Endocrinology, doi:10.1210/en.2008-1020
Endocrinology Vol. 149, No. 12 5963-5971
Copyright © 2008 by The Endocrine Society
Insulin-Like Growth Factors in the Peripheral Nervous System
Kelli A. Sullivan,
Bhumsoo Kim and
Eva L. Feldman
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-2200
Address all correspondence and requests for reprints to: Eva L. Feldman, M.D., Ph.D., Department of Neurology, University of Michigan, 5017 BSRB, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200. E-mail: efeldman{at}umich.edu.
 |
Abstract
|
|---|
IGF-I and -II are potent neuronal mitogens and survival factors. The actions of IGF-I and -II are mediated via the type I IGF receptor (IGF-IR) and IGF binding proteins regulate the bioavailability of the IGFs. Cell viability correlates with IGF-IR expression and intact IGF-I/IGF-IR signaling pathways, including activation of MAPK/phosphatidylinositol-3 kinase. The expression of IGF-I and -II, IGF-IR, and IGF binding proteins are developmentally regulated in the central and peripheral nervous system. IGF-I therapy demonstrates mixed therapeutic results in the treatment of peripheral nerve injury, neuropathy, and motor neuron diseases such as amyotrophic lateral sclerosis. In this review we discuss the role of IGFs during peripheral nervous system development and the IGF signaling system as the potential therapeutic target for the treatment of nerve injury and motor neuron diseases.
|
Introduction
|
|---|
NEUROTROPHIC FACTORS are a family of growth factors that support and influence the growth and regenerative capacity of neurons (1, 2, 3). These substances are produced by a number of tissues during development and direct the formation of the brain and spinal cord and their connections to target organs such as muscle. IGF-I and -II, signaling through the type I IGF receptor (IGF-IR), exert potent effects on neuronal growth, survival, and process outgrowth (4, 5). This review describes the role of the IGFs with regard to their developmental and adult localization in the peripheral nervous system and their regulation by and potential role in peripheral nerve injury and diabetic sensory neuropathy and motor neuron disease, specifically amyotrophic lateral sclerosis (ALS).
|
Peripheral Nervous System Development
|
|---|
The appearance of IGF-I and -II, IGF-IR, and the IGF binding proteins (IGFBPs) is well documented during development of the central nervous system (6, 7, 8, 9, 10), but little is published concerning their appearance during the development of the peripheral nervous system. During embryonic rat development, IGF-I mRNA is expressed in neurons and enriched in the cervicothoracic spinal cord (11) and the epithelium of spinal cord ventral floor plate (12, 13). IGF-I and -II are expressed in nerve target zones, including the limb buds, but not within the developing peripheral nerves (14, 15). IGF-I and the IGF-IR are reported in neurons in the developing trigeminal ganglia and their axonal target zones in facial mesenchyme (16). IGF-II is preferentially expressed in the brain stem glia (11) and nonneural cells of the ventral floor plate (17). In the mouse, IGF-II is expressed in neural crest (18) and neural crest derivatives including cranial sensory, dorsal root and sympathetic ganglia, and the adrenal medulla (19).
In adults IGF-I immunoreactivity is detectable in the ventral horn, sympathetic and dorsal root ganglia in the adult rat, and axons and Schwann cells of the sciatic nerve (20, 21). During development, both motor and sensory neurons also respond to IGF-I and -II with increased neurite outgrowth (22, 23, 24, 25, 26). This is also true in the adult nervous system (27). Local injection of either IGF-I or -II increased levels of growth associated protein (GAP)-43 and sprouting of intramuscular nerve fibers (28).
|
Axonal Targeting
|
|---|
IGF-I has specific effects on axonal guidance in olfactory neurons. IGF-I and IGF-IR are expressed within the developing olfactory bulb at embryonic d 14.5 (26). In mice lacking IGF-IR, there is a loss of symmetry of lateral projections to the olfactory bulb (26). A less dramatic phenotype is observed in mice null for IGF-I; however, the combined deletion of IGF-I and IGF-II results in an even more severe phenotype, similar to that observed in the IGF-IR knockout mice (26). Primary cultures of olfactory neurons and cerebellar granule neuron demonstrate a clear chemoattractant property of IGF-I (26). In in vitro growth cone turning assays, both olfactory and cerebellar granule neuron growth cones display a significant turn toward a gradient of IGF-I (26). This effect is blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and is not due to a simple increase in axon extension because axon length is not different from buffer-treated neurons (26). Although it has not been directly tested, the expression of IGF-I in the epithelium of spinal cord ventral floor plate (12, 13, 17), an area important in guiding commissural axons (29), indicates that IGF-I may have a trophic or guidance effect for these axons.
