Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages.

Abstract

STRACTIn newborn rats the levels of nerve growth fa tor (NGF) mRNA (mRNANGF) and NGF receptor mRNA ( A') in the sciatic nerve were 10 and 120 times higher, r pectively, than in adult animals. mRNAL levels decreased st adily from birth, approaching adult levels by the third stnatal week, whereas mRNANUF levels decreased only after th first postnatal week, although also reaching adult levels by the third week. Transection of the adult sciatic nerve resulted in a marked biphasic increase in mRNANGF with time. On the p oximal side of the cut, this increase was confined to the area immediately adjacent to the cut; peripherally, a similar biphasic increase was present in all segments. mRNAL levels were al markedly elevated distal to the transection site, in agreem nt with previous results obtained by immunological transection of the sciatic nerve, local NGF synthesis increases dramatically. Augmented NGF synthesis is observed in all segments distal to the transection site but is confined proximally to those parts of the nerve stump immediately adjacent to the lesion (9). This part of the nerve stump may be considered as a "substitute target" for the axotomized and then regenerating axons of the sympathetic and sensory neurons. Although the NGF concentrations in the proximal nerve stump correspond to those of a densely innervated peripheral target organ (10, 11), the volume ofthe "substitute organ" is too small to fully replace the interrupted supply from the peripheral physiological target tissues. This is apparent from the fact that the NGF levels in the proximal unlesioned part of the sciatic nerve reach only 40% of their normal values (9). Simultaneously with the enhanced synthesis of NGF, the transection of the sciatic nerve leads also to reexpression of NGF receptors by Schwann cells (12), receptors normally seen only in earlier stages of development (13,14).In the present study we asked whether the reexpression of NGF receptors and the enhanced synthesis of NGF by Schwann cells are mediated by a common mechanism. We first followed the developmental changes in the levels of mRNA encoding NGF (mRNANGF) and of mRNA encoding NGF receptor (mRNArec) from birth to adulthood and then compared the time course of the levels of these two mRNAs after sciatic nerve transection both distally and proximally to the lesion. In experiments using a crush injury rather than transection, we studied whether neuronal regeneration brought about the return of mRNANGF and mRNA1 to normal levels. MATERIALS AND METHODSPreparation of Sciatic Nerves. Wistar rats (male or female, 150-200 g) were anesthetized with diethyl ether and the sciatic nerve was cut or crushed at the sciatic notch. After cutting, the distal stump of the nerve was diverted into muscle tissue in order to minimize regrowth of fibers. For crushing of the nerve, forceps were cooled in liquid nitrogen and the crush site was marked by a thread.At various times after nerve injury, animals were killed, the nerves were cut into three segments [B (proximal)

The autotomy relief effect of a silicone tube covering the proximal nerve stump

“…31,32 Our examination showed a marked increase in NGF-IR in the PNS. Our model may have been easily influenced by conditions such as inflammation in the surrounding tissue.…”

“…31,52 On the other hand, in an immunohistological report examining the NGF receptors in traumatic human peripheral nerve neuroma, a marked increase in TrkA was observed. 53 Our study showed an increase in TrkA-IR in the PNS.…”

“…11,30 In Wallerian-degenerated nerves, macrophages and Schwann cells increase. 8,[31][32][33] Infiltration of macrophages in the experimental neuroma might promote neuropathic pain. 10 Macrophages promote increases of pro-inflammatory cytokines such as tumor necrosis factor-a, interleukin-6, and interleukin-1b, [34][35][36] cytokines that are involved in pain.…”

Developing Neonatal Rat Sympathetic and Sensory Neurons Differ in Their Regulation of 5-HT3Receptor Expression

“…The increase in 5-HT 3 R expression cannot be explained by changes in neurotrophin receptor expression by nodose neurons over this time in culture (D. W. and E. C., unpublished results). Because neurotrophins are released from non-neuronal cells in degenerating peripheral nerve stumps after axotomy (Heumann et al, 1987;Raivich et al, 1991), as well as from target tissues, this mechanism could ensure that, after a brief delay (24 hr), regenerating nodose axons will continue to express 5-HT 3 R. Conceivably, neurotrophins also play a role in regulating 5-HT 3 R expression in SCG neurons.…”

Schwann cell proliferation during Wallerian degeneration is not necessary for regeneration and remyelination of the peripheral nerves: Axon-dependent removal of newly generated Schwann cells by apoptosis

“…However, our data indicates that the S100 + cells found in adult PNS following nerve injury are susceptible to death in the absence of axonal contact. A possible mechanism of S100 + Schwann cell death in adult mice is the up-regulation of the p75NGFR expression following axotomy (Heumann et al 1987). A role of p75NGFR in mediating cell death has been implicated in several cell types (Barrett and Bartlett 1994;Casaccia-Bonnefil et al 1996;Frade et al 1996;Rabizadeh et al 1993;Syroid et al 2000).…”