Traumatic brain injury (TBI) is a significant health concern, affecting 1.4 million people in the United States each year at a cost of $56 billion. The most common cognitive impairment among severely head-injured patients is memory loss. Although a number of therapeutic trials for TBI have been undertaken, there are no pharmacological therapies identified for TBI. Recently, attention has focused on potential therapeutic agents that enhance endogenous neuroplasticity including neurogenesis after brain injury, with a final goal of improving functional outcome. It is our objective to develop a restorative treatment for TBI by using recombinant human erythropoietin (rhEPO). Erythropoietin (EPO) is produced by the fetal liver and adult kidney and is the major cytokine that regulates erythropoiesis. In recent years, EPO has been demonstrated to have important nonhematopoietic functions in the nervous system. Our recent studies have shown that rhEPO enhances neurogenesis and improves cognitive function in TBI induced by controlled cortical impact (CCI). CCI causes selective neuronal death in the hippocampal CA3 region and the dentate gyrus (DG) both in rats and mice, leading to spatial learning and memory deficits. Although TBI evokes neurogenesis, a large proportion of the cells newly generated in the DG during the early phase after TBI die, during the late phase after TBI. The central hypothesis behind the proposed research is that the spatial learning impairment can be improved by manipulating the brain microenvironment (angiogenesis and molecular targets) by rhEPO. However, dose-response and therapeutic window studies using rhEPO have not been performed, nor have the mechanisms underlying therapeutic benefit for the treatment of TBI been established. In light of the potential of rhEPO to improve neurological outcome after TBI, three specific aims are proposed.
Specific Aim 1 : To measure the dose-response of rhEPO treatment on spatial learning function in rats after TBI. In addition, the therapeutic time window for rhEPO of TBI will be determined.
Specific Aim 2 : To study the effect of rhEPO treatment on the temporal and spatial profiles of neurogenesis and angiogenesis in the dentate gyrus after TBI.
Specific Aim 3 : To identify the molecular targets of rhEPO-induced neurogenesis and angiogenesis after TBI, the contribution of growth factors (vascular endothelial growth factor, brain-derived neurotrophic factor, and fibroblast growth factor) and the phosphoinositide 3-kinase/threonine protein kinase (PI3K/Akt) signal transduction pathway will be investigated. We expect to demonstrate that this therapy has promise for the improvement of spatial learning associated with TBI through upregulation of growth factors and PI3K/Akt signal pathway and the subsequent induction of angiogenesis and neurogenesis. The long-term goal of this application is to translate our finding of therapeutic benefit after treatment of TBI with rhEPO to the patient.

Public Health Relevance

Although a number of therapeutic trials for traumatic brain injury (TBI) have been undertaken, there are no pharmacological therapies identified for TBI. Given the enormity of the clinical problem of TBI, affecting 1.4 million people in the United States each year at a cost of $56 billion, it is imperative that therapeutic approaches designed to improve functional recovery after TBI be developed. In this proposal, based on the newly discovered neuroprotective/neurorestorative properties of recombinant human erythropoietin (rhEPO), we seek to investigate its effect on neurogenesis and functional outcome in the rat after TBI and the mechanisms underlying therapeutic benefit of rhEPO for treatment of TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062002-03
Application #
7893712
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hicks, Ramona R
Project Start
2008-09-25
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
3
Fiscal Year
2010
Total Cost
$282,614
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Meng, Yuling; Chopp, Michael; Zhang, Yanlu et al. (2014) Subacute intranasal administration of tissue plasminogen activator promotes neuroplasticity and improves functional recovery following traumatic brain injury in rats. PLoS One 9:e106238
Xiong, Ye; Mahmood, Asim; Chopp, Michael (2013) Animal models of traumatic brain injury. Nat Rev Neurosci 14:128-42
Xiong, Ye; Mahmood, Asim; Meng, Yuling et al. (2012) Neuroprotective and neurorestorative effects of thymosin ?4 treatment following experimental traumatic brain injury. Ann N Y Acad Sci 1270:51-8
Xiong, Ye; Zhang, Yanlu; Mahmood, Asim et al. (2012) Neuroprotective and neurorestorative effects of thymosin ?4 treatment initiated 6 hours after traumatic brain injury in rats. J Neurosurg 116:1081-92
Zhang, Yanlu; Chopp, Michael; Mahmood, Asim et al. (2012) Impact of inhibition of erythropoietin treatment-mediated neurogenesis in the dentate gyrus of the hippocampus on restoration of spatial learning after traumatic brain injury. Exp Neurol 235:336-44
Ning, Ruizhuo; Xiong, Ye; Mahmood, Asim et al. (2011) Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury. Brain Res 1384:140-50
Xiong, Ye; Zhang, Yanlu; Mahmood, Asim et al. (2011) Erythropoietin Mediates Neurobehavioral Recovery and Neurovascular Remodeling Following Traumatic Brain Injury in Rats by Increasing Expression of Vascular Endothelial Growth Factor. Transl Stroke Res 2:619-632
Xiong, Ye; Mahmood, Asim; Meng, Yuling et al. (2011) Treatment of traumatic brain injury with thymosin ?? in rats. J Neurosurg 114:102-15
Meng, Yuling; Xiong, Ye; Mahmood, Asim et al. (2011) Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats. J Neurosurg 115:550-60
Xiong, Ye; Mahmood, Asim; Zhang, Yanlu et al. (2011) 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. J Neurosurg 114:549-59

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