Treatment of traumatic brain injury in rats with N-acetyl-seryl-aspartyl-lysyl-proline
Zhang Y, Zhang ZG, Chopp M, Meng Y, Zhang L, Mahmood A, and Xiong Y. Treatment of traumatic brain injury in rats with N-acetyl-seryl-aspartyl-lysyl-proline. J Neurosurg 2017; 126(3):782-795.
Journal of neurosurgery
OBJECTIVE The authors' previous studies have suggested that thymosin beta 4 (Tβ4), a major actin-sequestering protein, improves functional recovery after neural injury. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an active peptide fragment of Tβ4. Its effect as a treatment of traumatic brain injury (TBI) has not been investigated. Thus, this study was designed to determine whether AcSDKP treatment improves functional recovery in rats after TBI. METHODS Young adult male Wistar rats were randomly divided into the following groups: 1) sham group (no injury); 2) TBI + vehicle group (0.01 N acetic acid); and 3) TBI + AcSDKP (0.8 mg/kg/day). TBI was induced by controlled cortical impact over the left parietal cortex. AcSDKP or vehicle was administered subcutaneously starting 1 hour postinjury and continuously for 3 days using an osmotic minipump. Sensorimotor function and spatial learning were assessed using a modified Neurological Severity Score and Morris water maze tests, respectively. Some of the animals were euthanized 1 day after injury, and their brains were processed for measurement of fibrin accumulation and neuroinflammation signaling pathways. The remaining animals were euthanized 35 days after injury, and brain sections were processed for measurement of lesion volume, hippocampal cell loss, angiogenesis, neurogenesis, and dendritic spine remodeling. RESULTS Compared with vehicle treatment, AcSDKP treatment initiated 1 hour postinjury significantly improved sensorimotor functional recovery (Days 7-35, p < 0.05) and spatial learning (Days 33-35, p < 0.05), reduced cortical lesion volume, and hippocampal neuronal cell loss, reduced fibrin accumulation and activation of microglia/macrophages, enhanced angiogenesis and neurogenesis, and increased the number of dendritic spines in the injured brain (p < 0.05). AcSDKP treatment also significantly inhibited the transforming growth factor-β1/nuclear factor-κB signaling pathway. CONCLUSIONS AcSDKP treatment initiated 1 hour postinjury provides neuroprotection and neurorestoration after TBI, indicating that this small tetrapeptide has promising therapeutic potential for treatment of TBI. Further investigation of the optimal dose and therapeutic window of AcSDKP treatment for TBI and the associated underlying mechanisms is therefore warranted.
Medical Subject Headings
Angiogenesis Inducing Agents; Animals; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Infusion Pumps; Male; Maze Learning; Neurogenesis; Neurons; Neuroprotective Agents; Oligopeptides; Random Allocation; Rats, Wistar; Recovery of Function