Erythropoietin Mediates Neurobehavioral Recovery and Neurovascular Remodeling Following Traumatic Brain Injury in Rats b
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ORIGINAL ARTICLE
Erythropoietin Mediates Neurobehavioral Recovery and Neurovascular Remodeling Following Traumatic Brain Injury in Rats by Increasing Expression of Vascular Endothelial Growth Factor Ye Xiong & Yanlu Zhang & Asim Mahmood & Yuling Meng & Changsheng Qu & Michael Chopp
Received: 31 August 2011 / Revised: 11 October 2011 / Accepted: 14 October 2011 / Published online: 29 October 2011 # Springer Science+Business Media, LLC 2011
Abstract Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). Here, we investigated the role of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) on EPO-induced therapeutic efficacy in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury and then infused intracerebroventricularly with either a potent selective VEGFR2 inhibitor SU5416 or vehicle dimethyl sulfoxide. Animals from both groups received delayed EPO treatment (5,000 U/kg in saline) administered intraperitoneally daily at 1, 2, and 3 days post-injury. TBI rats treated with saline administered intraperitoneally daily at 1, 2, and 3 days post-injury served as EPO treatment controls. 5Bromo-2′-deoxyuridine was administered to label dividing cells. Spatial learning and sensorimotor function were assessed using a modified Morris water maze test and modified neurological severity score, respectively. Animals were sacrificed at 4 days post-injury for measurement of VEGF and VEGFR2 or 35 days post-injury for evaluation of cell proliferation, angiogenesis, and neurogenesis. EPO treatment promoted sensorimotor and cognitive functional Y. Xiong (*) : Y. Zhang : A. Mahmood : Y. Meng : C. Qu Department of Neurosurgery, Henry Ford Hospital, E&R Building, Room # 3096 2799 West Grand Boulevard, Detroit, MI 48202, USA e-mail: [email protected] M. Chopp Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA M. Chopp Department of Physics, Oakland University, Rochester, MI 48309, USA
recovery after TBI. EPO treatment increased brain VEGF expression and phosphorylation of VEGFR2. EPO significantly increased cell proliferation, angiogenesis, and neurogenesis in the dentate gyrus after TBI. Compared to the vehicle, SU5416 infusion significantly inhibited phosphorylation of VEGFR2, cell proliferation, angiogenesis, and neurogenesis as well as abolished functional recovery in EPO-treated TBI rats. These findings indicate the VEGF⁄ VEGFR2 activation plays an important role in EPOmediated neurobehavioral recovery and neurovascular remodeling after TBI. Keywords Angiogenesis . Erythropoietin . Neurogenesis . Traumatic brain injury . Vascular endothelial growth factor
Introduction Traumatic brain injury (TBI) is the leading cause of death and disability in young people [1]. The most prevalent and debilitating features in survivors of TBI are cognitive deficits and motor dysfunctions [2]. Despite advances in basic research as well as improved neurological intensive care in recent years, no effective pharmacological therapy for T
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