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.
AndersonK.J, MillerK.M, FugacciaI, & ScheffS.W. (2005). Regional distribution of fluoro-jade B staining in the hippocampus following traumatic brain injury. Experimental Neurology, 193(1), 125–130.
2.
AyadiA.E, ZigmondM.J, & SmithA.D. (2016). IGF-1 protects dopamine neurons against oxidative stress: Association with changes in phosphokinases. Experimental Brain Research, 234(7), 1863–1873.
3.
BakeS, SelvamaniA, CherryJ, & SohrabjiF. (2014). Blood brain barrier and neuroinflammation arecritical targets of IGF-1-mediated neuroprotection in stroke for middle-aged female rats.. PLoS One, 9(3), e91427.
4.
CarlsonS.W, MadathilS.K, SamaD.M, GaoX, ChenJ, & SaatmanK.E. (2014). Conditional overexpression of insulin-like growth factor-1 enhances hippocampal neurogenesis and restores immature neuron dendritic processes after traumatic brain injury. Journal of Neuropathology and Experimental Neurology, 73(8), 734–746.
5.
CarlsonS.W, & SaatmanK.E. (2018). Central Infusion of IGF-1 Increases Hippocampal Neurogenesis and Improves Neurobehavioral Function after Traumatic Brain Injury.. Journal of Neurotrauma, April 2017. (Epub ahead of print).
6.
ChenC, MaT.Z, WangL.N, WangJ.J, TuY, ZhaoM.L, …LiX.H. (2016). Mild hypothermia facilitates the long-term survival of newborn cells in the dentate gyrus after traumatic brain injury by diminishing a pro-apoptotic microenvironment. Neuroscience, 335, 114–121.
7.
ClellandC.D, ChoiM, RombergC, ClemensonG.DJr, FragniereA, TyersP, …BusseyT.J. (2009). A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science, 325(5937), 210–213.
8.
ColicosM.A, DixonC.E, & DashP.K. (1996). Delayed, selective neuronal death following experimental cortical impact injury in rats: Possible role in memory deficits. Brain Research, 739(1-2), 111–119.
9.
DashP.K, MachS.A, & MooreA.N. (2001). Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. Journal of Neuroscience Research, 63(4), 313–319.
10.
DennisA.M, HaselkornM.L, VagniV.A, GarmanR.H, Janesko-FeldmanK, BayirH, …KochanekP.M. (2009). Hemorrhagic shock after experimental traumatic brain injury in mice: Effect on neuronal death. Journal of Neurotrauma, 26(6), 889–899.
11.
DodgeJ.C, HaidetA.M, YangW, PassiniM.A, HesterM, ClarkeJ, …KasparB.K. (2008). Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Molecular Therapy, 16(6), 1056–1064.
DyerA.H, VahdatpourC, SanfeliuA, & TropeaD. (2016). The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience, 325, 89–99.
14.
GaoX, & ChenJ. (2013). Moderate traumatic brain injury promotes neural precursor proliferation without increasing neurogenesis in the adult hippocampus. Experimental Neurology, 239, 38–48.
15.
GaoX, Deng-BryantY, ChoW, CarricoK.M, HallE.D, & ChenJ. (2008). Selective death of newborn neurons in hippocampal dentate gyrus following moderate experimental traumatic brain injury. Journal of Neuroscience Research, 86(10), 2258–2270.
16.
HattonJ, RappR.P, KudskK.A, BrownR.O, LuerM.S, BukarJ.G, …YoungB. (1997). Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: A phase II safety and efficacy trial. Journal of Neurosurgery, 86(5), 779–786.
17.
IbrahimS, HuW, WangX, GaoX, HeC, & ChenJ. (2016). Traumatic Brain Injury Causes Aberrant Migration of Adult-Born Neurons in the Hippocampus. Scientific Reports, 6, 21793.
18.
JablonkaS, HoltmannB, SendtnerM, & MetzgerF. (2011). Therapeutic effects of PEGylated insulin-like growth factor I in the pmn mouse model of motoneuron disease. Experimental Neurology, 232(2), 261–269.
19.
KasparB.K, LladoJ, SherkatN, RothsteinJ.D, & GageF.H. (2003). Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science, 301(5634), 839–842.
20.
KletzlH, GuentherA, HoflichA, HoflichC, FrystykJ, StaackR.F, …MetzgerF. (2017). First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I. Growth Hormone and IGF Research, 33, 9–16.
21.
