The effects of neurotrophic substances on primary sensory neurons following peripheral nerve injury

Abstract

Sensory impulses from the periphery is transmitted by primary sensory neurons located in dorsal root and cranial nerve ganglia. The primary sensory neurons are phenotypically diverse with regard to their expression of various chemical components. Thus, various subpopulations of dorsal root ganglion (DRG) cells express the peptides substance P (SP) and calcitonin gene related peptide (CGRP), the enzyme fluoride-resistant acid phosphatase (FRAP) and bind the lectin Griffonia (Bandeiraea) simplicifolia I (B4), or the enzyme carbonic anhydrase II (CAII).

Injury to peripheral sensory axons results in prominent changes in the cell bodies as well in the central termination areas of the affected primary sensory neuron. A significant fraction of the DRG cells downregulate SP, CGRP, FRAP and CAII and some undergo neuronal death. There is also changes in the termination pattern of afferents in the dorsal horn. Depletion of normally available target derived trophic factors seems to play an important role in the neuronal changes following axotomy. The effect of nerve growth factor (NGF) is mediated through the TrkA receptor whereas TrkB and TrkC interact with the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), respectively. NGF, BDNF and NT-3 have been shown to have distinct and overlapping effects on the survival and differentiation of sensory neurons and motoneurons and have been proposed as critical target-derived factors.

Various sciatic nerve injuries in female but not male rats lead to a significant decrease in DRG numbers. This loss is not affected by increasing age. Even a short-term or delayed NGF application was able to counteract the loss of DRG neurons following axotomy. NGF also restored the depletion of SP, CGRP and to some extent that of FRAP, but did not affect B4-binding or CAII. However, the same NGF-dose that rescued the axotomized DRG neurons was not sufficient to reduce the axotomy-induced depletion in SP and CGRP. Three weeks of treatment with BDNF or NT-3 rescued axotomized neonatal DRG neurons, but not motoneurons. The activation of microglial and astroglial cells occurs already twenty-four hours, peak around one week after injury whereafter follows a considerably slower decrease. NGF application in doses sufficient to reduce neuronal death and neuropeptide depletion could not counteract the glial cell reactions. NGF, but not BDNF and NT-3 was found to counteract the axotomy-induced expansion of myelinated afferents into lamina II.

In conclusion, the results show that the loss of DRG neurons and some of the biochemical and central connectivity changes after a peripheral nerve injury can be counteracted by application of NGF, BDNF or NT-3. The non-neuronal cells as well as some non-peptidergic biochemical changes cannot be affected, however. These findings indicate that exogenous neurotrophins influence the response of axotomized DRG neurons in a manner which may be significant for the functional recovery after peripheral nerve injury.