Whereas IGF-IR is highly expressed in developing brain (6, 7, 8, 9, 10), many of the studies mentioned above fail to determine the localization of IGF-IR during peripheral nerve development. In vitro studies of IGF-I and -II clearly point to signaling via IGF-IR as the dominant mechanism of IGF actions in the nervous system (2, 24, 30, 31, 32, 33, 34, 35).
|
Neurite Outgrowth
|
|---|
The expression of IGF-I and -II in neural crest cells and nerve target zones indicates the importance of these factors in neuron migration, axonal targeting, and neurotrophic maintenance of those connections. Neurite outgrowth is an important aspect of neuronal development, especially for peripherally projecting motor and sensory neurons. IGF-I signaling via IGF-IR plays a role in this process.
In a cell culture model of neurite outgrowth, Leventhal et al. (36) reported IGF-I activation of IGF-IR resulted in phosphorylation and activation of focal adhesion kinase (FAK) and paxillin, two proteins involved in neurite extension. Activation of FAK and paxillin resulted in increased formation of lamellipodia in SH-SY5Y cells, a neuroblastoma (NBL) model of peripheral neurons. Treatment of SH-SY5Y cells with 
IR-3, an antibody that blocks binding of IGF-I to IGF-IR, prevents activation of FAK and paxillin and subsequent lamellipodia formation (30, 36). Further examination demonstrated that signaling through the MAPK/ERK pathway mediated the effects of IGF-I (2, 30). In addition to stimulating neurite extension, IGF-I induces motility in two types of NBL cells, the neuronal SH-SY5Y and Schwann cell-like SHEP cells (37). Pharmacological blocking of either the PI3K or MAPK pathways decreased the motility of these cell lines. The downstream signaling pathways linking IGF-I/IGF-IR to process extension and motility include activation of rac, LIM kinase, and cofilin (38). These proteins modulate actin dynamics critical to extending and maintaining neurites (38). Whereas this work was performed in NBL cells rather than primary neurons, it is highly correlative of descriptions of the effects of IGF-I on primary neurons and the observed effects of IGF on neurite extension in vivo.
Chick dorsal root ganglia neurons grown in 2% fetal calf serum survive and extend neurites in response to proinsulin and insulin but exhibit an even more robust response to somatomedin multiplication-stimulating activity, also called IGF-I (22): 25 times more insulin was required to elicit neurite outgrowth compared with IGF-I. Neurite outgrowth is stimulated by both IGF-I and -II in neurons of the enteric plexus (23). Kimpinski and Mearow (24) demonstrated a clear effect of IGF-I on neurite outgrowth cultured adult rat dorsal root ganglia. IGF-I was compared with epidermal growth factor, fibroblast growth factor, and nerve growth factor (NGF). IGF-I had a similar effect on neurite outgrowth as NGF. The effects of IGF-I were blocked by inhibiting the PI3K pathway with LY294002 as well as the MAPK kinase kinase pathway with PD98059 (24). IGF-I promotes axon extension in corticospinal motor neurons (25) and vestibulospinal neurons (39). This effect was independent of the ability of IGF-I to promote the survival of these cells. This effect was blocked by prevention of IGF-I binding to IGF-IR and treatment with inhibitors of PI3K and MAPK signaling. These data were confirmed in vivo by applying an anti-IGF-IR antibody to corticospinal motor neurons and observing a lack of axonal outgrowth (25).
Considering the high levels of IGF expression and the widespread distribution of the IGF-IR in the nervous system and the potent effects of IGF on neurite outgrowth and guidance, one would expect severe nervous system derangement when the function or availability of one of these proteins or its receptor are lacking during development. This is not the case. Knockout of IGF-I or IGF-II results in small mice with intact, seemingly normal nervous systems at birth (40, 41). Because both IGF-I and -II bind and act through IGF-IR, the knockout of either is compensated by the other. This was verified by Ye et al. (42), who reported an increase in IGF-II levels in IGF-I knockout mouse brain. IGF-I knockout does affect central nervous system myelination and neurons numbers in specific brain regions (42, 43). Deletion of IGF-IR, which results in no IGF signaling, is perinatally lethal. Under these conditions, the spinal cord ventral horn contains small, seemingly underdeveloped neurons (40, 41), but the peripheral nervous system appears intact.
|
Response to Injury
|
|---|
IGF expression correlates with process regrowth after peripheral nerve injury. In the sciatic nerve, IGF-I immunohistochemistry is detected in axons and Schwann cells and after nerve crush accumulates in damaged axons within 2 h of injury. Colchicine treatment blocks accumulation proximal to the lesion (21 , indicating that IGF-I is anterogradely transported from neurons within the spinal cord and ganglia (sympathetic and dorsal root). Neurotransmitter colocalization was not examined in these studies; therefore, the exact neuronal populations responding to the injury were not identified. IGF-I also accumulated in the distal stump but to a lesser degree (21). The source of IGF in the distal stump is most likely Schwann cells. IGF-I immunohistochemistry peaks at 2 wk after transection in rat sciatic nerve (44). The expression is mainly localized within Schwann cells (44, 45). IGF-I is localized in Schwann cells for up to 2 wk after transection in the proximal nerve stump (44). IGF-I is lower but remains elevated compared with noninjured nerves at 4 wk after injury (46, 47). Vibration injury elicits a similar response. IGF-I is up-regulated in Schwann cells of peripheral nerves including plantar tibial and sciatic; the more distal the nerve, the more damage and the more IGF-I is detected in the Schwann cells. Levels returned to normal after 10 d (48). IGF-IR is also up-regulated in Schwann cells after transection (45). It is not clear from these studies what aspect of the injury induces IGF-I, but these factors could include local signaling from damaged Schwann cells, disruption of normal retrograde flow of target derived neurotrophic factors, or disruption of the blood-nerve barrier and subsequent invasion by mast cells and macrophages.
