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 [1], 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.

Traumatic brain injury represents a major public health issue that affects 1.7 million Americans each year and is a primary contributing factor (30.5%) of all injury-related deaths in the United States. The occurrence of traumatic brain injury is likely underestimated and thus has been termed “a silent epidemic”. Exendin-4 is a long-acting glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus that not only effectively induces glucose-dependent insulin secretion to regulate blood glucose levels but also reduces apoptotic cell death of pancreatic β-cells. Accumulating evidence also supports a neurotrophic and neuroprotective role of glucagon-like peptide-1 in an array of cellular and animal neurodegeneration models. In this study, we evaluated the neuroprotective effects of Exendin-4 using a glutamate toxicity model in vitro and fluid percussion injury in vivo. We found neuroprotective effects of Exendin-4 both in vitro, using markers of cell death, and in vivo, using markers of cognitive function, as assessed by Morris Water Maze. In combination with the reported benefits of ex-4 in other TBI models, these data support repositioning of Exendin-4 as a potential treatment for traumatic brain injury.

Mild traumatic brain injury (mTBI) accounts for the majority of head trauma cases. Despite some lasting cognitive, emotional, and behavioral deficits, there are frequently no overt morphological defects, suggesting that changes may result from alterations in the physiology of individual neurons. We investigated hippocampal neural activity in rats during a working memory task to determine the effect of mTBI on cellular physiology. Male Sprague-Dawley rats (300-350 g) underwent mTBI via lateral fluid percussion (1.5 atm), and were compared with sham-operated rats. The rats then underwent bilateral implantation of electrodes into the CA1 and CA3 hippocampal subfields and were trained to perform in a delayed nonmatch-to-place swim T-maze. Single-neuron activity was analyzed during task performance 30-90 days after trauma. There were no histological differences between control and mTBI rats. Stereological analysis demonstrated no neuronal loss. Nevertheless, rats subjected to mTBI demonstrated significantly poorer performance on the task with increasing delay. Examination of single-neuron spiking activity revealed no significant difference in firing rates or spike characteristics, but rats exposed to mTBI were found to have significantly fewer cells with activity spatiotemporally correlated with location in the maze ("task-specific cells," p<0.05 by Fisher's exact test). Memory deficits, including disorganized patterns of hippocampal neural activity after mTBI, were seen in rats. Because it is seen in the absence of clear morphological defects, these data suggest that functional impairment after mTBI may result from alterations in the activity of individual neurons.