Affiliations: [a]
Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, USA
| [b] Present address: Department of Neurological Surgery, Safar Center for Resuscitation Research, University of Pittsburgh, PA, USA
| [c]
Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse, Basel, Switzerland
| [d] Versameb AG, Peter Merian-Strasse, Basel, Switzerland
Correspondence:
[*]
Corresponding author: Kathryn E. Saatman, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, 741 S. Limestone St., Lexington, KY 40536, USA. Tel.: +1 859 323 5145; E-mail: k.saatman@uky.edu.
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.
