Background The need for effective pharmaceuticals within animal models of traumatic brain injury (TBI) continues to be paramount, as TBI remains the major cause of brain damage for children and young adults. While preventative measures may act to reduce the incidence of initial blunt trauma, well-tolerated drugs are needed to target the neurologically damaging internal cascade of molecular mechanisms that follow. Such processes, known collectively as the secondary injury phase, include inflammation, excitotoxicity, and apoptosis among other changes still subject to research. In this article positive treatment findings to mitigate this secondary injury in rodent TBI models will be overviewed, and include recent studies on Exendin-4, N-Acetyl-l-cycteine, Salubrinal and Thrombin. Conclusions These studies provide representative examples of methodologies that can be combined with widely available in vivo rodent models to evaluate therapeutic approaches of translational relevance, as well as drug targets and biochemical cascades that may slow or accelerate the degenerative processes induced by TBI. They employ well-characterized tests such as the novel object recognition task for assessing cognitive deficits. The application of such methodologies provides both decision points and a gateway for implementation of further translational studies to establish the feasibility of clinical efficacy of potential therapeutic interventions.

Mild traumatic brain injury (mTBI) is recognized as a common injury among children, sportsmen, and elderly population. mTBI lacks visible objective structural brain damage but patients frequently suffer from long-lasting cognitive, behavioral and emotional difficulties associated with biochemical and cellular changes. Currently there is no effective treatment for patients with mTBI. The thioredoxin reductase/thioredoxin pathway (TrxR/Trx1) has both anti-inflammatory and anti-oxidative properties. If the system is compromised, Trx1 remains oxidized and triggers cell death via an ASK1-Trx1 signal transduction mechanism. We previously showed tri and tetra peptides which were derived from the canonical -CxxC- motif of the Trx1-active site, called thioredoxin mimetic (TXM) peptides, reversed inflammatory and oxidative stress damage mimicking Trx1 activity. Here, TXM-peptides were examined for protecting cognitive function following weight drop closed-head injury in a mouse model of mTBI. TXM-CB3 (AcCys-Pro-CysNH2), TXM-CB13 (DY-70; AcCys-Met-Lys-CysNH2) or AD4 (ACysNH2) were administered at 50 mg/kg, 60 min after injury and cognitive performance was monitored by the novel-object-recognition and Y-maze tests. Behavioral deficits subsequent to mTBI injury were reversed by a single dose of TXM-CB3, TXM-CB13 and, to a lesser extent, by AD4. TXM-CB13 similar to TXM-CB3 and AD4 reversed oxidative stress-induced phosphorylation of mitogen-activated kinases, p38MAPK and c-Jun N-terminal kinase, (JNK) in human neuronal SH-SY5Y cells. We conclude that significantly improved cognitive behavior post mTBI by the TXM-peptides could result from anti-apoptotic, and/or anti-inflammatory activities. Future preclinical studies are required to establish the TXM-peptides as potential therapeutic drugs for brain injuries.