Variation in chronic nicotinamide treatment after traumatic brain injury can alter components of functional recovery independent of histological damage

Abstract

Previously, we have shown that the window of opportunity for nicotinamide (NAM) therapy (50 mg/kg) following cortical contusion injuries (CCI) extended to 4-8 hrs post-CCI when administered over a six day post-CCI interval. The purpose of the present study was to determine if a more chronic NAM treatment protocol administered following CCI would extend the current window of opportunity for effective treatment onset. Groups of rats received either unilateral CCI's or sham procedures. Initiation of NAM therapy (50 mg/kg, ip) began at either 15-min, 4-hrs, 8-hrs or 24-hrs post-injury. All groups received daily systemic treatments for 12 days post-CCI at 24 hr intervals. Behavioral assessments were conducted for 28 days post injury and included: vibrissae forelimb placing, bilateral tactile adhesive removal, forelimb asymmetry task and locomotor placing testing. Behavioral analysis on both the tactile removal and locomotor placing tests showed that all NAM-treated groups facilitated recovery of function compared to saline treatment. However, on the vibrissae-forelimb placing and forelimb asymmetry tests only the 4-hr and 8-hr NAM-treated groups were significantly different from the saline-treated group. The lesion analysis showed that treatment with NAM out to 8 hrs post-CCI significantly reduced the size of the injury cavity. The window of opportunity for NAM treatment is task-dependent and in some situations can extend to 24 hrs post-CCI. These results suggest that a long term treatment regimen of 50 mg/kg of NAM starting at the clinically relevant time points may prove efficacious in human TBI.

Keywords: recovery of function; therapy; traumatic brain injury; vitamin; window of opportunity.

Figure 1

Lesion analysis. Plotted is the mean (±SEM) remaining cortical volume for each group. NAM at the 4-hr (*p < 0.05) and 8-hr (!p < 0.05) time points significantly reduced the amount of injury-induced tissue loss compared to the vehicle group.

Figure 2

Histology plate. Shown are representative cresyl violet images (40 µm) of sections from the saline-treated injured brain (A) and an 8-hr NAM brain (B) at coordinates 1.68 mm, 0.72 mm and −0.36 mm relative to bregma (0.44x, scale bar = 2 mm).

Figure 3

The effects of a 13 day regimen of NAM (50 mg/kg, ip) or saline administered following CCI or sham surgery on the bilateral tactile adhesive removal test. The graph shows the plotted mean (±SEM) latencies to remove the stimuli from both forelimbs. Treatment with the 4-hr, 8-hr and 24-hr NAM groups significantly improved performance compared to the saline-treated group. Symbols indicate significant differences (p < 0.05) between comparisons of NAM-treated groups and the saline-treated group.

Figure 4

The effects of a 13 day regimen of NAM or vehicle administered following frontal CCI or sham surgery on the vibrissae-forelimb placing test. The graph shows the plotted mean (±SEM) percentage of unsuccessful placing attempts. Treatment with the 4-hr and 8-hr NAM groups significantly improved performance compared to the saline-treated group. Symbols indicate significant differences (p < 0.05) between comparisons of NAM-treated groups and the saline-treated group.

Figure 5

The effects of a 13 day regimen of NAM (50 mg/kg, ip) or saline administered following CCI or sham surgery on the locomotor placing test. The graph shows the plotted mean (±SEM) forelimb foot-faults impairment scores. Treatment with the 4-hr, 8-hr and 24-hr NAM groups significantly improved performance compared to the saline-treated group. Symbols indicate significant differences (p < 0.05) between comparisons of NAM-treated groups and the saline-treated group.

Figure 6

The effects of a 13 day regimen of NAM or vehicle administered following frontal CCI or sham surgery on the forelimb asymmetry test. The graph shows the plotted mean (±SEM) percentage of forelimb asymmetry scores. The no bias line at 50% demonstrates a level of performance where both forelimbs are being used equally on this test. Treatment with the 4-hr and 8-hr NAM groups significantly improved performance compared to the saline-treated group. Symbols indicate significant differences (p < 0.05) between comparisons of NAM-treated groups and the saline-treated group.