Sequential mRNA Expression for Immediate Early Genes, Cytokines, and Neurotrophins in Spinal Cord Injury

Abstract

In this communication, we demonstrate the sequential expression of endogenous molecules, including immediate early genes (IEGs), cytokines, neurotrophins, and neurotrophin receptors in the injured spinal cord. In the acute phase, expression of IEGs and cytokines mRNAs were rapidly upregulated within 1 h in nonneuronal cells in the lesioned sites and the surrounding spinal white and gray matter. Maximal expression was observed at 1 h for c-fos and TNF-alpha mRNAs, at 3 h for c-jun and IL-6 mRNAs, and at 6 h for IL-1 beta mRNA, and these signals were virtually nondetectable after 6-12 h from the onset of the injury. Some of these genes products may promote the degeneration of damaged cells and tissues, while others may be involved in the subsequent repair processes. In the subacute phase, expression of NGF, BDNF, NT-3, p75LNGFR and Trk B mRNAs began to increase in the nonneuronal cells and neuronal cells from 6 h, and peaked at 24-72 h in the area where expression of mRNAs for IEGs and cytokines overlapped. Signals for IL-6 mRNA were also observed in motoneurons at 24-72 h after the injury, with the suggestion that these molecules may be involved in promoting axonal sprouting in the injured spinal cord. Of further interest was the finding that this upregulation of IL-1 beta, BDNF, and NT-3 mRNAs in injured spinal cord was attenuated by treatment with high dose glucocorticoids, with the suggestion that the downregulation of BDNF and NT-3 might be disadvantageous to survival and axonal sprouting of spinal neurons.

Post-traumatic inflammation following spinal cord injury

“…This is claimed to trigger the proliferative aspect of microglia activation, thus having a neuroprotective function. 5,6,98 However, injection of fibroblasts secreting hyperinterleukin-6 (cytokine growth factor, IL-6, and its alpha receptor) did result in a marked increase in number of neutrophils and in the area occupied by activated microglia and macrophages, correlating with a two-fold increase in the lesion size. 99 Following experimental SCI, transcripts of both the proinflammatory cytokines, TNF-a, IL-1b, and IL-6 and the chemokines, MIP-1a and MIP-1b, are upregulated within the first hour postinjury.…”

“…99 Following experimental SCI, transcripts of both the proinflammatory cytokines, TNF-a, IL-1b, and IL-6 and the chemokines, MIP-1a and MIP-1b, are upregulated within the first hour postinjury. 100 However, the expression of TNF-a is nearly completely downregulated by 24 h. 2,5,57,101 Therefore, CNS cells, and not the invading non-CNS resident cells, seem to be the source of the transcripts. In juvenile rats, an age-related 'window of susceptibility' to the inflammatory stimulus on leucocytes and BBB permeability secondary to an intracerebral IL-1b injection has been demonstrated.…”

“…[1][2][3][4][5][6][7][8] SCIinduced inflammation may result in further reduction in functional recovery because of the development of scar tissue, as well as necrosis or apoptosis of neurons and oligodendrocytes. However, a potentially beneficial role of the inflammatory process has also been reported, illustrating the dual nature of post-traumatic inflammation.…”

Spinal shock revisited: a four-phase model

“…Selective increases in some factors and receptors are seen in both neurons and glia. [58][59][60][61][62][63] The signal that triggers increased expression of NTs, GFs, and NT-Rs and GF-Rs is unknown, 64 but lipopolysaccharides from degenerating axons or cytokine release by glia are candidates, as is spinal neuron inactivity. 65 Administration of NTs and GFs has a range of effects.…”

“…BDNF, CNTF, and possibly NGF and NT-3 mRNA transcription peaks at several days post-SCI and then gradually wanes, with expression in neurons and glia. [58][59][60][61] NTs are released by hypoactive spinal neurons and are thus candidates for a retrograde signal to induce new synapse growth by reflex afferents over a time-course of weeks to months. [87][88][89][90] New synapse growth by dorsal root afferents can be blocked by intrathecal infusion of antibody to NGF 88 and enhanced by intrathecal infusion of other NTs.…”