To determine the source of IGF protein, experiments by Glazner et al. (49) detected significant elevations of IGF-I and -II mRNA distal to the site of a nerve crush injury. This expression was affected by the ability of the nerve to regenerate. When regeneration was prevented by nerve transection, IGF-I and -II mRNA level remained elevated 20 d. These 20-d levels were comparable with the peak expression after crush injury at approximately 6 d after injury (49). Changes were also detected in denervated muscles; IGF-II was up-regulated in muscle. This regulation was delayed from that observed in nerve, which peaked at 6 d; muscle expression peaked at 20 d after crush (49). Whereas both IGF-I and -II were up-regulated in crushed nerve and muscle compared with uninjured tissues, IGF-I was preferentially increased in the nerve and IGF-II in muscle (49, 50).
|
Induction of Regeneration
|
|---|
The accumulation of IGF-I after peripheral nerve damage could be the result of disrupted axonal transport or a local therapeutic response. The relevance of post injury up-regulation of IGF has been addressed in multiple studies. Addition of IGF-I increases the length of regenerating axons (47). Transected sciatic nerves were placed in a Y-shaped chamber, and either IGF-I or control media were placed in either arm of the Y. The IGF-I-treated side had a significant effect on axonal length; however, axons grew into both arms. These data differ from the directional effects of IGF-I on olfactory and cerebellar granule neurons reported by Scolnick et al. (26) and may indicate that IGF-I may not be chemotactic for regenerating axons from mature neurons (47).
Kanje et al. (51) reported that IGF-I significantly increased axonal regeneration by 49% in a rat sciatic nerve crush/transection model. This effect was unique to IGF-I because NGF treatment had no effect. The in vivo mechanisms of IGF action are assumed similar to those activated in primary neuronal cultures. Studies applying pathway-specific inhibitors are not available; however, antibodies to IGF-I but not NGF or insulin completely blocked the ability of IGF-I to promote axonal regrowth (51, 52). Further work by this group examined the effects of a preconditioning transection that was performed before nerve crush (53). Under these conditions, regeneration was more robust than crush alone. This augmented regeneration is blocked by inhibitors of protein or RNA synthesis or retrograde axonal transport (53). Perfusion of IGF-I is able to overcome the effects of cycloheximide (protein synthesis inhibitor), indicating that locally produced IGF-I is retrogradely transported to the cell body in which it exerts its positive effects (53).
After their observation that IGF-I and-II are up-regulated after side-to-side neurorrhaphy (54), the laboratory of Terzis and colleagues investigated treatment of nerve injury with IGF. IGF-II treatment of transection followed by a side-to-side nerve graft in the rat brachial plexus demonstrated increased axon counts and myelin thickness and increased muscle innervation and function (55). Both 100 and 50 µg/ml were effective in promoting axonal regeneration into an end-to-side nerve repair in this model (56). IGF-I treatment increases the number of innervated motor endplates in another nerve grafting model using the orbicularis oculi muscle and a cross-facial nerve graft (57). Introduction of a nonviral vector containing human IGF-I into paralyzed rat larynx increased the number of innervated motor endplates and prevented denervation-related muscle atrophy (58, 59) and increased the number of regenerating axons in the pudendal nerve (60). These studies indicated a clear positive effect of IGF-I and IGF-II treatment on axonal outgrowth and reinnervation of motor endplates after nerve injury.
Circulating IGF-I is under the control of GH. An early study examined the effects of nerve regeneration in hypophysectomized (hypox) rats, i.e. rats with no pituitary and no GH. Regeneration was blunted after nerve crush in the hypox rats and restored in rats treated with exogenous GH (61). IGF-I was low in the hypox rats and rose in the GH-replaced animals; however, there was no correlation between the levels of circulating IGF-I and the rate of regeneration (61). This supports the idea that local up-regulation of IGF is important for its neurite inducing function. In a study of systemically administered IGF-I, no functional recovery was detected 14 d after nerve transection (62). These investigators did not examine the repaired nerve or the muscle; failure of IGF-I to initiate neuromuscular recovery was based solely on muscle function and weight (62).
