Efficacy of N-acetyl cysteine in traumatic brain injury

Abstract

In this study, using two different injury models in two different species, we found that early post-injury treatment with N-Acetyl Cysteine (NAC) reversed the behavioral deficits associated with the TBI. These data suggest generalization of a protocol similar to our recent clinical trial with NAC in blast-induced mTBI in a battlefield setting, to mild concussion from blunt trauma. This study used both weight drop in mice and fluid percussion injury in rats. These were chosen to simulate either mild or moderate traumatic brain injury (TBI). For mice, we used novel object recognition and the Y maze. For rats, we used the Morris water maze. NAC was administered beginning 30-60 minutes after injury. Behavioral deficits due to injury in both species were significantly reversed by NAC treatment. We thus conclude NAC produces significant behavioral recovery after injury. Future preclinical studies are needed to define the mechanism of action, perhaps leading to more effective therapies in man.

Figure 1. MWM performance.

Post injury administration of NAC significantly improves MWM performance. MWM performance as measured by latency to reach the goal platform was compared between groups: TBI (n = 9), TBI-NAC (n = 8), and Sham (n = 9). Both Sham and TBI-NAC groups have significantly shorter latencies to reach the goal platform as compared to the TBI group. Additionally, treatment with NAC after TBI improved performance in the MWM that reached sham levels. Data are presented as the mean ± SEM. *p<.05, ***p≤.001, sham relative to TBI. † p<.05 TBI-NAC relative to TBI.

Figure 2. MWM platform crossing.

Number of times animals crossed within a 7.5-way ANOVA showed significant differences between groups. Fisher's LSD post hoc showed that sham and TBI-NAC had significantly better retention of the platform location as compared to TBI alone. Data are presented as the mean ± SEM. Brackets indicate comparisons between groups. *p<0.05, **p<0.01.

Figure 3. Novel Object Recognition.

Preference index for the novel object in the Novel Object Recognition task across post-injury time points. Separate ANOVAs were used to compare the preference index for the novel object during the recall phase of the task. A) Weight drop injury resulted in significant object memory impairment on post-injury day (PID) 7 (A) and PID 30 (B) in injured vehicle-treated mice as compared to all other treatment groups. At both post-injury time points, post-TBI treatment with N-Acetylcysteine + topiramate (Drug) was protective against injury-induced deficits in recognition memory. Animals in the TBI-Drug group performed similarly to Sham-Vehicle and Sham-Drug groups. Values represent the mean ± SEM. ** p<0.01, *** p<0.001 compared to sham vehicle.

Figure 4. Y maze preference index.

Preference index for the Y maze spatial memory task on post-injury day (PID) 7 and 30. Separate ANOVAs were used to compare the preference index for the novel arm of the Y maze during the recall trial (i.e., 2^nd trial). (A) Weight drop injury resulted in significant object memory impairment in TBI-Vehicle animals relative to the other three treatment groups on post-injury day (PID) 7. (B) On PID 30, mice in the TBI-Vehicle group performed significantly worse as compared to the Sham-Vehicle and TBI-Drug groups (p<0.05). The Sham-Drug group did not differ significantly from any of the other groups. N-Acetylcysteine + topiramate (Drug) was protective against injury-induced deficits in performance in spatial memory-dependent tasks. Animals in the TBI-Drug group performed similarly to Sham-Vehicle. Values represent the mean ± SEM. * p<0.05 compared to sham vehicle.

Figure 5. Proposed mechanism of action of N-Acetylcysteine.