A re-assessment of minocycline as a neuroprotective agent in a rat spinal cord contusion model

Abstract

This study was initiated due to an NIH "Facilities of Research--Spinal Cord Injury" contract to support independent replication of published studies that could be considered for a clinical trial in time. Minocycline has been shown to have neuroprotective effects in models of central nervous system injury, including in a contusive spinal cord injury (SCI) model at the thoracic level. Beneficial effects of minocycline treatment included a significant improvement in locomotor behavior and reduced histopathological changes [Lee, S.M., Yune, T.Y., Kim, S.J., Park, D.O.W., Lee, Y.K., Kim, Y.C., Oh, Y.J., Markelonis, G.J., Oh, T.H., 2003. Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma. 20, 1017-1027.] To verify these important observations, we repeated this study in our laboratory. The NYU (MASCIS) Impactor was used to produce a moderate cord lesion at the vertebral level T9-T10 (height 12.5 mm, weight 10 g), (n=45), followed by administration of minocycline, 90 mg/kg (group 1: minocycline IP, n=15; group 2: minocycline IV, n=15; group 3: vehicle IP, n=8; group 4: vehicle IV, n=7) immediately after surgery and followed by two more doses of 45 mg/kg/IP at 12 h and 24 h. Open field locomotion (BBB) and subscores were examined up to 6 weeks after SCI and cords were processed for quantitative histopathological analysis. Administration of minocycline after SCI did not lead to significant behavioral or histopathological improvement. Although positive effects with minocycline have been reported in several animal models of injury with different drug administration schemes, the use of minocycline following contusive SCI requires further investigation before clinical trials are implemented.

Figure 1

Graph of the locomotor scores obtained with the BBB test (Mean ± SEM). The groups were not significantly different at any point in time. In fact, by day 7 post-injury, all groups have achieved similar mean scores and no additional functional improvement is observed.

Figure 2

Graph of the BBB subscores of the 4 groups (Mean ± SEM). There is no significant difference between groups using this behavioral assessment strategy that focuses on fine motor coordination including paw position and toe clearance.

Figure 3

Photomontage of a representative horizontal histological section from the injured spinal cord (IV minocycline group). Upper: The quantitative assessment parameters for area of spared tissue and cavity are shown (green = total cord area; red = total contusion area; blue = cavity; pink = central canal for landmark purposes). Lower: magnification at the epicenter of the injured region shows fluid-containing cavities surrounded by inflammatory and necrotic tissue.

Figure 4

Graph of mean total spared tissue (mm²; ± SEM) in 20-mm horizontal sections obtained from cords containing the central canal. The highest preservation corresponds to the group 3 (control IP), however, there was no statistically significant difference between groups.

Figure 5

Graph of the mean cavity area (mm²; ± SEM) obtained from horizontal sections containing central canal. There is no significant difference between groups.