Spinal cord injury (SCI) results in a number of deficits and triggers primary and secondary injury signaling cascades characterized by an early and prolonged inflammatory response. Early after SCI, IL-1B increases, an inflammatory agent, that triggers increased activation of the transcription factor Nuclear Factor-kB (NF-kB). NF-kB mediates secondary injuries via regulation of synthesis of proteins that are detrimental to the recovery process and can maintain inflammation in the injured spinal cord. There are different NF-kB subunits and subunit-specific inhibition can be accomplished with synthetic double stranded “decoy” deoxyoligonucleotides containing selective NF-kB protein dimer binding consensus sequences. In this project, DNA ”decoys” target the COX-2 gene promoter NF-kB binding site, attenuate the SCI-induced increases in the levels of COX-2 and iNOS protein levels and significantly decrease cell death and increases in inflammatory signaling. Spinal cord contusion injury and outcomes were measured as described in Experimental Design below. The results demonstrate a significant improvement in locomotor scores, mechanical allodynia (for both cutaneous and pressure), thermal hyperalgesia and improved clinical measures (weight and bladder) in the group treated with COX-2 decoys compared to the vehicle group. Decoy treatment also resulted in significant reductions in COX-2 and iNOS expression following SCI and neuronal rescue. These experiments demonstrate the efficacy of novel interventions in the inflammatory cascade triggered by SCI as a strategy for treatment of SCI-induced physiological functional impairments. The approach is innovative in that it assesses the use of a new technology (DNA promoter decoys) to selectively block injury response mechanisms that can result in neuropathy. Supported by Mission Connect/ TIRR Foundation, The M.D. Anderson Foundation, The Liddell and The Dunn Foundations and NS11255.

International Journal of Developmental NeuroscienceVolume 26, Issue 8 p. 854-854 Article [P1.38]: Effect of hyperoxia treatment on aquaporin 4 changes and edema formation in the contralateral brain after neonatal hypoxia/ischemia D.C. Ferrari, Corresponding Author D.C. Ferrari n/[email protected] University of Texas Medical Branch, USACorresponding author.Search for more papers by this authorO. Nesic-Taylor, O. Nesic-Taylor University of Texas Medical Branch, USASearch for more papers by this authorJ.R. Perez-Polo, J.R. Perez-Polo University of Texas Medical Branch, USASearch for more papers by this author D.C. Ferrari, Corresponding Author D.C. Ferrari n/[email protected] University of Texas Medical Branch, USACorresponding author.Search for more papers by this authorO. Nesic-Taylor, O. Nesic-Taylor University of Texas Medical Branch, USASearch for more papers by this authorJ.R. Perez-Polo, J.R. Perez-Polo University of Texas Medical Branch, USASearch for more papers by this author First published: 25 November 2008 https://doi.org/10.1016/j.ijdevneu.2008.09.088Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume26, Issue8Abstracts to the 17th Biennial Meeting of the International Society for Developmental Neuroscience, 1‐5 June 2008, Asilomar, USADecember 2008Pages 854-854 RelatedInformation

Central neuropathic pain (CNP) is an important problem following spinal cord injury (SCI), because it severely affects the quality of life of SCI patients. As in the patient population, the majority of rats develop significant allodynia (CNP rats) after moderate SCI. However, about 10% of SCI rats do not develop allodynia, or develop significantly less allodynia than CNP rats (non‐CNP rats). To identify transcriptional changes underlying CNP development after SCI, we used Affymetrix DNA microarrays and RNAs extracted from the spinal cords of CNP and non‐CNP rats. DNA microarry analysis showed significantly increased expression of a number of genes associated with inflammation and astrocytic activation in the spinal cords of rats that developed CNP. For example, mRNA levels of glial fibrilary acidic protein (GFAP) and Aquaporin 4 (AQP4) significantly increased in CNP rats. We also found that GFAP, S100β and AQP4 protein elevation persisted for at least 9 months throughout contused spinal cords, consistent with the chronic nature of CNP. Thus, we hypothesize that CNP development results, in part, from dysfunctional, chronically “over‐activated” astrocytes. Although, it has been shown that activated astrocytes are associated with peripheral neuropathic pain, this has not previously been demonstrated in CNP after SCI.

Spinal cord injury (SCI) induces neuronal death, including apoptosis, which is completed within 24 hr at and around the impact site. We identified early proapoptotic transcriptional changes, including upregulation of proapoptotic Bax and downregulation of antiapoptotic Bcl‐xL, Bcl‐2, and Bcl‐w, using Affymetrix DNA microarrays. Because Bcl‐xL is the most robustly expressed antiapoptotic Bcl‐2 molecule in adult central nervous system, we decided to characterize better the effect of SCI on Bcl‐xL expression. We found Bcl‐xL expressed robustly throughout uninjured spinal cord in both neurons and glia cells. We also found Bcl‐xL localized in different cellular compartments: cytoplasmic, mitochondrial, and nuclear. Bcl‐xL protein levels decreased in the cytoplasm and mitochondria 2 hr after SCI and persisted for 24 hr. To test the contribution of proapoptotic decreases in Bcl‐xL to neuronal death, we augmented endogenous Bcl‐xL levels by administering Bcl‐xL fusion protein (Bcl‐xL FP) into injured spinal cords. Bcl‐xL FP significantly increased neuronal survival, suggesting that SCI‐induced changes in Bcl‐xL contribute considerably to neuronal death. Because Bcl‐xL FP increases survival of dorsal horn neurons and ventral horn motoneurons, it could become clinically relevant in preserving sensory and motor functions after SCI. © 2005 Wiley‐Liss, Inc.

Perinatal hypoxia/ischemia (HI) is a common cause of neurological deficits in children. Interleukin-1 (IL-1) activity has been implicated in HI-induced brain damage. However, the mechanisms underlying its action in HI have not been characterized. We used a 7-day-old rat model to elucidate the role of nuclear factor-kappa B (NF-kappa B) activation in HI stimulation of IL-1 signaling. HI was induced by permanent ligation of the left carotid artery followed by 90 min of hypoxia (7.8% O-2). Using ELISA assays, we observed increased cell death and caspase 3 activity in hippocampus and cortex 3, 6, 12, 24 and 48 h post-HI. IL-1 beta protein expression increased, beginning at 3 h after HI and lasting until 24 h post-HI in hippocampus and 12 h post-HI in cortex. Intracerebroventricular injection of 2 mu g IL-1 receptor antagonist (IL-1Ra) 2 h after HI significantly reduced cell death and caspase 3 activity. Electrophoretic mobility shift assay analyses of hippocampus and cortex after HI for NF-kappa B activity showed increased p65/p50 DNA-binding activity at 24 h post-HI. Western blot analyses showed significant nuclear translocation of p65. Protein expression levels of two known inflammatory agents, inducible nitric oxide synthase and cycloxygenase 2, known to be transcriptionally regulated by NF-kappa B, also increased at 24 h after HI. All these HI-induced changes were reversed by IL-1Ra blockade of IL-1 signaling, consistent with IL-1 triggering of inflammatory apoptotic outcomes via NF-kappa B transcriptional activation. The observed increase in cytoplasmic phosphorylated inhibitor kappa B alpha (I kappa B alpha) and nuclear translocation of Bcl-3 24 h after HI was also significantly attenuated by IL-1Ra blockade, suggesting that HI-induced IL-1 activation of NF-kappa B is via both the degradation of I kappa B alpha and the nuclear translocation of Bcl-3.