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Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015.

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Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects.

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Chapter 7IGF-1/IGF-R Signaling in Traumatic Brain Injury

Impact on Cell Survival, Neurogenesis, and Behavioral Outcome

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Growing interest in post-traumatic brain plasticity events has fueled investigations of therapeutic approaches that promote endogenous neurorepair. Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with critical roles in regulating brain plasticity mechanisms. This chapter summarizes literature related to how expression of IGF-1 and its signaling components are altered after traumatic brain injury (TBI). To understand the potential effects of changes in endogenous IGF-1, the major roles of IGF-1 in CNS function are reviewed, with attention to how these IGF-mediated events may impact the response to TBI. In light of the multiplicity of CNS functions mediated by IGF-1, supplementation of endogenous IGF-1 may provide neuroprotection and promote neuronal repair in the injured brain. Coupled with a handful of preclinical studies in TBI, a larger literature in other CNS injuries such as stroke, hypoxic ischemia and spinal cord injury demonstrates potential beneficial effects of IGF-1 following injury.

TBI pathophysiology is multifaceted, including primary and secondary events. Primary injury results from the mechanical forces including acceleration, deceleration, and impact forces at the moment of injury, producing diffuse or focal pathology. This initial phase is characterized by tissue deformation, membrane depolarization, disruption of blood vessels and axons, ischemia, and cell membrane damage (Beauchamp et al., 2008; Dietrich et al., 1994; Gaetz, 2004). Secondary injury evolves from this early damage over a period of hours to days and even weeks to months, characterized by a complex network of biochemical events (Dikmen et al., 2009; Farkas and Povlishock, 2007; McIntosh et al., 1999). Excitatory amino acids and inflammatory cytokines released early in the secondary injury cascade lead to altered calcium homeostasis. Excessive intracellular calcium can signal various biochemical pathways initiating inflammation, free radical generation, and cytoskeletal damage. Increased calcium can activate proteases including calpains and caspases. Once activated, these proteases can cause widespread cell damage via cytoskeletal protein degradation and necrotic or apoptotic cell death pathways initiated within hours and continuing for days after brain injury. Secondary injury responses ultimately culminate in white matter damage and neurodegeneration contributing to behavioral morbidity.

In response to destructive events, the brain also has the capacity to promote cell repair through various compensatory mechanisms commonly referred to as neuroplasticity. Altered growth factor signaling, synaptogenesis, angiogenesis, neurogenesis, and gliogenesis are among these posttrauma brain remodeling events (Kernie and Parent, 2009; Schoch et al., 2012; Stein and Hoffman, 2003; Yu et al., 2008). Expression and release of endogenous neurotrophic factors is altered by various forms of central nervous system (CNS) injuries including TBI. An increase in their expression is considered as one of the mechanisms to promote neuroprotection and neurorepair after damage (Guan et al., 2003). After TBI, expression of growth factors such as neurotrophin 4/5, nerve growth factor, basic fibroblast growth factor, brain-derived neurotrophic factor (BDNF), and IGF-1 are increased (Conte et al., 2003; Madathil et al., 2010; Royo et al., 2006). Many of these growth factors play important roles in brain development and thus their increased expression after brain injury can recapitulate many of the processes involved in brain growth, accelerating neuronal repair.

Despite the improved understanding of TBI pathology, no therapeutic approach for treatment has yet been proved efficacious. Pharmacological approaches under research for TBI can be grouped as either neuroprotective or neuroreparative depending on their mode of action. Neuroprotective strategies that promote neuronal survival are focused mainly on attenuating acute damage from glutamate excitotoxicity, free radicals, or calcium influx. Neurorepair approaches promote neuroregeneration or neuroplasticity events. IGF-1, because of the multiplicity of its actions, provides a combined approach by attenuating cell death and promoting brain repair events (Aberg et al., 2000, 2006; Anderson et al., 2002; Lopez-Lopez et al., 2004).


7.2.1. IGF-1 Signaling

The IGF-1 mature protein is a 70-amino acid peptide with structural similarity to insulin. The IGF-1 peptide is coded by a single IGF-1 gene consisting of six exons (Figure 7.1). Alternate splicing of these exons leads to different IGF-1 protein isoforms, all of which are 70-amino acid peptides and signal through the IGF-1 receptor (IGF-1R) (Sussenbach et al., 1992). In addition to the isoforms, posttranslational processing of IGF-1 protein by acid proteases leads to two biologically active peptides in the brain (Sara et al., 1986) that act through IGF-1R. Another brain-specific cleavage product derived from IGF-1 by acid proteases is the glycyl-prolyl-glutamate tripeptide (GPE) that acts through glutamate receptors rather than the IGF-1R (Cacciatore et al., 2012; Sara et al., 1989).

FIGURE 7.1. IGF-1 gene and splicing variants.


IGF-1 gene and splicing variants. The IGF-1 gene contains six exons. Alterative splicing can generate multiple mRNAs. Exons 1 and 2 together with part of exon 3 code for the signal peptide. Exons 1 and 2 are leader sequences and are interchangeable. Although (more...)

