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1. Reducing neuropathic pain in the chronic phase of spinal cord injury by targeting inflammation Jennifer N. Dulin The University of Texas Medical School Houston, TX

2. Spinal cord injury & inflammation Inflammation plays a central role in the pathophysiology of spinal cord injury (SCI) Acute inflammation (hours to days) contributes to many pathological processes Loss of BSCB integrity, glial scar formation, cytotoxicity, sensitization of neural pathways Less is known about inflammation in the far chronic phase of SCI

3. Spinal cord injury & inflammation 1,275,000 Americans living with SCI (Christopher & Dana Reeve Foundation, 2009) Many experience SCI-associated neuropathic pain (Baastrup & Finnerup, 2008) Understanding the mechanisms driving neuropathic pain-associated changes is important 1 month post-SCI, inflammation contributes to the maintenance of neuropathic pain in the rat (Hains 2006; Zhao 2007) Is inflammation an ongoing process, detectable months to years after injury? If so, what are its pathological consequences?

4. Hypothesis Inflammation is an ongoing process that persists for months to years after the initial injury to the spinal cord. Inflammation in the chronic phase of SCI has pathological consequences such as neuropathic pain.

5. Female, Sprague-Dawley rats Moderate severity contusion injury at T10 150 kdynes, 1 sec dwell Animals were evaluated 9 months post-SCI, during the “far chronic” phase of injury Before After Model of chronic SCI

8. Pro-inflammatory mediators in the chronically injured spinal cord

9. Licofelone (Merckle) Dual COX/5-LOX inhibitor Anti-inflammatory activity Studies have shown analgesic and anti-hyperalgesic effects Passed phase III clinical trials for osteoarthritis Drugdevelopment-technology.com

10. Experimental timeline Beginning 7 mo post-SCI, rats were treated with 50 mg/kg Licofelone or vehicle (p.o.) 1x/daily for 28 days Behavior tests were conducted pre- and post-treatment Spinal cords were harvested on day 28 and a metabolomic analysis was performed

11. Metabolomic analysis:SCI-induced changes in spinal cord metabolites We observed a significant increase in several metabolites associated with oxidative stress, and decreases in antioxidant compounds

12. Licofelone treatment induced increases in the levels of several metabolites with anti-inflammatory and/or anti-oxidant properties in the chronic SCI spinal cord *, p < 0.01 vs control #, p < 0.05 vs vehicle

13. Effects of Licofelone on neurosensory behavior

14. Licofelone increases hindlimb mechanical withdrawal thresholds in chronic SCI rats *, p < 0.05 vs vehicle

15. Licofelone enhances spontaneous exploratory activity in chronic SCI rats *, p < 0.05 vs control *, p < 0.001 vs control #, p < 0.05 vs vehicle

16. Licofelone enhances spontaneous exploratory activity in chronic SCI rats

17. Conclusions Inflammation is not transient, but may be an ongoing process throughout chronic SCI Treatment of chronic SCI rats with the dual COX/5-LOX inhibitor Licofelone enhances anti-inflammatory and anti-oxidant pathways within the injured cord Licofelone treatment also attenuates pain behavior associated with chronic SCI

18. Acknowledgments Center for Clinical and Translational Sciences ------- T32 training grant (2010 – 2012) ------ Advisor: Dr. Raymond Grill Dr. Gerard Francisco, TIRR Memorial Hermann Collaborators: Dr. Edward Karoly, Metabolon Inc. Dr. Henry Strobel, UTMS-H Dr. Ying Wang, UTMS-H