KreberL.A, GriesbachG.S, & AshleyM.J. (2016). Detection of Growth Hormone Deficiency in Adults with Chronic Traumatic Brain Injury. Journal of Neurotrauma, 33(17), 1607–1613.
22.
KriegerF, ElfleinN, SaengerS, WirthgenE, RakK, FrantzS, …JablonkaS. (2014). Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1. Brain, 137(Pt 5), 1374–1393.
23.
LiuX.F, FawcettJ.R, ThorneR.G, FreyW.H.. 2nd (2001). Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neuroscience Letters, 308(2), 91–94.
24.
MaasA.I.R, MenonD.K, AdelsonP.D, AndelicN, BellM.J, BelliA, Investigators. (2017). Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. Lancet Neurology, 16(12), 987–1048.
25.
MadathilS.K, CarlsonS.W, BrelsfoardJ.M, YeP, D’ErcoleA.J, & SaatmanK.E. (2013). Astrocyte-Specific Overexpression of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons and Reduces Behavioral Deficits following Traumatic Brain Injury in Mice.. PLoS One, 8(6), e67204.
26.
MadathilS.K, EvansH.N, & SaatmanK.E. (2010). Temporal and regional changes in IGF-1/IGF-1R signaling in the mouse brain after traumatic brain injury. Journal of Neurotrauma, 27(1), 95–107.
27.
MadathilS.K, & SaatmanK.E. (2015). IGF-1/IGF-R Signaling in Traumatic Brain Injury: Impact on Cell Survival, Neurogenesis, and Behavioral Outcome. In KobeissyF. H. (Ed.). Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL).
28.
MartinsK.J, GehrigS.M, NaimT, SaengerS, BaumD, MetzgerF, & LynchG.S. (2013). Intramuscular administration of PEGylated IGF-I improves skeletal muscle regeneration after myotoxic injury. Growth Hormone and IGF Research, 23(4), 128–133.
29.
MetzgerF, SajidW, SaengerS, StaudenmaierC, van der PoelC, SobottkaB, …SchoenfeldH.J. (2011). Separation of fast from slow anabolism by site-specific PEGylation of insulin-like growth factor I (IGF-I). Journal of Biological Chemistry, 286(22), 19501–19510.
30.
NaganoI, IlievaH, ShioteM, MurakamiT, YokoyamaM, ShojiM, & AbeK. (2005). Therapeutic benefit of intrathecal injection of insulin-like growth factor- in a mouse model of Amyotrophic Lateral Sclerosis. Journal of the Neurological Sciences, 235(1-2), 61–68.
31.
National Research Council. (2011). Guide for the Care and Use of Laboratory Animals–8th edNational Academies PressWashington, DC.
32.
Nieto-EstevezV, DefteraliC, & Vicario-AbejonC. (2016). IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain. Frontiers in Neuroscience, 10, 52.
33.
OsierN.D, CarlsonS.W, DeSanaA, & DixonC.E. (2015). Chronic Histopathological and Behavioral Outcomes of Experimental Traumatic Brain Injury in Adult Male Animals. Journal of Neurotrauma, 32(23), 1861–1882.
34.
OsierN.D, & DixonC.E. (2016). The Controlled Cortical Impact Model: Applications, Considerations for Researchers, and Future Directions. Frontiers in Neurology, 7, 134.
35.
ParkerK, BerrettaA, SaengerS, SivaramakrishnanM, ShirleyS.A, MetzgerF, & ClarksonA.N. (2017). PEGylated insulin-like growth factor-I affords protection and facilitates recovery of lost functions post-focal ischemia. Scientific Reports, 7(1), 241.
36.
PleasantJ.M, CarlsonS.W, MaoH, ScheffS.W, YangK.H, & SaatmanK.E. (2011). Rate of neurodegeneration in the mouse controlled cortical impact model is influenced by impactor tip shape: Implications for mechanistic and therapeutic studies. Journal of Neurotrauma, 28(11), 2245–2262.
37.
RizkN.N, Myatt-JonesJ, RafolsJ, & DunbarJ.C. (2007). Insulin like growth factor-1 (IGF-1) decreasesischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine, 31(1), 66–71.
38.
RolaR, MizumatsuS, OtsukaS, MorhardtD.R, Noble-HaeussleinL.J, FishmanK, …FikeJ.R. (2006). Alterations in hippocampal neurogenesis following traumatic brain injury in mice. Experimental Neurology, 202(1), 189–199.
39.