The liver is the major source of circulating IGF-1, where its synthesis is stimulated by growth hormone (GH). In contrast, synthesis of IGF-1 locally in the brain is not regulated by GH. Brain and systemic IGF-1 tightly bind to IGF binding proteins (IGFBPs) that protect IGF-1 from degradation, prolong its half-life, and deliver them to appropriate receptors (Duan, 2002; Rosenfeld et al., 1999). Among the IGFBP family of six proteins, IGFBPs 2, 4, and 5 are highly expressed in the brain (Duan, 2002; Russo et al., 2005). IGF-1 is expressed predominantly in neurons and its levels are high during brain development and decline with age (Bach et al., 1991; Beck et al., 1988). Physiological actions of IGF-1 are mediated through the IGF-1R (Czech, 1989). After binding of IGF-1, the IGF-1R can activate multiple pathways including the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways (Cheng et al., 2000; Parrizas et al., 1997; Zheng et al., 2002). Although IGF-1 can act through multiple kinases, the PI3K/Akt pathway predominates in the nervous system (Leinninger et al., 2004a; Sun and D’Ercole, 2006). Activated Akt phosphorylates multiple substrates including GSK3β and mTOR that mediate many of IGF-1’s effects in the brain (Figure 7.2).

FIGURE 7.2. IGF-1/IGF-1R signaling cascade.


IGF-1/IGF-1R signaling cascade. IGF-1 is the major ligand for IGF-1R. IGF-1R is a transmembrane tyrosine kinase that consists of two alpha and two beta chains. In the nervous system, IGF-1R signals through two major pathways to mediate its functions. (more...)

7.2.2. Changes in IGF-1 Expression after TBI

Changes in serum IGF-1 levels are reported in brain-injured patients. The majority of clinical studies report reduced serum IGF-1 concentrations starting as early as one day that continue even years after injury (Agha et al., 2004a; Olivecrona et al., 2013; Popovic et al., 2004; Sanus et al., 2007; Wagner et al., 2010; Zgaljardic et al., 2011). Although quite a few of the studies included only moderate to severe trauma patients, reduced levels of circulating IGF-1 were also observed after mild TBI (Robles et al., 2009; Wagner et al., 2010). In contrast to the majority of clinical studies showing reduced IGF-1 levels after brain injury, one study reported no change in serum IGF-1 levels when measured months after severe closed-head trauma (Bondanell et al., 2002), whereas another reported elevated serum IGF-1 levels for 14 weeks after injury in patients with polytrauma or TBI alone (Wildburger et al., 2001). Although the reason for the differing observations is unclear at this time, TBI clinical reports commonly include a diverse patient population, with different trauma types, gender, injury severity, patient age, and brain region/regions affected, making comparisons across studies difficult.

Reduced serum IGF-1 levels after TBI may be attributed to pituitary dysfunction (Agha et al., 2004a, 2004b; Aimaretti et al., 2004; Berg et al., 2010; Herrmann et al., 2006). The pituitary gland, residing at the base of the brain, secretes many hormones, including GH. Hypopituitarism after TBI results in reduced levels of GH that in turn affect IGF-1 synthesis by the liver. Approximately 70% of the total circulating IGF-1 is produced by the liver (Iresjo et al., 2013). Although the brain synthesizes IGF-1 locally, serum IGF-1 also crosses the blood–brain barrier and may affect neural tissue and modulate IGF-1 expression. In liver-specific IGF-1–deficient mice, low circulating IGF-1 induced a decrease in hippocampal IGF-1 expression (Mitschelen et al., 2011). Low levels of serum IGF-1 have been implicated in the development of cognitive dysfunction (Koopmans et al., 2006; Trejo et al., 2004). Furthermore, a meta-analysis study showed a positive correlation between blood IGF-1 levels and cognitive function in aged people (Arwert et al., 2005). Thus it is possible that low levels of circulating IGF-1 is one of the underlying causes of cognitive dysfunction after TBI. Supporting this notion, low serum IGF-1 positively correlated with cognitive impairment in TBI survivors tested a year after their injury (Popovic et al., 2004).

Although limited in number, animal studies are in agreement with the majority of clinical reports that show reduced serum IGF-1 levels in TBI survivors. Serum IGF-1 levels were decreased at 1 week and 1 month after repeated TBI in adolescent rats (Greco et al., 2013). Although single mild TBI did not cause any pituitary dysfunction, repeated TBI induced vascular damage and disrupted the GH/IGF-1 axis (Greco et al., 2013). After weight drop injury in rat pups, serum IGF-1 levels were found to be decreased at 7 days and 3 weeks postinjury (Ozdemir et al., 2012). This study also analyzed cognitive function using a Morris water maze paradigm. Serum IGF-1 was positively correlated with the time spent in the target quadrant (better cognition) and negatively correlated with the time spent on the opposite quadrant (impaired cognition), supporting the role of circulating IGF-1 in mediating cognitive function after trauma. The study also reported a strong negative correlation between serum IGF-1 levels and the number of apoptotic cells in various brain regions, including the hippocampal CA-1 area. Studies in experimental models allows researchers to examine pathophysiological events in the brain in relation to reduced serum IGF-1 levels. Furthermore, serum IGF-1 levels can be altered by exogenous administration or genetic manipulations in animal models to understand therapeutic benefits of IGF-1 in TBI.