|
Neuropathy
|
|---|
Motor and sensory conduction velocities are significantly slowed in mice with reduced or absent IGF-I (63). These mice have a normal number of myelinated fibers, but whole fiber size is reduced (63). Replacement by exogenous IGF-I restores normal conduction velocities (63); therefore, the role of IGF-I in peripheral neuropathy has been investigated. Diabetic neuropathy is the most characterized with regard to the IGF system. In addition to elevated blood glucose and decreased circulating insulin, circulating IGF-I levels are also diminished (64). Insulin and IGF-I bind to each other’s receptors and insulin has neurotrophic effects in nervous tissue (65). IGF-I and-II mRNAs are reduced in peripheral nerves (66, 67) and superior cervical ganglia (68) of diabetic rats, and this reduction is partially rescued by insulin treatment. Concordantly, IGF-IR is reduced in sensory neurons (69), lumbar spinal cord (70, 71), and superior cervical ganglia (68) of diabetic rats. Replacement of IGF prevents neuropathy in diabetic nerves in the presence of persistent hyperglycemia (67). Nerve regeneration is severely blunted in diabetic rats and restoration of insulin restores nerve regeneration as well as circulating IGF-I (64). In this particular study, it is not clear how insulin, IGF-I, and hyperglycemia are contributing to blunting and restoration of nerve regeneration (64). As described above, one of the earliest responses to nerve injury is the up-regulation of IGF-I at the injury site. In diabetic rats, up-regulation of IGF-I is delayed and IGF-IR does not increase (72). Direct application of IGF-I to the site of nerve crush in diabetic rats resulted in restoration of sensory regeneration (67) and a prevention of hyperalgesia (73).
The autonomic nervous system is also affected by diabetes. Sympathetic neurons in culture respond to IGF-I with increased neurite outgrowth. In a cell culture model of diabetic autonomic neuropathy, IGF-I treatment rescues primary sensory neurons from cell death and restores neurite outgrowth blunted by hyperglycemia (74). Subcutaneous administration of IGF-I completely reversed diabetic autonomic neuropathy in diabetic rats (75). In human patients, those with diabetic neuropathy have a decrease in circulating IGF-I and decreased expression of IGF-IR per red cell (76). In contrast, in sural nerves from diabetic patients with axonal neuropathy, IGF-I mRNA is increased compared with controls and further increased in patients taking insulin (77). The expression of IGF-IR paralleled that of IGF-I (77).
Although there have been no therapeutic trials of IGF-I in diabetic neuropathy, Windebank et al. (78) completed a trial of sc IGF-I twice-daily injections in the treatment of painful idiopathic small fiber neuropathy. The primary clinical end point, a measure of pain, showed no improvement. In parallel, there was no effect of IGF-I treatment on quantitative measures of sensory or autonomic function or on clinical examination (78).
|
Dorsal Root Ganglia (DRG) Neurons and Diabetes
|
|---|
IGF-I significantly enhances neurite outgrowth in adult DRG neurons in vitro (79), and these neurons express both insulin receptors and IGF-IR (80). In vivo, IGF-I and IGF-IR are predominantly localized in small DRG neurons. The expression of both IGF-I and IGF-IR are reduced after streptozotocin-induced diabetes (81). Sciatic nerve crush reduced the expression of IGF-I, but IGF-IR expression remained stable (81). Embryonic DRG cultures provide an in vitro model of diabetic neuropathy (82, 83, 84, 85) and are used to demonstrate the protective effects of IGF-I against hyperglycemia-induced programmed cell death (82, 86). In this model system, IGF-I blocks the activation of caspase-3 through a PI3K/Akt-dependent mechanism (86). IGF-I prevents mitochondrial changes associated with hyperglycemia by preventing the translocation of BCL2-like 11 (apoptosis facilitator) and Bcl-2-associated X protein to the mitochondria (87). NGF is required for in vitro neuronal survival. IGF-I protects DRG neurons from NGF withdrawal-induced death (82). As with other effects of IGF-I/IGF-IR signaling, this effect was blocked by treating cells with LY294002, a PI3K inhibitor (83). To date, these are the most detailed examinations of how IGF-I prevents neuronal death in an in vitro system.
|
Schwann Cell Biology
|
|---|
Peripheral nerves consist of the peripheral projections and connections of neurons within the spinal cord and dorsal root and sympathetic ganglia to their target tissues, muscle, skin, and viscera. Another essential cellular component of peripheral nerve is the Schwann cell. As noted above, Schwann cells are a source of IGF after nerve injury. IGFs are also important factors in Schwann cell biology. IGF-I is a potent mitogen for Schwann cells in culture but requires forskolin or dibutyryl cAMP for this effect (88, 89, 90). IGF-II is not effective even with forskolin. Schwann cells also express the IGF-IR and expression is increased by treatment with forskolin (88). In vivo, IGF-II is more potent than IGF-I in inducing tritiated thymidine incorporation into sciatic nerve segments (91). IGF-I, IGF-II, and insulin promote the expression of the Schwann cell marker Po in Schwann cell cultures treated with 0.4 µM forskolin (89, 90). IGF-I protects primary Schwann cells from cell death resulting from serum withdrawal (31, 32, 33, 92). This effect is mediated by PI3K (31, 32, 33) inhibition of caspase activation (32) and c-jun N-terminal kinase (33).
