The Effect Of Mediating NF-κB Binding Activity On Neuronal And Glial Apoptosis And The Relationship Between NF-κB And P75NTR After Traumatic Spinal Cord Injury In Rats

Traumatic injury of the spinal cord initiates a series of cellular and molecular events that include both primary and secondary injury cascades. Secondary injury may contribute significantly to the neuropathology associated with the initial injury that cause extensive demyelination and axonal destruction. Neuronal and glial cell death, delayed waves of oligodendrocyte degeneration with morphological features suggestive of apoptosis is a major component of secondary injury and play a central role in regulating the pathogenesis of acute and chronic spinal cord injury (SCI). Many apoptotic responses are mediated by enhanced and/or induced gene expression. A principal player in the regulation of apoptotic gene expression is the nuclear factor-κB family of transcription factors. NF-κB may be important determinants is required for the transcriptional activation of genes regulating cell apoptotic responses in CNS.NF-κB has been shown to activate transcriptionally the genes encoding cytokines, prostaglandin synthase-2, cell adhesion molecules, and so on. Recently studies have shown that NF-κB has the potential to curb cell apoptosis. NF-κB exerts anti-apoptotic effects via an endogenous caspase inhibitory system mediated by cellular inhibitor of apoptosis proteint to limit caspase-3 activation. Another pivotal role is p75NTR, a low affinity nerve growth factor receptor, which has been reported to modulate many aspects of neuronal physiology including sensory functions, axon outgrowth, and survival or apoptotic effects of neurotrophins. p75 NTR acts via its cytoplasmic juxtamembrane region to promote apoptotic death cascades. In this study we examined the temporal and cellular expression of activated NF-κB after traumatic SCI, Effects of Blocking the initiation of NF-κB activation on CNS cell apoptosis and the influence of this transcription factor activated changes for p75NTR expression. We used a contusion model (Allen's impactor) to initiate the early biochemical and molecular changes that occur after traumatic injury to show that cell apoptosis is the key in secondary injury after SCI. Apoptotic cell is frequently but no necrosis occurrence in later SCI and suggesting that those are the reason of delayed extensive demyelination and axonal destruction. The activation of activated NF-κB was evaluated by using electrophoretic mobility shift assays (EMSA) study. Using immunohistochemical and western blot analysis, we evaluated the activation and distribution of NF-κB in the acutely injured spinal cord and demonstrated that activated NF-κB exerts anti-apoptotic effects via inhibiting caspase-3 activation. NF-κB and p75NTR exist some relationship, but the mechanism still unknown. This is the first in vivo demonstration of the relationship between NF-κB activation and p75NTR expression after spinal cord injury and may be useful toward understanding the molecular mechanisms responsible for secondary pathological changes after acute SCI. This study will likely provide new and important information on mechanisms of cell damage and provide opportunities for the development of novel and effective therapies to reduce CNS injury in trauma. The results and conclusions are: 1. apoptosis play an important role in secondary injury after SCI and this is the reason of delayed extensive demyelination and axonal destruction. To curb apoptosis can promote the hindlimb function in mice. 2. NF-κB exerts anti-apoptotic effects via inhibiting caspase-3 activation. 3. caspase-3 locate the downstream of the NF-κB signal cascades and caspase-3 expression is mediated by NF-κB. 4. There are some unknown relationships between NF-κB and p75NTR, it is positively that p75NTR belong to NF-κB signal cascades, maybe p75NTR locate the upstream of the signal system.