In addition to altering peripheral IGF-1 levels, TBI affects IGF-1 expression in the brain. After penetrating or weight drop brain injury in adult rats, IGF-1 messenger RNA (mRNA) levels increase in the cortex within days (Nordqvist et al., 1997; Sandberg Nordqvist et al., 1996; Walter et al., 1997). Consistent with findings in these adult CNS injury models, after a rat pediatric controlled cortical impact (CCI) injury, IGF-1 mRNA was increased from 1 to 14 days, peaking at 3 days postinjury (Schober et al., 2010). When different mRNA variants of IGF-1 were analyzed after CCI brain injury, IGF-1B peaked at 2 days postinjury, whereas IGF-1A peaked at 3 days (Schober et al., 2012). IGF-1B mRNA includes exon 5 and codes for the Eb peptide, whereas IGF-1A mRNA excludes exon 5 and codes for the Ea peptide (Figure 7.1). Muscle gene transfer of either IGF-1 Eb or IGF-1 Ea peptide enhanced motor neuron survival after facial nucleus avulsion injury. However, IGF-1 Eb isoform was more potent in its neuroprotective action compared with IGF-1 Ea peptide (Aperghis et al., 2004). Although TBI differentially upregulated the IGF-1 isoforms, the significance of this finding is still not known. IGF-1 Eb was upregulated after mechanical injury (Cheema et al., 2005), and thus early upregulation in IGF-1 Eb may be in response to mechanical, primary injury. Cortical increases in IGF-1 mRNA after trauma were found to be completely blocked by the NMDA inhibitor MK-801 (Nordqvist et al., 1997), indicating a role of glutamate receptor activation in mediating the posttraumatic response of IGF-1.

IGF-1 protein expression during the acute phase of injury (1 to 7 days postlesion) was increased surrounding the wound area after a penetrating brain injury (Walter et al., 1997). This increase in IGF-1 protein was found to be localized to neurons, astrocytes, and endothelial cells neighboring the injury epicenter. A transient increase in cortical IGF-1 levels was measured by enzyme-linked immunosorbent assay at 1 hour after CCI brain injury in adult mice (Figure 7.3) (Madathil et al., 2010). However, IGF-1 immunostaining revealed a limited increase in IGF-1 staining, confined to contused cortex and periphery, at 1 to 48 hours postinjury, which was mainly localized to neurons (Figure 7.4). A marked increase in IGF-1 expression was noted in the subcortical white matter. Both IGF-1 mRNA and protein expression increase acutely after trauma. Although increased IGF-1 expression may be part of the brain’s neuroprotective efforts, it appears to be insufficient in providing protection after TBI.

FIGURE 7.3. Quantification of IGF-1 levels after traumatic brain injury.


Quantification of IGF-1 levels after traumatic brain injury. Ipsilateral cortical samples were collected at different time points (1 to 72 hours) from mice that received a 0.5 mm (moderate) CCI brain injury. IGF-1 levels were measured using mouse-specific (more...)

FIGURE 7.4. IGF-1 is expressed in both neurons and astrocytes after brain injury.


IGF-1 is expressed in both neurons and astrocytes after brain injury. IGF-1 expression was increased in the cortical penumbra 24 to 48 hours after CCI brain injury in mice. Immunofluorescence staining showed colocalization of IGF-1 (red) and NeuN (green) (more...)

7.2.3. Changes in IGF-1R and IGFBP Expression after TBI

Upon IGF-1 binding, IGF-1R is autophosphorylated and activates downstream signaling. Thus changes in IGF-1R expression can influence the effectiveness of IGF-1 in regulating processes including cell survival, proliferation, and differentiation. After TBI in pediatric rodents, hippocampal IGF-1R mRNA levels decreased at 1 and 2 days postinjury and later showed a transient increase at 3 days, whereas IGF-1 message levels were higher from 1 to 14 days (Schober et al., 2010). It is possible that low IGF-1R synthesis at early time points can limit the potency of IGF-1. Alternatively, increased IGF-1 production could be a response to low IGF-1R levels to compensate for reduced signaling. Around 1 week after penetrating injury, IGF-1R peptide expression was increased in the neurons, astrocytes, and blood vessels bordering the lesion (Walter et al., 1997). Although no change in IGF-1R expression was observed using Western blot over 1 hour to 3 days after TBI in mice, immunostaining revealed increased vascular expression of IGF-1R in areas neighboring the contusion (Madathil et al., 2010). Proliferating endothelial cells are known to upregulate IGF-1R expression (Chisalita and Arnqvist, 2004) and thus increased vascular expression of IGF-1R after TBI may point to an active angiogenic response after trauma. The functional significance of changes in IGF-1R expression after TBI is not yet known; however, the characterization of IGF-1 and IGF-1R responses will help to design therapeutic interventions involving IGF-1 administration.

Biological effects of IGF-1 are modulated by IGFBPs, expressed in a variety of tissues including brain. mRNA and protein expression of all of the six IGFBPs were increased locally in neurons, astrocytes, and endothelial cells bordering an incisional wound by 5 to 7 days after injury (Walter et al., 1997). After penetrating brain injury, IGFBP-2 and IGFBP-4 mRNA expression was increased in neurons surrounding the cortical lesion (Sandberg Nordqvist et al., 1996). Similar to the IGF-1 response after penetrating brain injury, trauma-induced IGFBP upregulation was also blocked by treatment with the NMDA receptor antagonist MK-801, indicating a role for glutamate receptor activation in IGFBP synthesis after trauma (Nordqvist et al., 1997). The physiological significance of increased IGFBP expression after injury is still unclear. Local increases in IGFBPs after injury may help to maintain IGF-1 levels around the lesion site by protecting it from degradation. Increased IGFBP in endothelial cells after injury could be an adaptive response to bind IGF-1 and facilitate increased transport into the diseased parenchyma from circulation. However, IGFBP-1–overexpressing mice showed decreased gliogenesis after a knife lesion, indicating an inhibitory action on IGF-1’s proliferative effects (Ni et al., 1997).

