG neurons was associated with the greater length of regenerated axons 1 day after ulnar nerve crush following prior sciatic nerve injury as compared to controls with only ulnar nerve crush. The increased axonal regeneration capacity of cervical DRG neurons after a prior conditioning sciatic nerve lesion was confirmed by neurite outgrowth assay of in vitro cultivated DRG neurons. Intrathecal injection of IL-6 or a JAK2 inhibitor (AG490) revealed a role for the IL-6 signaling pathway in activating the pro-regenerative state in remote DRG neurons. Our results suggest that the pro-regenerative state induced in the DRG neurons non-associated with the injured nerve reflects a systemic reaction of these neurons to unilateral sciatic nerve injury.
Highlights
It is well-known that besides extrinsic factors, activation of a neuronal regenerative program is necessary for successful axon regeneration after peripheral nerve injury
Western blot analysis of growth-associated protein-43 (GAP-43) in cervical dorsal root ganglia (DRG) of rats surviving 1, 3, 7, and 14 days after SNC showed the protein level peaked at 7 days with a drop at 14 days when compared to cervical DRG of naïve or sham-operated rats (Figure 1)
superior cervical ganglion-10 (SCG-10) immunopositive axons displayed a significantly greater length from the point of ulnar nerve crush after prior SNC or CSNT than in controls without the conditioning lesion. These results demonstrated in vivo the enhanced pro-regenerative state of cervical DRG neurons corresponding with increased levels of GAP-43 or SCG-10 induced by the conditioning sciatic nerve lesion
Summary
It is well-known that besides extrinsic factors, activation of a neuronal regenerative program is necessary for successful axon regeneration after peripheral nerve injury. A conditioning lesion of the peripheral nerve, where peripheral axonal branches are injured beforehand, triggers a regenerative program in DRG neurons that is sufficient to allow regeneration of central axonal branches (Neumann and Woolf, 1999). This phenomenon of a conditioning peripheral nerve lesion with the activation of the pro-regenerative state in DRG neurons is at least partly associated with upregulation of some neuropoietic cytokines including IL-6 (Cafferty et al, 2001; Zigmond, 2011, 2012). It was shown that increased axon regeneration was conditioned in the homologous nerve contralateral to the injured nerve (Yamaguchi et al, 1999; Ryoke et al, 2000)
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