IGF-I and IGF-IR mRNA and protein are detected in Schwann cells throughout postnatal development (92). IGF-I treatment of Schwann cell/dorsal root ganglia cocultures increases de novo fatty acid synthesis as part of myelination (93). IGF-I activates ATP citrate ligase and fatty acid synthase via PI3K/Akt-dependent signaling (93). IGF-I signaling through the IGF-IR and PI3K enhances Schwann cell motility and process extension via activation of FAK and regulation of the actin cytoskeleton (94). Process extension is an important functional aspect of myelination, which, in addition to regulating fatty acid and protein synthesis, is promoted by IGF-I (89, 90, 93, 95). IGF-I promotes not only the expression of myelin proteins such as Po but also segmental myelination of dorsal root ganglia axons in culture, including the formation of nodes of Ranvier (95). Transmission electron microscopy reveals a lamellar structure indistinguishable from in vivo myelinated fibers (95).
|
Neuromuscular Junction
|
|---|
Motor neurons and skeletal muscle are codependent tissues, each relying on the other for trophic support and synaptic transmission/stimulation (96). IGF-I is synthesized by both motor neurons and skeletal muscle (96). IGF-I signaling is involved in neuromuscular junction formation as evidenced by the work of Caroni and Becker (97). As neuromuscular junctions are formed and become active, motor neurons naturally cease production of GAPs (97). This is highly correlated with a maturational decrease in IGF-I production by skeletal muscle. Indeed, IGF-I levels decrease as a result of normal aging with concomitant loss of motor endplates and decreased innervation of existing motor endplates (98). Sustained overexpression of IGF-I in skeletal muscle reverses these age-related changes (98). IGF-I overexpression also maintained neuromuscular junction complexity (98).
Disuse atrophy (hind limb isolation) decreases the expression of IGF-I in skeletal muscle (99, 100). This decrease in IGF-I is correlated with a compensatory up-regulation of IGF-IR in the spinal cord (99, 100). Injection of IGF-I into target skeletal muscle prevents down regulation of GAP expression by motor neurons (97). Similar results occur after injection of nonviral plasmids containing IGF-I mRNA. IGF-I protein was expressed for up to 28 d in injected muscle with no spillover into the general circulation. The biological activity of IGF-I was demonstrated by an up-regulation of GAP-43 within the sciatic nerve (101). Motor neuron expression of IGF-I also prevents loss of muscle force associated with neuromuscular aging (102). Tetanus toxin-linked IGF-I injected into muscle is retrogradely transported to spinal cord motor neurons (102). As a result, neuromuscular junctions were larger and more complex (102). This maintenance of complex innervation also prevents muscle fibers from becoming dependent on extracellular calcium to maintain contraction (102), another characteristic of muscle aging. As mentioned above, introduction of IGF-I gene expression in paralyzed larynx results in increased motor endplate innervation and prevention of muscle atrophy (59). IGF-I is effective in preventing decreased muscle fiber diameter, muscle weight fast twitch, and strength, all characteristics of permanent denervation (103).
The role of IGF-II was also investigated (104, 105). IGF-II is up-regulated in the gastrocnemius muscle after nerve crush and returned to normal after reinnervation (105). Cocultures of motor neurons and skeletal muscle reveal slightly different effects of the IGFs, both promoted differentiation of neurons and muscle but IGF-I effects were more pronounced in neurons and IGF-II effects more pronounced in muscle (104).
|
Motor Neurons
|
|---|
In addition to stimulating axonal outgrowth in motor neurons, IGF is neuroprotective under a number of experimental and disease conditions. IGF-I protects neonatal spinal cord motor neurons from programmed cell death due to axotomy (106, 107, 108) as well as increasing the number of neuromuscular junctions and maintaining normal muscle morphology (107). IGF-I is also effective in protecting noradrenergic neurons from chemical [6-hydroxydopamine (6-OHDA)] injury (109). In very young rats, e.g. newborns, systemic IGF-I prevents motor neuron death due to axotomy (108). This is in contrast to the fact that IGF-I or -II must be applied locally to have a positive effect on nerve regeneration in the adult (51, 62). This may be due to the IGFs acting on Schwann cells in the case of nerve injury. Additionally, the blood-brain barrier may be incomplete, allowing increased transport of the IGFs into the brain and spinal cord of young animals (106, 107); however, IGF-I is effective after 6-OHDA treatment in adult rats (109).
IGF-I also affects spinal cord neurotransmitter systems. In the rat lumbar enlargement, IGF-I treatment increases the expression of tyrosine hydroxylase and subsequent norepinephrine release (110). In rats treated with 6-OHDA, IGF-I treatment spared more than 50% of noradrenergic neurons, their spinal cord projections, and the hindlimb withdrawal reflex dependent on this motor pathway (109).