RubovitchV, EdutS, SarfsteinR, WernerH, & PickC.G. (2010). The intricate involvement of the Insulin-like growth factor receptor signaling in mild traumatic brain injury in mice. Neurobiology of Disease, 38(2), 299–303.
40.
SaatmanK.E, ContrerasP.C, SmithD.H, RaghupathiR, McDermottK.L, FernandezS.C, …McIntoshT.K. (1997). Insulin-like growth factor-1 (IGF-1) improves both neurological motor and cognitive outcome following experimental brain injury. Experimental Neurology, 147(2), 418–427.
41.
SaatmanK.E, DuhaimeA.C, BullockR, MaasA.I, ValadkaA, ManleyG.T, …Advisory PanelM. (2008). Classification of traumatic brain injury for targeted therapies. Journal of Neurotrauma, 25(7), 719–738.
42.
SaengerS, GoeldnerC, FreyJ.R, OzmenL, OstrowitzkiS, SpoorenW, …MetzgerF. (2011). PEGylation enhances the therapeutic potential for insulin-like growth factor I in central nervous system disorders. Growth Hormone and IGF Research, 21(5), 292–303.
43.
SaengerS, HoltmannB, NilgesM.R, SchroederS, HoeflichA, KletzlH, …MetzgerF. (2012). Functional improvement in mouse models of familial amyotrophic lateral sclerosis by PEGylated insulin-like growth factor I treatment depends on disease severity. Amyotrophic Lateral Sclerosis, 13(5), 418–429.
44.
SahayA, WilsonD.A, & HenR. (2011). Pattern separation: A common function for new neurons in hippocampus and olfactory bulb. Neuron, 70(4), 582–588.
45.
SchabitzW.R, HoffmannT.T, HeilandS, KollmarR, BardutzkyJ, SommerC, & SchwabS. (2001). Delayed neuroprotective effect of insulin-like growth factor-i after experimental transient focal cerebral ischemia monitored with mri. Stroke, 32(5), 1226–1233.
46.
SchmuedL.C, StowersC.C, ScalletA.C, & XuL. (2005). Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons. Brain Research, 1035(1), 24–31.
ScrantonR.A, & BaskinD.S. (2015). Impaired Pituitary Axes Following Traumatic Brain Injury. Journal of Clinical Medicine, 4(7), 1463–1479.
49.
SmithD.H, SoaresH.D, PierceJ.S, PerlmanK.G, SaatmanK.E, MeaneyD.F, …McIntoshT.K. (1995). A model of parasagittal controlled cortical impact in the mouse: Cognitive and histopathologic effects. Journal of Neurotrauma, 12(2), 169–178.
50.
SunD, McGinnM.J, ZhouZ, HarveyH.B, BullockM.R, & ColelloR.J. (2007). Anatomical integration of newly generated dentate granule neurons following traumatic brain injury in adult rats and its association to cognitive recovery. Experimental Neurology, 204(1), 264–272.
51.
TaylorC.A, BellJ.M, BreidingM.J, & XuL. (2017). Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths - United States, 2007 and 2013. MMWR: Surveillance Summaries, 66(9), 1–16.
52.
TongW, IgarashiT, FerrieroD.M, & NobleL.J. (2002). Traumatic Brain Injury in the Immature Mouse Brain: Characterization of Regional Vulnerability. Experimental Neurology, 176(1), 105–116.
53.
VaccarelloM.A, DiamondF.BJr, Guevara-AguirreJ, RosenbloomA.L, FielderP.J, GargoskyS, …RosenfeldR.G. (1993). Hormonal and metabolic effects and pharmacokinetics of recombinant insulin-like growth factor-I in growth hormone receptor deficiency/Laron syndrome. Journal of Clinical Endocrinology and Metabolism, 77(1), 273–280.
54.
VillasanaL.E, KimK.N, WestbrookG.L, & SchnellE. (2015). Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury (1,2,3). eNeuro, 2(5), 3.
YoshimuraS, TeramotoT, WhalenM.J, IrizarryM.C, TakagiY, QiuJ, …MoskowitzM.A. (2003). FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice. Journal of Clinical Investigation, 112(8), 1202–1210.
57.
ZhuW, FanY, FrenzelT, GasmiM, BartusR.T, YoungW.L, …ChenY. (2008). Insulin growth factor-1 gene transfer enhances neurovascular remodeling and improves long-term stroke outcome in mice. Stroke, 39(4), 1254–1261.
