Early and Sustained Increase in the Expression of Hippocampal IGF-1, But Not EPO, in a Developmental Rodent Model of Traumatic Brain Injury

Abstract

Pediatric traumatic brain injury (pTBI) is the leading cause of traumatic death and disability in children in the United States. Impaired learning and memory in these young survivors imposes a heavy toll on society. In adult TBI (aTBI) models, cognitive outcome improved after administration of erythropoietin (EPO) or insulin-like growth factor-1 (IGF-1). Little is known about the production of these agents in the hippocampus, a brain region critical for learning and memory, after pTBI. Our objective was to describe hippocampal expression of EPO and IGF-1, together with their receptors (EPOR and IGF-1R, respectively), over time after pTBI in 17-day-old rats. We used the controlled cortical impact (CCI) model and measured hippocampal mRNA levels of EPO, IGF-1, EPOR, IGF-1R, and markers of caspase-dependent apoptosis (bcl2, bax, and p53) at post-injury days (PID) 1, 2, 3, 7, and 14. CCI rats performed poorly on Morris water maze testing of spatial working memory, a hippocampally-based cognitive function. Apoptotic markers were present early and persisted for the duration of the study. EPO in our pTBI model increased much later (PID7) than in aTBI models (12 h), while EPOR and IGF-1 increased at PID1 and PID2, respectively, similar to data from aTBI models. Our data indicate that EPO expression showed a delayed upregulation post-pTBI, while EPOR increased early. We speculate that administration of EPO in the first 1-2 days after pTBI would increase hippocampal neuronal survival and function.

Traumatic Brain Injury Increased IGF-1B mRNA and Altered IGF-1 Exon 5 and Promoter Region Epigenetic Characteristics in the Rat Pup Hippocampus

“…Interestingly, experimental evidence supports the contention that IGF-1B is more neuroprotective than the IGF-1A isoform (Aperghis et al, 2004), and that unlike IGF-1, its product acts independently of the IGF-1 receptor (Armakolas et al, 2010;Dluzniewska et al, 2005;Gorecki et al, 2007;Siegfried et al, 1992). This independence from the IGF-1 receptor is particularly interesting in light of the fact that we had previously found that IGF-1 receptor mRNA levels decreased early after CCI (Schober et al, 2010) in the 17-day-old male rat hippocampus. In addition, studies in muscle devoid of IGF-1 receptor showed that overexpression of IGF-1B mRNA resulted in activation of pathways both in common and different from those resulting from administration of the IGF-1 mature peptide (Barton et al, 2010).…”

“…IGF-1 promotes survival and proliferation of neurons and glia in the developing and adult brain (Aberg, 2010). In mature and immature rodents, either TBI (Li et al, 1998;Schober et al, 2010), or hypoxic ischemic injury (Beresewicz et al, 2010;Yan et al, 2006), increase brain IGF-1 expression. Indeed, blockade of endogenous IGF-1 activity in the adult brain worsened outcome after ischemia (Yan et al, 2006).…”

“…IGF-1 mRNA levels increased in the mature and immature brain after TBI (Li et al, 1998;Madathil et al, 2010;Schober et al, 2010). In rats, IGF-1B expression relative to IGF-1A is highest early in development (Beresewicz et al, 2010).…”

“…To test our hypotheses, we performed controlled cortical impact (CCI) using 17-day-old male rats, an established model of developmental TBI (Schober et al, 2010). The rat CCI model, as first described by Dixon (Dixon et al, 1991), and later modified for use in 17-day-old rats by Adelson (Adelson et al, 1998), produces hippocampal neuronal death and impaired learning and memory (Robertson et al, 2007;Schober et al, 2010).…”

“…The rat CCI model, as first described by Dixon (Dixon et al, 1991), and later modified for use in 17-day-old rats by Adelson (Adelson et al, 1998), produces hippocampal neuronal death and impaired learning and memory (Robertson et al, 2007;Schober et al, 2010). All molecular studies were done using dissected hippocampi.…”