Influence of posttraumatic hypoxia on behavioral recovery and histopathological outcome following moderate spinal cord injury in rats.

Pulmonary dysfunction leading to secondary hypoxia is a common complication of spinal cord injury (SCI). The purpose of this study was to clarify the behavioral and histopathological consequences of posttraumatic hypoxia in an established model of traumatic SCI. Forty-five female Sprague-Dawley rats were randomly assigned to one of four groups, including (1) laminectomy and normoxia (n = 10), (2) laminectomy and hypoxia (n = 11), (3) NYU weight-drop and normoxia (n = 12), and (4) NYU weight-drop and hypoxia (n = 11). For these studies, a moderate injury was induced by adjusting the height of the weight drop (10 g) to 12.5 mm above the exposed spinal cord (T10). Immediately after injury, PaO2 in the hypoxic rats was kept between 30 and 35 mm Hg for 30 min. PaO2 in the normoxic group was maintained over 100 mm Hg, while PaCO2 in all rats was maintained at 35-40 mm Hg. The behavior of the rats was checked every 7 days using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. Rats were sacrificed at 8 weeks for quantitative histopathological analysis of lesion areas. During the hypoxic insults, the mean arterial blood pressure dropped in both sham control and weight-drop rats (p < 0.01). At the end of the 8-week monitoring period, BBB scores were 12.5 +/- 3.1 (mean +/- SEM) and 14.2 +/- 3.4 in the normoxic and hypoxic traumatized rats, respectively. No significant difference between the traumatized groups was documented with BBB monitoring. In contrast, the percent of gray matter necrosis at the impact epicenter was significantly increased in hypoxic versus normoxic SCI rats (p < 0.01). These data demonstrate that posttraumatic hypoxia complicated by mild hypotension aggravates the histopathological consequences of SCI and further emphasize the need to control for secondary hypoxic insults after experimental and clinical SCI. Potential explanations for the lack of a correlation between the behavioral and histopathological findings are discussed.

Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats.

In these studies, we examined the neuroprotective effects of the potent antiinflammatory cytokine interleukin-10 (IL-10) following spinal cord injury (SCI). Neuroprotection was assessed by using behavioral and morphological end points. We hypothesized that injury-induced inflammation contributes to the resulting neuropathology and subsequent loss of function. Therefore, by attenuating injury-induced inflammation, we should promote functional recovery. The New York University device was used to induce moderate SCI and study the resulting inflammatory response and functional consequences of inhibiting this response in rats. We determined that SCI induces the expression of tumor necrosis factor-alpha (TNF-alpha) in the spinal cord and by SCI-activated monocytes isolated from the peripheral circulation. IL-10 (5.0 microg) administered 30 minutes after-injury significantly reduced the expression of TNF-alpha protein in the spinal cord and in vitro by SCI-activated monocytes. Next, we investigated whether IL-10 would improve functional recovery after SCI. Randomized, double-blinded studies demonstrated that a single injection of IL-10 significantly improves hind limb motor function 2 months after injury, as determined by the Basso, Beattie and Bresnahan (BBB) open-field behavioral test. IL-10-treated animals had a mean BBB score of 18.0+/-0.5 (SEM, n = 9) compared with a score of 12.9+/-0.6 (SEM, n = 9) for the saline-treated controls. Morphological analysis demonstrated that IL-10 reduces lesion volume by approximately 49% 2 months after injury. These data suggest that acute administration of IL-10 reduces TNF-alpha synthesis in the spinal cord and by activated macrophages, is neuroprotective, and promotes functional recovery following SCI.