IGF-I protects mature spinal cord motor neurons from multiple insults including glutamate (111, 112, 113), ischemia (114, 115), and spinal cord injury (116). The signaling pathways activated by IGF-I that lead to cell survival are reviewed by Vincent and colleagues (34, 35) and include activation of the PI3K/Akt pathway, inhibition of caspase activation and increased activity of antiapoptotic proteins such as Bcl2 and BclX.
|
Motor Neuron Disease and ALS
|
|---|
Due to its positive effects on both muscle and motor neurons, the potential of IGF-I to ameliorate the neuronal loss and muscle weakness of ALS has been extensively examined (117). In human patients with or without motor neuron disease, IGF-I immunoreactivity is detected in motor neurons, astrocytes, Schwann cells, and skeletal muscle (118). IGF-II immunoreactivity was also detected in these same cell types but to a lesser degree than IGF-I (118). Dore et al. (119) report increased binding of IGF-I and -II in the spinal cords of ALS patients, indicating an increase in IGF-IR expression. Western blotting of postmortem human spinal cervical spinal cord revealed no change in total IGF-I levels between ALS and healthy patients; however, free IGF-I was reduced by 53% in ALS patients (120). Free IGF-I is IGF-I available to bind to IGF-IR and not complexed with IGFBPs. In this study, IGFBP-2 and -5 were significantly up-regulated, indicating a potential shift in IGF-I bioavailability (120).
ALS is classified as sporadic with no specific etiology or familial most often due to mutations of superoxide dismutase 1 (SOD1). Expression of a human mutation, G93A, in mice is the most common rodent model of ALS and used to examine the potential positive effects of IGF-I. IGF-I immunoreactivity is detected in the spinal cord of G93A SOD1 mice and is increased in astrocytes compared with control animals (121). Retrograde delivery of IGF-I delays the onset of symptoms and increases survival in the G93A SOD1 mouse by increasing the survival of motor neurons (122). Intrathecal administration of IGF-I is also effective in delaying symptoms and increasing survival (123, 124).
Models of sporadic ALS include treatment of motor neurons with proxidants or excess glutamate. As mentioned above, IGF-I protects motor neurons from glutamate-induced death (111, 112, 113). Vincent et al. (113) demonstrated expression and activation of IGF-IR in motor neuron cultures. IGF-I binding to IGF-IR stimulates the association of insulin receptor substrate (IRS)-1 and Shc with the receptor followed by phosphorylation/activation of PI3K and MAPK. MAPK was maximally phosphorylated at 5 min after stimulation, whereas PI3K/Akt peaked at 1 h. Blocking either pathway alone did not prevent IGF-I neuroprotection, but blocking both pathways simultaneously resulted in no IGF-I rescue (113). Transfection of transformed neurons with an adenoviral vector containing IGF-I provides protection against glutamate toxicity in not only the transfected cells but also nearby untransfected cells. This indicates that IGF-I may act as both a paracrine and autocrine neuroprotective factor in this disease (125).
Other viral vectors expressing IGF-I also provide neuroprotection to motor neurons in vitro and include rabies G protein-pseudotyped lentivirus (126) and adeno-associated virus (127). Intrathecally administered IGF-I is beneficial in ameliorating ALS in the G93A SOD1 mouse as evidenced by delayed onset of symptoms, sparing of motor neurons, and increased animal survival (123). The signaling mechanisms involved parallel those described in vitro and include increased phospho-Akt, phospho-ERK, and Bcl-2 (123). Another potential therapeutic target for IGF-I/ALS gene therapy is skeletal muscle. As mentioned above, IGF-I secreted by muscle is retrogradely transported to the spinal cord. A muscle-specific isoform of IGF-I was introduced into G93A SOD1 mice. This isoform is normally expressed after muscle damage and does not enter general circulation. Expression of muscle-specific IGF-I delayed disease onset and increased life span in these G93A SOD1 IGF-I transgenic mice (128). Another study of IGF-I overexpression yielded very different results. S1/S2 mice overexpress human IGF-I exclusively in skeletal muscle (129, 130, 131), whereas IGF-2/1 mice overexpress human IGF-I in the central nervous system (132). Direct crossing these mice with SOD1G93A mice failed to delay disease onset or increase survival (133). It is possible that the difference in IGF-I isoforms affected the results of these studies.
|
IGF-I Therapy in ALS Patients
|
|---|
Clinical trials of IGF-I in human ALS patients have yielded mixed results. Lai et al. (134) enrolled 266 patients in a double-blind, placebo-controlled trial of IGF-I. More than half of the patients enrolled were able to complete the 9-month trial. A modest (26%) slowing of disease progression measured by a functional score was reported in the high-dose group (0.10 mg/kg·d), and a similar trend was reported for those receiving low dose (0.05 mg/kg·d) therapy (134). Patient survival was, however, not affected by either dose of IGF-I (134). A similar smaller study (183 patients) used the same dose, and delivery for IGF-I revealed no beneficial effects of IGF-I therapy (135).
