Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA.

Abstract

Abstract. Nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF) are molecules which regulate the development and maintenance of specific functions in different populations of peripheral and central neurons, amongst them sensory neurons of neural crest and placode origin. Under physiological conditions NGF is synthesized by peripheral target tissues, whereas BDNF synthesis is highest in the CNS. This situation changes dramatically after lesion of peripheral nerves. As previously shown, there is a marked rapid increase in NGF mRNA in the nonneuronal cells of the damaged nerve. The prolonged elevation of NGF mRNA levels is related to the immigration of activated macrophages, interleukin-1 being the most essential mediator of this effect.Here we show that transsection of the rat sciatic nerve also leads to a very marked increase in BDNF mRNA, the final levels being even ten times higher than those of NGF mRNA. However, the time-course and spatial pattern of BDNF mRNA expression are distinctly different. There is a continuous slow increase of BDNF mRNA starting after day 3 post-lesion and reaching maximal levels 3-4 wk later. These distinct differences suggest different mechanisms of regulation of NGF and BDNF synthesis in non-neuronal cells of the nerve. This was substantiated by the demonstration of differential regulation of these mRNAs in organ culture of rat sciatic nerve and Schwann cell culture. Furthermore, using bioassays and specific antibodies we showed that cultured Schwann cells are a rich source of BDNF-and ciliary neurotrophic factor (CNTF)-like neurotrophic activity in addition to NGF. Antisera raised against a BDNF-peptide demonstrated BDNF-immunoreactivity in pure cultured Schwann cells, but not in fibroblasts derived from sciatic nerve.B RAIN-derived neurotrophic factor (BDNF) l and nerve growth factor (NGF) belong to a still growing family of neurotrophic molecules collectively called neurotrophins (6, 60). These proteins show a similar basic structure reflected by conserved domains arranged around the six cysteine residues which seem to be of great importance in determining the three-dimensional structure of these molecules, a prerequisite for their biological activity. However, BDNF and NGF also show distinctly different variable domains which determine the different spectra of their neuronal specificity. Both BDNF and NGF support neural crestderived sensory neurons in the periphery (placode-derived sensory neurons are supported only by BDNF and neurotrophin-3 [NT-3]) (27,28,37). The effects of different neurotrophins on DRG neurons are additive in vitro (BDNF and NGE see reference 37; BDNF and NT-3, see reference 28), suggesting that the various sub-populations of neurons are 1. Abbreviations used in this paper: BDNF, brain-derived neurotrophic factor; DRG, dorsal root ganglion; FK, forskolin; IL-1, intefleukin-1; NGF, nerve growth factor; supported by different members of the NGF gene family in a partly overlapping manner. Under physiological as well as culture conditions NGF ...

Expression of GTP-dependent and GTP-independent Tissue-type Transglutaminase in Cytokine-treated Rat Brain Astrocytes

“…In the present study we show that TGase is expressed by rat astrocytes; moreover, we show that the inflammation-associated cytokines IL-1␤ and, to a lesser extent, TNF-␣ cause up-regulation of TGase expression and also induce expression of an additional form of TGase not detectable in untreated cells. IL-1␤ and TNF-␣ have also been shown to cause elevated expression of other regeneration-supportive el- ements (33), such as basic fibroblast growth factor (34), nerve growth factor (35)(36)(37), and cell adhesion molecules. These cytokines may be deficient in the central nervous system due to inappropriate signaling for macrophage recruitment and activation (38 -40).…”

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

“…Transplantation of Schwann cells into sites of CNS injury, including the lesioned spinal cord, mimics the effects of peripheral nerve grafts and supports axonal regeneration [42,43]. In addition to potentially myelinating regenerated axons, Schwann cells express cell adhesion molecules, produce components of the extracellular matrix, and secrete multiple neurotrophic factors [44][45][46][47][48][49][50][51][52][53]. Whether grafted Schwann cells provide an advantage in comparision with other potential cell grafts remains to be determined; however, as the grafted cells survive poorly in the lesioned spinal cord, they are soon replaced by migrating endogenous Schwann cells [54,55].…”

“…Sciatic lesion in neonatal mice results in a loss of approximately two-thirds of the lower motor neurons in the lumbar enlargement, which is completely ameliorated with the application of BDNF, NT-3, or insulin-like growth factor I (IGF-I) [78]. This death of neonatal motor neurons is in stark contrast to lower motor neurons that not only survive, but regenerate following adult sciatic nerve injury; sciatic injury has been shown to result in increased NGF, BDNF, IGFs, cilliary neurotrophic factor, and glial-derived neurotrophic factor secretion from Schwann cells [44][45][46][47][48][49][50][51][52][53]. Antibody depletion of Schwann cell-produced BDNF leads to decreased regeneration and deficits in myelination of lower motor neurons and sensory neurons [79][80][81].…”

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

“…Functionally, macrophage activation within the DRG and peripheral nerve following peripheral nerve injury is known to help remove degenerating neuronal debris and myelin as well as contribute to subsequent regeneration (Lu and Richardson 1993, Perry and Brown 1992, Hu and McLachlan 2002. Recently, it has been recognized that inflammatory responses in the DRG may also contribute to the development pathological pain states (Cui et al, 2000;Xie et al, 2006) through the release of a variety of proinflammatory factors which are capable of sensitizing primary afferent neurons whose cell bodies are housed in the DRG (Taniuchi et al, 1986;Lindholm et al, 1987;Meyer et al, 1992;Hammarberg et al, 1996;Ma & Eisenach, 2002.…”