Improvement In Cognitive Dysfunction Following Blast Induced Traumatic Brain Injury By Thymosin Alpha 1 In Rats: Involvement Of Inhibition Of Tau Phosphorylation At The Thr205 Epitope

Cognitive impairment is a significant sequela of traumatic brain injury (TBI) especially blast induced traumatic brain injury (bTBI), which is characterized by rapid impairments of learning and memory ability. Although several neuro-protective agents have been postulated as promising drugs for bTBI in animal studies, very few ideal therapeutic options exist to improve cognitive impairment following bTBI. Thymosin alpha 1(T alpha 1), a 28-amino-acid protein that possesses immunomodulatory functions, has exhibited beneficial effects in the treatment of infectious diseases, im-munodeficiency diseases and cancers. However, it remains unclear whether T alpha 1 has a therapeutic role in bTBI. Thus, we hypothesized that T alpha 1 administration could reverse the outcomes of bTBI. The blast induced TBI (bTBI) rat model was established with the compressed gas driven blast injury model system. A consecutive T alpha 1 therapy (in 1 ml saline, twice a day) at a dose of 200 mu g/kg or normal saline (NS) (1 ml, twice a day) for 3 days or 2 weeks was performed. Utilizing our newly designed bTBI model, we investigated the beneficial effects of T alpha 1 therapy on rats exposed to bTBI including: cognitive functions, general histology, regulatory T (Treg) cells, edema, inflammation reactions and the expression and phosphorylation level of tau via Morris Water Maze test (MWM test), HE staining, flow cytometry, brain water content (BWC) calculation, IL-6 assay and Western blotting, respectively. T alpha 1 treatment seemed to reduce the 24 -hour mortality, albeit with no statistical significance. Moreover, T alpha 1 treatment markedly improved cognitive dys-function by decreasing the escape latency in the acquisition phase, and increasing the crossing numbers in the probe phase of MWM test. More interestingly, T alpha 1 significantly inhibited tau phosphorylation at the Thr205 epitope, but not at the Ser404 and Ser262 epitopes. T alpha 1 increased the percentage of Treg cells and inhibited plasma IL-6 production on 3d post bTBI. Moreover, T alpha 1 suppressed brain edema as demonstrated by decrease of BWC. However, there was a lack of obvious change in histopathology in the brain upon T alpha 1 treatment. This is the first study showing that T alpha 1 improves neurological deficits after bTBI in rats, which is potentially related to the inhibition of tau phosphorylation at the Thr205 epitope, increased Treg cells and decreased inflammatory reactions and brain edema.