As in animals studies of IGF-I therapy, the method of IGF-I delivery in patients is a major factor in determining its effects. IGFs are proteins and subject to enzymatic degradation and sc injection of IGF-I places it at a substantial distance from the therapeutic target, motor neurons. An alterative delivery system, intrathecal administration of IGF-I, was examined in nine patients (136). Both low (0.5 µg/kg) and high (3 µg/kg) doses infused every 2 wk for 40 wk (136). Even with more directed IGF-I administration, only a modest decrease in disease progression was detected (136). The Great Lakes ALS Consortium under the direction of the Mayo Clinic enrolled 330 patients in a double-blind placebo control of sc IGF-I and reported no therapeutic effect (www.alsa.org). In this trial, the primary end point was a composite strength score. IGF-I is well tolerated and no adverse events were reported in any of the clinical trials published to date (134, 135, 136). More clinical trials with targeted delivery of IGF-I to motor neurons are needed to clarify the efficacy of IGF-I therapy in the treatment of ALS (137).
|
Conclusion
|
|---|
The potent effects of IGFs on the survival, proliferation, and differentiation of neurons and glia makes them attractive candidates for the treatment of diseases involving neuronal death, axonal damage, and/or demyelination (113, 138) (Fig. 1
). Beneficial effects of IGF-I have been demonstrated in animal models of stroke, physical trauma to the brain, peripheral neuropathies, and demyelinating diseases (4, 5). The combined in vitro and in vivo data have led to the use of IGF-I in head injured patients (139), patients with ALS (134, 135, 136), and patients with peripheral small fiber neuropathy (78). The use of neurotrophic factors including IGF-I for the treatment of peripheral neuropathy and diseases of the central nervous system was extensively reviewed by Apfel and Kessler (140, 141) and Feldman and colleagues (142), respectively. Despite the positive results in animal models, these therapies have not translated into successful treatment for human patients (78, 137, 143). Lack of IGF-I efficacy is most often due to inadequate delivery of IGF-I. The IGFs are regulated by a family of IGFBPs (144, 145, 146) that protect them from enzymatic degradation in the circulation and sequester IGF in tissue compartments. The function of the IGFBPs is beyond the scope of this minireview but cannot be ignored when considering IGF therapy.
View larger version (32K):
[in this window]
[in a new window]
|
FIG. 1. IGFs in the peripheral nervous system. A, IGF-I, IGF-II, and IGF-IR play critical roles for the survival, proliferation, and differentiation of sensory and motor neurons as well as skeletal muscles and surrounding Schwann cells. B, Most of the physiological effects of IGFs are mediated by the type I IGF-IR. Upon ligand binding of the IGF-IR, autophosphorylation of its β-subunits occurs, resulting in binding of the major IGF-IR substrates, IRS-1, and IRS-2. Tyrosine phosphorylation of IRS proteins recruits and activates two major downstream signaling pathways of IGF-IR: MAPK pathway mainly for neuronal motility and neurite outgrowth and PI3K/Akt pathway responsible for neuron survival.
|
|
Data are also lacking in the area of in vivo signaling mechanisms. IGF signaling is well characterized in in vitro models including neuroblastoma cell lines and primary motor and sensory neurons. Less detailed information is available concerning these same intracellular pathways in nervous tissues (123). Microarray analysis detailing factors that affect the expression of the IGF system and those genes regulated by IGF signaling is another important area of research regarding the function of the IGF system in the peripheral nervous system.
|
Footnotes
|
|---|
This work was supported by the National Institutes of Health Grant UO1 DK076160, the Juvenile Diabetes Research Foundation Center for the Study of Complications in Diabetes, and the A. Alfred Taubman Medical Research Institute.
Disclosure Statement: The authors have nothing to disclose.
First Published Online August 21, 2008
Abbreviations: ALS, Amyotrophic lateral sclerosis; DRG, dorsal root ganglia; FAK, focal adhesion kinase; GAP, growth associated protein; hypox, hypophysectomized; IGFBP, IGF binding protein; IGF-IR, type I IGF receptor; IRS, insulin receptor substrate; NBL, neuroblastoma; NGF, nerve growth factor; 6-OHDA, 6-hydroxydopamine; PI3K, phosphatidylinositol 3-kinase; SOD1, superoxide dismutase 1.
Received July 9, 2008.
