title: Treatment of traumatic brain injury in rats with N-acetyl-seryl-aspartyl-lysyl-proline.
abstract: 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.
authors.affiliation: Departments of 1 Neurosurgery and.
authors.forename: Yanlu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Neurology, Henry Ford Hospital, Detroit; and.
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: Neurology, Henry Ford Hospital, Detroit; and.|Department of Physics, Oakland University, Rochester, Michigan.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: Departments of 1 Neurosurgery and.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Neurology, Henry Ford Hospital, Detroit; and.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Departments of 1 Neurosurgery and.
authors.forename: Asim
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: Departments of 1 Neurosurgery and.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D004195:Disease Models, Animal; D007260:Infusion Pumps; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D011897:Random Allocation; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects
chemical_list: D043925:Angiogenesis Inducing Agents; D018696:Neuroprotective Agents; D009842:Oligopeptides; C058504:goralatide
keywords: ACE = Angiotensin I–converting enzyme; AcSDKP= N-acetyl-seryl-aspartyl-lysyl-proline; BBB = blood-brain barrier; BrdU = 5-bromo-2′-deoxyuridine; CA1, CA2, CA3 = cornu ammonis region 1, 2, 3; CDC = Centers for Disease Control and Prevention; DG = dentate gyrus; EBA = endothelial barrier antigen; GFAP = glial fibrillary acidic protein; MWM = Morris water maze; N-acetyl-seryl-aspartyl-lysyl-proline; NF-κB = nuclear factor–κB; NeuN = neuronal nuclei; PBS = phosphate-buffered saline; TBI = traumatic brain injury; TGF-β1 = transforming growth factor–β1; Tβ4 = thymosin β4; angiogenesis; controlled cortical impact; functional outcome; mNSS = modified Neurological Severity Score; neurogenesis; traumatic brain injury