On traumatic lesion to the spinal cord and dorsal spinal roots : factors influencing axonal regrowth across the border between the central and peripheral nervous system in the rat and man

Abstract

Nerve cells are depending on their environment. Glial cells, astrocytes and oligodendrocytes in the central nervous system (CNS) make up a totally different milieu and characteristics than the distinguishing qualities of the peripheral nervous system (PNS), where the nerve cells are surrounded by Schwann cells. The surrounding cells in the CNS and PNS give the tissues different reaction patterns following a nerve trauma situation. Traumatised axons in the PNS can most often be healed compared to the fact that this seldom is seen in the CNS. To enhance the understanding concerning the matter of the environment it could be of interest to thoroughly study the reaction after injury to the parts of the nervous system that has its course both in the CNS and in the PNS.

To gain insight in how the adhesion modulating molecule tenascin might influence neuronal regeneration, the expression patterns of tenascin-R, tenascin-J1, tenascin-C and tenascin-X mRNA were analyzed in the perinatal adult rat spinal cord and olfactory system, as well as after a ventral funiculus lesion (VFL) of the spinal cord. All tenascin forms were up regulated in the scar tissue after VFL of the spinal cord. Thus tenascin expression in the adult primary olfactory pathway could not be correlated to tenascin expression in the scar tissue after spinal cord lesion.

The data collected in this study showed that there was an early down-regulation of mRNAs for TN-R and J1 in the alpha-motoneurons in the ventral cord after a VFL. The data did also support a macroscopic up-regulation of macrophages in the ventral funiculus of the spinal cord. Our findings suggest that inflammatory cells invading the nerve tissue in the CNS may down-regulate TN mRNAs in axotomized motoneurons as a result of a persisting BBB dysfunction following a traumatic injury close to the motor nuclei.

In order to gain further insight of the interplay between neuronally derived NRGs and Erb receptors we have examined the distribution of mRNA for NRG1, ErbB3 and ErbB4-receptor tyrosine kinases after a VFL, in two situations where growth of axons can occur across the CNS/PNS border. Regenerative sprouts from injured motor axons penetrate the CNS-type scar tissue and reach the supportive Schwann cells in the ventral root. The results in the present study indicated that NRG1 mRNA is constitutively expressed by adult spinal alfa-motoneurons. Our data show that ErbB3 in the ventral roots was upregulated after a VFL and that NRG1 mRNA was initially downregulated in the motoneurons. The lesion-induced changes in the expression of NRG l and ErbB3 in the injured spinal cord and denervated ventral root can be assumed to be of importance for axonal growth and the regulation of glial cell survival.

To further elucidate the complex interactions between the action as a family of chemorepellents and/or chemoattracants, the semaphorins; Sema3A, SEMA3F, SEMA4F,and NP1, NP2 and VEGF mRNA, was analyzed after VFL as well as their expression in the ventral roots in adult rats. This study shows that an involvement of semaphorins and their receptors are involved in the posttraumatic response in spinal motoneurons after central axon injury. Though, the results suggest that the response in motoneuron expression of Sema3A and its receptor neuropilin 1 is dissimilar after lesions in the central and peripheral nervous systems.

If the presence of VEGF, binding and blocking NP1, can have inhibiting effects on the chemorepulsive actions of Sema3A, it might imply a new incitament for VEGF as a positive molecule for nerve growth and regeneration.

This study also shows that semaphorins and their receptors are involved in the posttraumatic response in rat and human dorsal root ganglia (DRG) neurons. The Sema3A receptor NP1, and SEMA3F receptor NP2, was significantly upregulated in the rat DRG neurons after dorsal rooot transection (DRT), sciatic nerve transection (SNT) and sciatic nerve crush (SNC). SEMA4F was upregulated after a SNT/SNC. The expression of mRNA for VEGF in rat DRG'S after DRT showed a significant upregulation that was high even a year after the injuries. These data suggest a significant role for the semaphorins, neuropilins, VEGF and J1 in the reactions after dorsal root lesions.