W1941 Increased Susceptibility to NSAID-Induced GI Injury in Rats with Chronic Spinal Cord Injury (Sci) and It's Reversal with PC-NSAIDs

Abstract

Background & Aim: SCI is associated with chronic pain syndrome compelling patients to consume NSAIDs and other analgesics in high concentration. Due to the established GI toxicity of NSAIDs we compared NSAID-induced GI bleeding in uninjured/naive rats vs rodents with experimentally-induced chronic spinal cord injury. We also evaluated the GI toxicity of phosphatidylcholine (PC)-associated NSAIDs in naive and SCI rats. Methods: A thoracic T-10 level contusion of the spinal cord was induced using an Infinite Horizon Impactor in adult female Sprague-Dawley rats with an impacting force of 150 kdyne. 12 rats at 6 months post-SCI and 10 age matched naive rats were included in this study. Ibuprofen (Ibu, 25mg/kg) was intragastrically administered twice daily for 7 days via oral gavage. GI bleeding associated with NSAID use was analyzed by the hemoglobin (Hb) assay. NSAID-induced anemia, presumably caused byGI bleeding, was also monitored bymeasuring hematocrit (HCT). In a 2nd experiment, 24 chronic SCI rats were randomized into 3 groups, in which ibuprofen 25 mg/kg, ibuprofen-PC (25 mg/kg of ibuprofen) or saline was given twice daily for 6 days respectively; 4 age-matched naive rats were intragastrically administered saline. Fecal pellets were collected and analyzed for the detection of Hb to assess GI bleeding. Results: Ibu at a dose of 25 mg/kg, which is safe for age-matched naive rats (HCT values are 0.48±0.01 before dosing and 0.46±0.01 after dosing), caused GI toxicity which was noted initially by a significant decrease in HCT in SCI rats from a baseline value of 0.45±0.01 to 0.36±0.01 respectively. Fecal Hb analysis showed that the Ibu caused greater GI bleeding in the SCI rats (Hb values are 91.92±11.89 mg/100ml on day 1 and 91.81±33.87 on day 2) than observed in age-matched naive rats (fecal Hb values are 13.78±4.04 mg/100ml on day 1 and 7.53±0.86 on day 2). In the 2nd experiment we compared Ibu vs Ibu-PC in SCI rats and it was determined that Ibu induced a significant increase in fecal Hb after 1 and 6 days of treatment (22.76±12.98 and 43.47± 16.05), whereas ibuprofen-PC induced no obvious bleeding over control values (3.83±2.21 and 14.90± 1.40 respectively). Conclusion: Rats with chronic SCI rats have a higher susceptibility to GI bleeding than age/gender matched naive rats consuming a relatively low, non-toxic dose of Ibu. Our evidence also suggests association of PC with Ibu can significantly reverse this increased susceptibility of SCI rats to the GI toxic actions of NSAIDs (Supported by US Army grant PR 043199).