In the CNS, cellular responses initiated by IGF-1 binding to its receptor are mainly mediated by the PI3-kinase/Akt pathway (Brywe et al., 2005; Sun and D’Ercole, 2006; Ye et al., 2010; Zheng et al., 2000). Akt phosphorylation was increased in cortical samples collected acutely (within 24 hours after the injury) from brain-injured patients (Zhang et al., 2006), suggesting the activation of the PI3K/Akt survival pathway. In animal models of CNS injuries, a transient increase in Akt activation has been observed (Janelidze et al., 2001; Madathil et al., 2010; Namura et al., 2000; Noshita et al., 2002; Yano et al., 2001; Zhang et al., 2006), which was associated with increased neuronal survival after TBI in rodents (Noshita et al., 2002). Akt activation was accompanied by phosphorylation of downstream substrates BAD and GSK3b after TBI in mice (Noshita et al., 2002). Although these studies demonstrate activation of the PI3K/Akt pathway after TBI, they do not confirm the involvement of IGF-1. However, increased Akt phosphorylation subsequent to IGF-1 upregulation suggests a role for IGF-1 in initiating PI3K/Akt pathways after TBI (Madathil et al., 2010).


7.3.1. Overview

Many reviews are available that summarize the physiological actions of IGF-1 in the CNS (Aber et al., 2006; McMorris et al., 1993; Ye and D’Ercole, 2006). Among the variety of functions regulated by IGF-1, metabolic functions, cell proliferation, survival effects, myelination, and neurite outgrowth are significant in the context of TBI. Although brain injury activates intrinsic neuronal survival and regenerative mechanisms, several vital physiological processes are affected adversely ending in neural tissue loss and behavior complications. Changes in the IGF-1/IGF-1R axis after TBI may affect multiple physiological events as IGF-1 is known to regulate several of these mechanisms. Although increased expression of IGF-1 and its signaling molecules may promote neuronal protection and recovery, low serum IGF-1 or IGF-1R expression after TBI may confound pathology and adversely affect repair mechanisms. Next we discuss major biological functions of IGF-1 in the CNS and how they are important in the setting of brain injury.

7.3.2. Brain Glucose Utilization

Glucose is the brain’s primary energy source. Low glucose levels are reported to cause intellectual deficits in diabetic children (Rovet and Ehrlich, 1999), pointing to the importance of glucose in mediating cognitive functions. Glucose utilization is reduced after injury in various animal models of TBI (Hayes et al., 1988; Robertson et al., 2013; Scafidi et al., 2009; Xing et al., 2009; Yoshino et al., 1991) and postinjury administration of glucose provides significant neuroprotection in the cortex and hippocampus (Moro et al., 2013). Neuronal IGF-1, which is more abundant than insulin in the brain, has anabolic functions similar to insulin. Glucose utilization is markedly reduced in the brains of IGF-1 KO mice indicating its insulin-like anabolic functions (Cheng et al., 2000). In a neuronal cell line, IGF-1 enhanced glucose transport and protected cells from low glucose levels (Russo et al., 2004). Ependymal cells with robust expression of glucose transporters and glucokinase serve as cerebral glucose-sensing cells. IGF-1 was more potent than insulin in stimulating glucose uptake in ependymal cells, possibly through regulation of GLUT1 transporters (Verleysdonk et al., 2004), pointing to the predominant role of IGF-1 in regulating brain glucose uptake. IGF-1–mediated Akt activation may play a role in glucose utilization. Translocation of glucose transporters to the plasma membrane is increased after Akt activation. Therefore, one of the mechanisms behind IGF-1’s neuroprotective potential may be enhanced glucose uptake in neurons exposed to trauma-induced hypoglycemia. However, to our knowledge, no study has yet confirmed this possibility.

7.3.3. Neuroprotection

Exogenous IGF-1 promotes neuronal survival in both in vitro and in vivo conditions. In a number of cell types including neurons, IGF-1 inhibits apoptosis induced by various stimuli such as hypoxia and excitotoxicity (Chung et al., 2007; Leinninger et al., 2004b; Lu et al., 2008; Lunn et al., 2010; Stohr et al., 2011; Subramaniam et al., 2005; Yang et al., 2013). Many of these studies also report that the cell survival effects of IGF-1 are mediated through PI3K/Akt or MAPK/Erk pathways (Figure 7.2) (Feldman et al., 1997; Parrizas et al., 1997; Russell et al., 1998; Zheng et al., 2000). Although IGF-1 administration reduces neuronal loss in a variety of in vivo CNS injury and neurodegenerative disease models (Bluthe et al., 2005; Jablonka et al., 2011; Kim et al., 2012; Miltiadous et al., 2010, 2011; Quesada et al., 2008; Saenger et al., 2012; Shavali et al., 2003; Traub et al., 2009), relatively few studies have addressed neuroprotective efficacy after TBI. IGF-1, when administered intracerebrally after a penetrating type of brain injury, reduced Hsp70 expression and cell death (Kazanis et al., 2004). IGF-1 overexpression in a transgenic mouse model was effective in reducing acute (3 days postinjury) hippocampal neurodegeneration and promoting neuronal survival 10 days after TBI (Madathil et al., 2013). Moreover, when IGF-1 was overexpressed, phosphorylation of Akt was increased consistent with a role for the PI3K/Akt pathway in mediating IGF-1’s neuroprotective effects after TBI. More studies are necessary to validate the neuroprotective efficacy of IGF-1 in various trauma models and also to understand how IGF-1 mediates neuroprotection after brain injury.

