Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury

Abstract

Study design: Experimental laboratory investigation of the role and pathways of reactive oxygen species (ROS)-mediated motor neuron cell death in a mouse model of compression spinal cord injury. Objectives: To analyze ROS-mediated oxidative stress propagation and signal transduction leading to motor neuron apoptosis induced by compression spinal cord injury. Setting: University of Louisville Health Science Center. Methods: Adult C57BL/6J mice and transgenic mice overexpressing SOD1 were severely lesioned at the lumbar region by compression spinal cord injury approach. Fluorescent oxidation, oxidative response gene expression and oxidative stress damage markers were used to assay spinal cord injury-mediated ROS generation and oxidative stress propagation. Biochemical and immunohistochemical analyses were applied to define the ROS-mediated motor neuron apoptosis resulted from compression spinal cord injury. Results: ROS production was shown to be elevated in the lesioned spinal cord as detected by fluorescent oxidation assays. The early oxidative stress response markers, NF-kB transcriptional activation and c-Fos gene expression, were significantly increased after spinal cord injury. Lipid peroxidation and nucleic acid oxidation were also elevated in the lesioned spinal cord and motor neurons. Cytochrome c release, caspase-3 activation and apoptotic cell death were increased in the spinal cord motor neuron cells after spinal cord injury. On the other hand, transgenic mice overexpressing SOD1 showed lower levels of steady-state ROS production and reduction of motor neuron apoptosis compared to that of control mice after spinal cord injury. Conclusion: These data together provide direct evidence to demonstrate that the increased production of ROS is an early and likely causal event that contributes to the spinal cord motor neuron death following spinal cord injury. Thus, antioxidants/antioxidant enzyme intervention combined with other therapy may provide an effective approach to alleviate spinal cord injuryinduced motor neuron damage and motor dysfunction.

Early Response of Endogenous Adult Neural Progenitor Cells to Acute Spinal Cord Injury in Mice

“…The experimental model for acute mouse compression SCI was essentially similar to that previously described by Farooque [37] but with minor modifications [38]. Briefly, animals were deeply anesthetized with pentobarbital in a dose of 20 mg/kg body weight by i.p.…”

“…The acute compression injury mouse model was selected to analyze the early response of NPCs to SCI according to a similar procedure described by Farooque [37] but with minor modifications [38]. Mild (15 g of weight for 5 minutes), moderate (20 g of weight for 5 minutes), and severe (30 g of weight for 5 minutes) lesion conditions were applied to generate different degrees of SCI.…”

The Effect of Antioxidants on the Production of Pro-Inflammatory Cytokines and Orthodontic Tooth Movement

“…Because previous studies have demonstrated that hypoxic condition or mechanical compression stimulates ROS generation, we first examined whether the intracellular ROS level is increased by mechanical compression or hypoxic treatment in human PDLFs cultured in vitro (Chandel et al, 1998;Xu et al, 2005). The levels of intracellular ROS were significantly increased when PDLFs were exposed to a mechanical compression of 0.5 to 3 g/cm 2 for 4 h (Fig.…”

“…Previous studies have shown that mechanical compression of cartilage or the spinal nerve increases the recruitment of inflammatory cells to these tissues, resulting in ROS production, inflammatory responses and subsequent tissue damage (Burkhardt et al, 1986;Xu et al, 2005). However, it is not clear whether the mechanical compression of cells induces ROS production in vitro.…”

“…Both hypoxia and compression stimulate the production of reactive oxygen species (ROS) (Chandel et al, 1998;Xu et al, 2005). Several lines of evidence indicate that activation of NF-κB can be controlled by ROS, and antioxidants block pro-inflammatory cytokine transcription by preventing NF-κB migration to the nucleus (Janssen-Heininger et al, 2000;Schubert et al, 2002).…”