Thymosin β4 (Tβ4) is a regenerative multifunctional peptide. The aim of this study was to test the hypothesis that Tβ4 treatment initiated 6 hours postinjury reduces brain damage and improves functional recovery in rats subjected to traumatic brain injury (TBI).
Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex in young adult male Wistar rats. The rats were randomly divided into the following groups: 1) saline group (n = 7); 2) 6 mg/kg Tβ4 group (n = 8); and 3) 30 mg/kg Tβ4 group (n = 8). Thymosin β4 or saline was administered intraperitoneally starting at 6 hours postinjury and again at 24 and 48 hours. An additional group of 6 animals underwent surgery without TBI (sham-injury group). Sensorimotor function and spatial learning were assessed using the modified Neurological Severity Score and the Morris water maze test, respectively. Animals were euthanized 35 days after injury, and brain sections were processed to assess lesion volume, hippocampal cell loss, cell proliferation, and neurogenesis after Tβ4 treatment.
Compared with saline administration, Tβ4 treatment initiated 6 hours postinjury significantly improved sensorimotor functional recovery and spatial learning, reduced cortical lesion volume and hippocampal cell loss, and enhanced cell proliferation and neurogenesis in the injured hippocampus. The high dose of Tβ4 showed better beneficial effects compared with the low-dose treatment.
Thymosin β4 treatment initiated 6 hours postinjury provides both neuroprotection and neurorestoration after TBI, indicating that Tβ4 has promising therapeutic potential in patients with TBI. These data warrant further investigation of the optimal dose and therapeutic window of Tβ4 treatment for TBI and the associated underlying mechanisms.
Abbreviations used in this paper:BSA = bovine serum albumin; CCI = controlled cortical impact; mNSS = modified Neurological Severity Score; PBS = phosphate-buffered saline; Tβ4 = thymosin β4.
Address correspondence to: Ye Xiong, M.D., Ph.D., Henry Ford Health System, Department of Neurosurgery, E&R Building, Room 3096, 2799 West Grand Boulevard, Detroit, Michigan 48202. email: email@example.com.
Please include this information when citing this paper: published online February 10, 2012; DOI: 10.3171/2012.1.JNS111729.
BednarekRBoncelaJSmolarczykKCierniewska-CieslakAWyrobaECierniewskiCS: Ku80 as a novel receptor for thymosin beta4 that mediates its intracellular activity different from G-actin sequestering. J Biol Chem283:1534–15442008
ChenJLiYZhangRKatakowskiMGautamSCXuY: Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. Brain Res1005:21–282004
EmeryDLFulpCTSaatmanKESchützCNeugebauerEMcIntoshTK: Newly born granule cells in the dentate gyrus rapidly extend axons into the hippocampal CA3 region following experimental brain injury. J Neurotrauma22:978–9882005
KleindienstAMcGinnMJHarveyHBColelloRJHammRJBullockMR: Enhanced hippocampal neurogenesis by intraventricular S100B infusion is associated with improved cognitive recovery after traumatic brain injury. J Neurotrauma22:645–6552005
LuDMahmoodAZhangRCoppM: Upregulation of neurogenesis and reduction in functional deficits following administration of DEtA/NONOate, a nitric oxide donor, after traumatic brain injury in rats. J Neurosurg99:351–3612003
LuDQuCGoussevAJiangHLuCSchallertT: Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma24:1132–11462007
MengYXiongYMahmoodAZhangYQuCChoppM: Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats. Laboratory investigation. J Neurosurg115:550–5602011
SunDMcGinnMJZhouZHarveyHBBullockMRColelloRJ: Anatomical integration of newly generated dentate granule neurons following traumatic brain injury in adult rats and its association to cognitive recovery. Exp Neurol204:264–2722007
XiongYLuDQuCGoussevASchallertTMahmoodA: Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. Laboratory investigation. J Neurosurg109:510–5212008
XiongYMahmoodALuDQuCKazmiHGoussevA: Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system. Brain Res1230:247–2572008
XiongYMahmoodAMengYZhangYQuCSchallertT: Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose. Laboratory investigation. J Neurosurg113:598–6082010
XiongYMahmoodAZhangYMengYZhangZGQuC: Effects of posttraumatic carbamylated erythropoietin therapy on reducing lesion volume and hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome in rats following traumatic brain injury. Laboratory investigation. J Neurosurg114:549–5592011