7.3.4. Myelination

Traumatic axonal injury in white matter tracts resulting from tensile forces or tissue shear strain is a common occurrence during TBI (Adams et al., 1989; Bramlett et al., 1997; Povlishock et al., 1999; Saatman et al., 2009). White matter damage characterized by features such as microbleeds, axonal transport disruption, axonal swelling, proteolysis, and demyelination persists years after TBI in humans (Johnson et al., 2013a, 2013b). After TBI, demyelination can occur by various mechanisms including mechanical damage, oligodendrocyte death, and myelin degradation by proteases. Myelin increases signal conduction velocity in axons and, when the myelin sheath is damaged or lost as in demyelinating disorders, it impairs neuronal signaling because of reduced speed of electrical signals. Demyelinated axons can be remyelinated by new myelin. However, when oligodendrocytes are lost, remyelination can fail, causing chronic demyelination. Oligodendrocyte loss and subsequent hypomyelination were reported in animal models of TBI (Conti et al., 1998; Flygt et al., 2013; Lotocki et al., 2011). Degradation of structural proteins associated with the myelin sheath may contribute to demyelination or hypomyelination. Myelin basic protein, one of the most abundant myelin-associated proteins, was cleaved into smaller fragments within hours to days after TBI in patients (Su et al., 2012) and experimental animals (Liu et al., 2006), an event that may initiate posttraumatic demyelination. Because there is limited remyelination after TBI, demyelination can be progressive and last months to years (Bramlett and Dietrich, 2002), and may contribute to cognitive dysfunction observed after TBI (Kinnunen et al., 2011; Kraus et al., 2007).

IGF-1 promotes oligodendrocyte proliferation, survival, and differentiation and stimulates myelin synthesis (Cui et al., 2012; D’Ercole et al., 2002; DePaula et al., 2014; McMorris et al., 1993; Palacios et al., 2005; Stangel and Hartung, 2002). Although IGF-1 deficiency in mice induces hypomyelination, constitutive IGF-1 overexpression increases oligodendrocyte numbers, myelin synthesis, and expression of myelin-related genes (Beck et al., 1995; Carson et al., 1993; Mason et al., 2000; Ye et al., 1995, 2002). Furthermore, IGF-1 administration reduces hypomyelination in experimentally induced autoimmune encephalomyelitis (Yao et al., 1996) and in animal models of multiple sclerosis (Chesik et al., 2008). Collectively, these reports suggest the strong influence of IGF-1 in regulating myelin synthesis in the CNS and highlight its therapeutic benefits in demyelinating disorders. Therefore, strategies such as IGF-1 therapy that limit myelin loss either by preventing its degradation or by promoting remyelination by reducing oligodendrocyte loss after TBI carry immense therapeutic potential.

7.3.5. Neurogenesis

The adult CNS is capable of generating new neurons in specific brain regions called neurogenic niches. The hippocampal subgranular zone and the forebrain subventricular zone (SVZ) are the major neurogenic niches in the adult mammalian brain. Brain injury is known to stimulate neurogenesis in both these regions, purportedly to replace lost neurons (Blaiss et al., 2011; Dash et al., 2001, Emery et al., 2005; Kernie et al., 2001; Kernie and Parent, 2009; Rola et al., 2006). Neurons born after injury contribute to posttraumatic functional recovery and tissue recovery (Blaiss et al., 2011; Emery et al., 2005; Kernie and Parent, 2009). Thus, strategies that promote this endogenous regenerative potential of the brain carry significance in TBI therapy. Although IGF-1’s mitogenic potential and its ability to promote maturation and differentiation of neural precursors are well described in the context of the developing brain, its influence on adult mammalian neurogenesis is not completely understood (Aberg et al., 2006; Anderson et al., 2002). IGF-1 administration stimulates cell proliferation and neurogenesis in adult and aged rats (Aberg, 2010; Annenkov, 2009; Koltai et al., 2011; Perez-Martin et al., 2010). In mice with conditional IGF-1 overexpression, modest brain overgrowth (approximately 10% more than wild-type littermates) was observed even when IGF-1 overexpressed only after the first 4 weeks of postnatal development (Ye et al., 2004). Together these studies suggest that IGF-1 enhances neurogenesis and cell proliferation in the uninjured adult brain.

