A reassessment of a classic neuroprotective combination therapy for spinal cord injured rats: LPS/pregnenolone/indomethacin

• Published in: Experimental neurology 2012-02, Vol.233 (2), p.677-685
• Main Authors: Popovich, Phillip G., Tovar, C. Amy, Wei, Ping, Fisher, Lesley, Jakeman, Lyn B., Basso, D. Michele
• Format: Article
• Language: English
• Subjects: Animals; Drug Evaluation, Preclinical - methods; Drug Therapy, Combination; Female; Indomethacin - administration & dosage; Lipopolysaccharides - administration & dosage; LPS; Neuroinflammation; Neuroprotective Agents - administration & dosage; Pilot Projects; Pregnenolone - administration & dosage; Rats; Rats, Sprague-Dawley; Recovery of Function - drug effects; Recovery of Function - physiology; Replication; Spinal Cord Injuries - pathology; Spinal Cord Injuries - physiopathology; Spinal Cord Injuries - prevention & control; Spinal cord injury; Steroids
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2011.11.045

These experiments were completed as part of an NIH-NINDS contract entitled “Facilities of Research Excellence-Spinal Cord Injury (FORE-SCI)—Replication”. Our goal was to replicate data from a paper published by Dr. Lloyd Guth and colleagues in which combined injections of lipopolysaccharide, indomethacin and pregnenolone (referred to herein as LIP therapy) conferred marked neuroprotection in a pre-clinical model of spinal cord injury (SCI). Specifically, post-injury injection of the combination LIP therapy was found to significantly reduce tissue damage at/nearby the site of injury and significantly improve recovery of locomotor function. In this report, we confirm the primary observations made by Guth et al., however, the effects of LIP treatment were modest. Specifically, LIP treatment improved myelin and axon sparing, axonal sprouting while reducing lesion cavitation. However, spontaneous recovery of locomotion, as assessed using historical (Tarlov scoring) and more current rating scales (i.e., BBB scoring), was not affected by LIP treatment. Instead, more refined parameters of functional recovery (paw placement accuracy during grid walk) revealed a significant effect of treatment. Possible explanations for the neuroprotective effects of LIP therapy are described along with reasons why the magnitude of neuroprotection may have differed between this study and that of Guth and colleagues. ► Partial replication of a classic SCI experiment in rats using forceps compression injury model. ► A novel triple combination therapy is neuroprotective and promotes partial recovery of function. ► Data show comparisons of historical Tarlov open field scoring with modern BBB scoring. ► Combination of drugs that regulates pro-­and anti-­inflammatory signaling may have therapeutic benefit.