Identifying the long-term role of iNOS in contusive spinal cord injury (SCI) using a transgenic mouse model

Abstract The inflammatory mediator iNOS is thought to play an important role in the pathophysiology of SCI. Specific inhibition of iNOS is beneficial after acute SCI, but little is known about its role over longer post-injury periods. The current study was carried out to assess the role of iNOS after contusive SCI through the use of chronic iNOS inhibition by a knockout mouse approach. Wild type (WT) and iNOS(−/−) mice were injured and then subjected to behavioral testing (BMS) and histological evaluation of healthy white and gray matter tissue volumes. Behaviorally, iNOS(−/−) mice displayed a significantly faster recovery of function compared to WT in open-field locomotion during the first 4 wk (WT 2.2±0.2, iNOS(−/−) 3.38±0.43; p < 0.05).At the endpoint of the experiment (8wk) however, iNOS(−/−) mice showed a trend towards worsened functional outcome. Histological analysis revealed that i-NOS(−/−) mice had a significant decrease in the volumes of both healthy gray (53%) and healthy white matter (15%) as compared to WT. The present study shows that acute inhibition of iNOS could be behaviorally beneficial after SCI, however, chronic inhibition likely hampers important wound healing functions of NO, leading to a lack of efficacy at later stages. FUNDING: The Miami Project to Cure Paralysis, The Buoniconti Fund, The US Army Medical Research and Material Command