Exogenous IGF-1 administration has also been shown to promote neurogenesis in animal models of CNS injury. IGF-1 incorporated microspheres increased numbers of new neurons migrating from the SVZ toward the injured striatum in a mouse model of stroke (Nakaguchi et al., 2012). Intranasal administration of IGF-1 after hypoxic-ischemic injury increased immature neuron number in neonatal rats (Lin et al., 2009). Postischemic viral delivery of IGF-1 effectively promoted neurogenesis in the SVZ and subcortical white matter (Zhu et al., 2008, 2009). These studies point to neurogenic effects of IGF-1 in the injured adult brain. The contribution of IGF-1 in stimulating posttraumatic neurogenesis is still not known. Recent work in our laboratory using IGF-1 overexpressing mice demonstrates that IGF-1 enhances the density of immature neurons in the injured hippocampus at 10 days after cortical impact TBI without significantly increasing cell proliferation (Carlson et al., 2014). It is possible that IGF-1 promoted immature neuronal survival or increased neuronal differentiation in the hippocampal subgranular zone area or that both these effects contributed to the IGF-1–mediated increase in newborn neuron density. Additional research needs to be done to address these possibilities and to further understand IGF-1’s neurogenic potential, including long-term survival and functional integration of newborn neurons into the existing circuitry.

7.3.6. Neurite Outgrowth

Neurite injury and degeneration, which includes both dendritic and axonal damage, are common neuropathological consequences of TBI (Bramlett et al., 1997; Gao et al., 2011; Stone et al., 2004). Reduced dendrite branching complexity and degenerating dendritic spines are observed within days after TBI (Campbell et al., 2012a, 2012b; Gao et al., 2011; Winston et al., 2013). Axonal damage including cytoskeletal damage, transport impairment, and swelling and beading of axons starts acutely and continues for years after TBI (Johnson et al., 2013b; Saatman et al., 2009). Neurites are important in forming functional synapses that mediate neuronal signaling. Damaged dendrites and axons disrupt neuronal connectivity culminating in functional impairment (Gao et al., 2011; Kinnunen et al., 2011; Won et al., 2012). However, during the recovery phase, the brain also stimulates axonal and dendritic sprouting, and enhances functional synaptogenesis (Beck et al., 1993; Campbell et al., 2012b; Wieloch and Nikolich, 2006), a finding that may have implications for functional recovery, but also for complications such as the development of posttraumatic epilepsy.

IGF-1 is known to promote neurite extension in cultured cortical (Shiraishi et al., 2006), retinal (Dupraz et al., 2013), and peripheral (Jones et al., 2003; Kimpinski and Mearow, 2001) neurons. In rat cortical slices, IGF-1 treatment increased both apical and basal dendritic branching (Niblock et al., 2000), and enhanced dendritic arbor complexity to a greater degree than other trophic factors (Figure 7.5). Systemic IGF-1 administration after sciatic nerve crush promoted axon regeneration (Contreras et al., 1995). Brain-specific IGF-1 overexpression promoted a transient increase in hippocampal synaptic densities per neuron in mice (O’Kusky et al., 2000), whereas IGF-1 gene knock out resulted in reduced axonal diameter and peripheral nerve conduction velocities (Gao et al., 1999). Chronic subcutaneous infusion of recombinant IGF-1 to IGF-1–deficient mice restored motor and sensory nerve conduction velocities to normal. Intracerebroventricular infusion of IGF-1 increased dendritic arborization in doublecortin-positive immature neurons after excitotoxic lesion in the hippocampus (Liquitaya-Montiel et al., 2012), an observation whose functional consequence is yet to be explored. In conclusion, IGF-1 appears to be important in maintaining axonal and dendritic morphology, promoting growth of axons and dendrites, and improving synaptic function. Thus, IGF-1 may serve as an effective treatment option to promote neurite outgrowth and synaptogenesis after TBI. However, enhanced neurite outgrowth may not be always desirable after TBI. Aberrant mossy fiber sprouting and mTOR activation contributes to the development of posttraumatic epilepsy (Guo et al., 2013). More research is necessary to understand if the enhanced neurite growth after IGF-1 treatment is targeted appropriately.

FIGURE 7.5. Dendritic arbor after trophic factor treatment.


Dendritic arbor after trophic factor treatment. Brain slices prepared from rat pups (P10) were treated with IGF-1, BDNF, or neurotrophin-3 (NT-3) for 24 hours. Slices were fixed and neurons in slice culture were filled with biotin for visualization using (more...)

7.3.7. Angiogenesis

Angiogenesis in the adult brain occurs by sprouting of new blood vessels from existing ones. Sprouts are formed by endothelial cells proliferating in response to an angiogenic stimulus. Neovascularization in the adult brain usually occurs after certain stimuli such as exercise or brain injury. During the primary injury phase, blood vessels are damaged because of mechanical disruption. In the initial days after TBI, new vessels appear at the contusion periphery and then spread into damaged tissue by one week postinjury (Guo et al., 2009). Brain injury upregulates the expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR1, the major regulators of angiogenesis (Skold et al., 2005), at a time point that parallels the trauma-induced angiogenic response. Moreover, when VEGFR signaling was blocked after TBI, neuronal and glial degeneration was accelerated (Skold et al., 2006), suggesting a neuroprotective role for new blood vessels. Confirming this neuroprotective effect, VEGF administration after closed head injury reduces cortical tissue loss while also stimulating angiogenesis and neurogenesis (Thau-Zuchman et al., 2010). Enhanced vascular perfusion through newly formed blood vessels formation has been shown to improve functional outcome after stroke and TBI (Beck and Plate, 2009; Kreipke et al., 2007; Lu et al., 2004). Experimental studies over years clearly demonstrate the occurrence of angiogenesis after brain injury. New blood vessels formed in and around injured tissue are presumed to be important in restoring adequate perfusion that in turn accelerates recovery mechanisms. More research is needed to explain how postinjury angiogenesis influences outcomes after TBI.

