Diana M Sama1, Shaun W Carlson1,2, Binoy Joseph1, Stefanie Saenger3, Friedrich Metzger3,4, Kathryn E Saatman1. 1. Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, USA. 2. Present address: Department of Neurological Surgery, Safar Center for Resuscitation Research, University of Pittsburgh, PA, USA. 3. Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse, Basel, Switzerland. 4. Versameb AG, Peter Merian-Strasse, Basel, Switzerland.
Abstract
BACKGROUND: Traumatic brain injury can result in lasting cognitive dysfunction due to degeneration of mature hippocampal neurons as well as the loss of immature neurons within the dentate gyrus. While endogenous neurogenesis affords a partial recovery of the immature neuron population, hippocampal neurogenesis may be enhanced through therapeutic intervention. Insulin-like growth factor-1 (IGF-1) has the potential to improve cognitive function and promote neurogenesis after TBI, but its short half-life in the systemic circulation makes it difficult to maintain a therapeutic concentration. IGF-1 modified with a polyethylene glycol moiety (PEG-IGF-1) exhibits improved stability and half-life while retaining its ability to enter the brain from the periphery, increasing its viability as a translational approach. OBJECTIVE: The goal of this study was to evaluate the ability of systemic PEG-IGF-1 administration to attenuate acute neuronal loss and stimulate the recovery of hippocampal immature neurons in brain-injured mice. METHODS: In a series of studies utilizing a well-established contusion brain injury model, PEG-IGF-1 was administered subcutaneously after injury. Serum levels of PEG were verified using ELISA and histological staining was used to investigate numbers of degenerating neurons and cortical contusion size at 24 h after injury. Immunofluorescent staining was used to evaluate numbers of immature neurons at 10 d after injury. RESULTS: Although subcutaneous injections of PEG-IGF-1 increased serum IGF-1 levels in a dose-dependent manner, no effects were observed on cortical contusion size, neurodegeneration within the dentate gyrus, or recovery of hippocampal immature neuron numbers. CONCLUSIONS: In contrast to its efficacy in rodent models of neurodegenerative diseases, PEG- IGF-1 was not effective in ameliorating early neuronal loss after contusion brain trauma.
BACKGROUND: Traumatic brain injury can result in lasting cognitive dysfunction due to degeneration of mature hippocampal neurons as well as the loss of immature neurons within the dentate gyrus. While endogenous neurogenesis affords a partial recovery of the immature neuron population, hippocampal neurogenesis may be enhanced through therapeutic intervention. Insulin-like growth factor-1 (IGF-1) has the potential to improve cognitive function and promote neurogenesis after TBI, but its short half-life in the systemic circulation makes it difficult to maintain a therapeutic concentration. IGF-1 modified with a polyethylene glycol moiety (PEG-IGF-1) exhibits improved stability and half-life while retaining its ability to enter the brain from the periphery, increasing its viability as a translational approach. OBJECTIVE: The goal of this study was to evaluate the ability of systemic PEG-IGF-1 administration to attenuate acute neuronal loss and stimulate the recovery of hippocampal immature neurons in brain-injured mice. METHODS: In a series of studies utilizing a well-established contusion brain injury model, PEG-IGF-1 was administered subcutaneously after injury. Serum levels of PEG were verified using ELISA and histological staining was used to investigate numbers of degenerating neurons and cortical contusion size at 24 h after injury. Immunofluorescent staining was used to evaluate numbers of immature neurons at 10 d after injury. RESULTS: Although subcutaneous injections of PEG-IGF-1 increased serum IGF-1 levels in a dose-dependent manner, no effects were observed on cortical contusion size, neurodegeneration within the dentate gyrus, or recovery of hippocampal immature neuron numbers. CONCLUSIONS: In contrast to its efficacy in rodent models of neurodegenerative diseases, PEG- IGF-1 was not effective in ameliorating early neuronal loss after contusion brain trauma.
Authors: Shinichi Yoshimura; Tetsuyuki Teramoto; Michael J Whalen; Michael C Irizarry; Yasushi Takagi; Jianhua Qiu; Jun Harada; Christian Waeber; Xandra O Breakefield; Michael A Moskowitz Journal: J Clin Invest Date: 2003-10 Impact factor: 14.808
Authors: Stefanie Saenger; Bettina Holtmann; Mark R Nilges; Susanne Schroeder; Andreas Hoeflich; Heidemarie Kletzl; Will Spooren; Susanne Ostrowitzki; Taleen Hanania; Michael Sendtner; Friedrich Metzger Journal: Amyotroph Lateral Scler Date: 2012-08-07
Authors: S Saenger; C Goeldner; J R Frey; L Ozmen; S Ostrowitzki; W Spooren; T M Ballard; E Prinssen; E Borroni; F Metzger Journal: Growth Horm IGF Res Date: 2011-08-23 Impact factor: 2.372
Authors: Karen J B Martins; Stefan M Gehrig; Timur Naim; Stefanie Saenger; Dale Baum; Friedrich Metzger; Gordon S Lynch Journal: Growth Horm IGF Res Date: 2013-04-19 Impact factor: 2.372