IGF-1 is a well-known angiogenic factor for the developing and adult brain. In patients with genetic defects in IGF-1 signaling, retinal vessel morphology is altered indicating the importance of IGF-1 in the development of proper retinal vasculature (Hellstrom et al., 2002). IGF-1 enhances both human and mice endothelial cell proliferation in culture systems (Li et al., 2009). Age-related declines in serum IGF-1 and GH levels are associated with decreased microvascular density, and administration of GH increases serum IGF-1 levels and enhances cerebral microvascular density in aged rats (Sonntag et al., 1997). Although systemic IGF-1 administration in adult mice increased brain angiogenesis, IGF-1 antibody infusion inhibited new vessel formation (Lopez-Lopez et al., 2004). In an experimental stroke model, postischemic IGF-1 gene transfer enhanced angiogenesis, and improved blood flow (Zhu et al., 2008; Zhu et al., 2009). In summary, IGF-1 represents one of the important regulators of adult brain angiogenesis and may enhance new blood vessel formation after brain injury.


7.4.1. Overview

Brain injury stimulates the production of several neurotrophins including IGF-1 (Madathil et al., 2010; Schober et al., 2010). However, TBI appears to induce only transient increases in IGF-1 and its signaling molecules, which are probably not sufficient to provide neuroprotection or stimulate subacute repair or regenerative mechanisms. Therefore, exogenous administration of IGF-1 may supplement and extend the actions of endogenous IGF-1. Moreover, IGF-1 has proven to be effective in treating CNS injuries including stroke and spinal cord injury, which share many pathological mechanisms with TBI (Guan et al., 2003; Guan et al., 2001; Hollis et al., 2009; Hung et al., 2007). As described previously, IGF-1 is a pluripotent molecule with both neuroprotective and regenerative potential. Thus IGF-1 is armed with multiple functions and may intervene at various points, halting the progression of TBI pathology and promoting brain repair.

7.4.2. Preclinical Studies Using IGF-1

Few studies have evaluated the therapeutic efficacy of IGF-1 using experimental animal models of TBI. Subcutaneous continuous delivery of recombinant human (rh) IGF-1 to rats for a period of 2 weeks following lateral fluid percussion injury improved both motor and cognitive function (Saatman et al., 1997) (Figure 7.6). Functional improvement in response to IGF-1 has been observed in other TBI animal models as well. Systemic injection of IGF-1 at 24 and 48 hours after a mild closed head injury improved cognitive function in mice (Rubovitch et al., 2010). Brain-specific IGF-1 overexpression in mice attenuated both cognitive and motor impairment after contusion brain injury (Madathil et al., 2013). IGF-1 overexpression also reduced acute hippocampal neurodegeneration and enhanced neuronal survival at 10 days after CCI brain injury (Madathil et al., 2013), (Figure 7.7). Intracranial stereotaxic IGF-1 administration of three equal doses at 15, 45, and 75 minutes after penetrating brain injury increased expression of neurotrophic factors, reduced apoptotic cell death, improved the metabolic status of injured rats, and also improved their motor activity (Kazanis et al., 2003; Kazanis et al., 2004). Systemic IGF-1 administration after weight drop closed head injury resulted in the stimulation of transcription factor C/EBP homologous protein, suggesting the activation of endoplasmic reticulum regulated antiapototic mechanisms (Rubovitch et al., 2011). Although limited in number, these studies confirm that IGF-1 has neuroprotective effects and can improve functional outcome, consistent with animal studies in other CNS injury models (Fletcher et al., 2009; Franz et al., 2009; Schabitz et al., 2001; Yao et al., 1995; Zhu et al., 2008). More studies are necessary to understand the therapeutic window of IGF-1 administration, signaling mechanisms, and regenerative potential after TBI.

FIGURE 7.6. Systemic IGF-1 administration after brain injury improved cognitive function.


Systemic IGF-1 administration after brain injury improved cognitive function. IGF-1 was administered subcutaneously at 4 mg/kg/day for 2 weeks following fluid percussion injury in rats. On postinjury days 13 and 14, learning trials were conducted in a (more...)

FIGURE 7.7. IGF-1 overexpression promoted hippocampal neuronal survival after traumatic brain injury.


IGF-1 overexpression promoted hippocampal neuronal survival after traumatic brain injury. Both wild-type (WT) and IGF-1 overexpressing (IGF-1Tg) mice received a severe (1.0 mm) CCI brain injury. Representative hippocampal (HP) images are from Nissl stained (more...)

7.4.3. IGF-1–Derived Peptides and Mimics

Similar to IGF-1, its truncated product GPE is reported to have neuroprotective properties in in vitro and in vivo models of CNS injuries (Guan, 2011; Guan and Gluckman, 2009). However, GPE is reported to have an extremely short plasma half-life (less than 2 minutes) when compared with IGF-1 (10 to 30 minutes), necessitating continuous infusion (Batchelor et al., 2003; Guan, 2011; Guler et al., 1987). To increase the stability of GPE, NNZ-2566, a GPE analogue, was created that is resistant to enzyme degradation but retains the neuroprotective effects of GPE (Guan and Gluckman, 2009; Lu et al., 2009a, 2009b; Wei et al., 2009). Systemic NNZ-2566 administration after a penetrating ballistic-type brain injury attenuated injury-induced upregulation of inflammatory cytokines and improved motor function (Lu et al., 2009a; Wei et al., 2009). NNZ-2566 treatment after penetrating ballistic-type brain injury reduced proapoptotic signaling and increased the expression of transcription factor ATF3, a negative regulator of pro-inflammatory cytokines (Cartagena et al., 2013; Lu et al., 2009a). The findings that NNZ-2566 reduced inflammation and provided functional improvement while providing an increased plasma half-life makes this compound highly desirable for TBI treatment. However, NNZ-2566 does not activate IGF-1R and its downstream signaling like full-length IGF-1 (Guan and Gluckman, 2009). Thus NNZ-2566 may not possess all the pleiotropic properties of IGF-1. Comparative studies of NNZ-2566 and IGF-1 are necessary to determine the differential effects these compounds may have in TBI. To date, NNZ-2566 has been tested only in a blast injury model of TBI. More studies in multiple trauma models are clearly required to confirm the neuroprotective effects of GPE and its analogue.

7.4.4. IGF-1 Clinical Trials

Despite a shortage of preclinical studies, IGF-1 has been already tested alone and in combination with growth hormone in TBI patients. Starting acutely after injury and lasting for weeks postinjury, patients have low serum IGF-1 and negative caloric balance (Aimaretti et al., 2004; Berg et al., 2010; Clifton et al., 1984; Fruin et al., 1986; Gottardis et al., 1990; Hatton et al., 1997). Low serum IGF-1 is thought to contribute to inefficient use of protein after TBI. Therefore, supplementation with rhIGF-1 was hypothesized to improve metabolic status for TBI patients. An IGF-1 phase II safety and efficacy trial was conducted in moderate-to-severe TBI patients (Glasgow Coma Scale 4–10). Continuous administration of rhIGF-1 (0.01 mg/kg/hour) for 14 days by intravenous infusion maintained serum IGF-1 concentrations within physiological levels (150–400 ng/mL). However, despite continuous infusion, serum IGF-1 levels greater than 350 ng/mL were maintained for only around 7 days. IGF-1–treated patients gained weight and had higher nitrogen retention than placebo controls despite a low nitrogen intake in treated patients (Hatton et al., 1997). However, systemic IGF-1 administration in brain-injured patients lowered GH and IGFBP-3 concentrations, an effect reported in other IGF-1 clinical trials (Cioffi et al., 1994; Clemmons et al., 1992; Mauras et al., 1992; Turkalj et al., 1992). Because GH administration had been shown to increase levels of IGFBP-3 (Laursen et al., 1995), a subsequent clinical trial investigated the effects of administering IGF-1 in combination with GH in moderate-to-severe brain-injured patients (Rockich et al., 1999), with the goal of achieving higher sustained serum IGF-1 concentrations. IGF-1 (0.01 mg/kg/hour) and GH (0.05 mg/kg/hour) were administered intravenously for 14 days. Patients treated with IGF-1 and GH had significantly elevated IGFBP-3 concentrations compared with control patients (Rockich et al., 1999). Moreover, this study showed that a IGF-1/GH combination was effective in maintaining supraphysiological levels of IGF-1 (>1000 ng/mL) in circulation compared with the infusion of IGF-1 alone, where the plasma IGF-1 concentrations declined over time regardless of continuous IGF-1 administration. In a follow-up study using an identical administration regimen, TBI patients receiving combined IGF-1 and GH showed sustained improvement in nutritional and metabolic status (Hatton et al., 2006). In conclusion, IGF-1 clinical trials in TBI demonstrate that IGF-1 administration either alone or in combination with GH was safe to humans and successful in improving metabolic parameters in moderate-to-severe TBI patients.


TBI initiates a short-lived increase in IGF-1 expression in the brain coupled with a more persistent decrease in serum levels of IGF-1. Altered IGF-1 levels after TBI suggest a role for IGF-1 in modulating TBI pathophysiology. IGF-1 is a pleiotropic molecule that mediates many physiological functions in the developing and adult nervous system. Thus changes in IGF-1 and its signaling components may affect multiple cellular events, contributing to either neuroprotection or neurodegeneration. Administration of exogenous IGF-1 after experimental TBI promotes neuroprotection and improved functional outcomes. Although IGF-1 administration stimulates regenerative events including neurogenesis and angiogenesis in other CNS injury models, its brain repair potential after TBI is not yet known. Importantly, IGF-1 was well tolerated by patients in early-phase clinical trials for TBI and IGF-1–treated patients showed improved metabolic outcome compared to placebo-treated patients. Studies using GPE and GPE analogues open up a new area of investigation as its signaling mechanisms are different from IGF-1.

In conclusion, IGF-1 with its pleiotropic effects appears to be an ideal candidate for TBI therapy, although to move forward with IGF-1 or IGF-1–derived peptide clinical trials, more preclinical studies are absolutely essential. Research is required to delineate the mechanisms of IGF-1–mediated improvements after TBI. Studies are needed in various clinically relevant trauma models to see if IGF-1 is effective over different types of brain trauma. These studies may also help to determine therapeutic window and effective dosage for clinical trials.


Supported, in part, by National Institutes of Health grant R01 NS072302.


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