Accepted for publication August 11, 2008.
|
References
|
|---|
- Matthews CC, Odeh H, Feldman EL 1997 Insulin-like growth factor-I is an osmoprotectant in human neuroblastoma cells. Neuroscience 79:525–534[CrossRef][Medline]
- Kim B, Leventhal PS, Saltiel AR, Feldman EL 1997 Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires MAP kinase activation. J Biol Chem 272:21268–21273[Abstract/Free Full Text]
- Feldman EL, Sullivan KA, Kim B, Russell JW 1997 Insulin-like growth factors regulate neuronal differentiation and survival. Neurobiol Dis 4:201–214[CrossRef][Medline]
- Anlar B, Sullivan KA, Feldman EL 1999 Insulin-like growth factor-I and central nervous system development. Horm Metab Res 31:120–125[Medline]
- Leventhal PS, Russell JW, Feldman EL, Rosenfeld R, Roberts Jr CT 1999 IGFs and the nervous system. In: Contemporary endocrinology: the IGF system. Totowa, NJ: Humana Press; 425–455
- Sara VR, Hall K, Misaki M, Fryklund L, Christensen N, Wetterberg L 1983 Ontogenesis of somatomedin and insulin receptors in the human fetus. J Clin Invest 71:1084–1094[Medline]
- Lund PK, Moats-Staats BM, Hynes MA, Simmons JG, Jansen M, D'Ercole AJ, Van Wyk JJ 1986 Somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II mRNAs in rat fetal and adult tissues. J Biol Chem 261:14539–14544[Abstract/Free Full Text]
- Adamo M, Raizada MK, LeRoith D 1989 Insulin and insulin-like growth factor receptors in the nervous system. Mol Neurobiol 3:71–100[Medline]
- Werner H, Woloschak M, Adamo M, Shen-Orr Z, Roberts Jr CT, LeRoith D 1989 Developmental regulation of the rat insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA 86:7451–7455[Abstract/Free Full Text]
- Kar S, Chabot JG, Quirion R 1993 Quantitative autoradiographic localization of [125 I]insulin-like growth factor I, [125 I]insulin-like growth factor II, and [125 I]insulin receptor binding sites in developing and adult rat brain. J Comp Neurol 333:375–397[CrossRef][Medline]
- Rotwein P, Burgess SK, Milbrandt JD, Krause JE 1988 Differential expression of insulin-like growth factor genes in rat central nervous system. Proc Natl Acad Sci USA 85:265–269[Abstract/Free Full Text]
- Schuller A, van Neck J, Lindenbergh-Kortleve D, Groffen C, De Jong I, Zwarthoff E, Drop S 1993 Gene expression of the IGF binding proteins during post-implantation embryogenesis of the mouse; comparison with the expression of IGF-I and -II and their receptors in rodent and human. Adv Exp Med Biol 343:267–277[Medline]
- Santos A, Yusta B, Fernandez-Moreno MD, Blazquez E 1994 Expression of insulin-like growth factor-I (IGF-I) receptor gene in rat brain and liver during development and in regenerating adult rat liver. Mol Cell Endocrinol 101:85–93[CrossRef][Medline]
- Bondy CA, Werner H, Roberts Jr CT, LeRoith D 1990 Cellular pattern of insulin-like growth factor-I (IGF-I) and type I IGF receptor gene expression in early organogenesis: comparison with IGF-II gene expression. Mol Endocrinol 4:1386–1398[Abstract/Free Full Text]
- Streck RD, Wood TL, Hsu MS, Pintar JE 1992 Insulin-like growth factor I and II and insulin-like growth factor binding protein-2 RNAs are expressed in adjacent tissues within rat embryonic and fetal limbs. Dev Biol 151:586–596[CrossRef][Medline]
- Ayer-Le Lievre C, Ståhlbom PA, Sara VR 1991 Expression of IGF-I and -II mRNA in the brain and craniofacial region of the rat fetus. Development (Cambridge, England) 111:105–115
- Wood TL, Brown AL, Rechler MM, Pintar J 1990 The expression pattern of an insulin-like growth factor (IGF)-binding protein gene is distinct from IGF-II in the midgestational rat embryo. Mol Endocrinol 4:1257–1263[Abstract/Free Full Text]
- Lee JE, Pintar J, Efstratiadis A 1990 Pattern of the insulin-like growth factor II gene expression during early mouse embryogenesis. Development (Cambridge, England) 110:151–159
- Stylianopoulou F, Efstratiadis A, Herbert J, Pintar J 1988 Pattern of the insulin-like growth factor II gene expression during rat embryogenesis. Development 103:497–506[Abstract]
- Hansson HA, Nilsson A, Isgaard J, Billig H, Isaksson O, Skottner A, Andersson IK, Rozell B 1988 Immunohistochemical localization of insulin-like growth factor I in the adult rat. Histochemistry 89:403–410[CrossRef][Medline]
- Hansson HA, Rozell B, Skottner A 1987 Rapid axoplasmic transport of insulin-like growth factor I in the sciatic nerve of adult rats. Cell Tissue Res 247:241–247[Medline]
- Bothwell M 1982 Insulin and somatomedin MSA promote nerve growth factor-independent neurite formation by cultured chick dorsal root ganglionic sensory neurons. J Neurosci Res 8:225–231[CrossRef][Medline]
- Mulholland MW, Romanchuk G, Simeone DM, Flowe K 1992 Stimulation of myenteric plexus neurite outgrowth by insulin and IGF I and II. Life Sci 51:1789–1796[CrossRef][Medline]
- Kimpinski K, Mearow K 2001 Neurite growth promotion by nerve growth factor and insulin-like growth factor-1 in cultured adult sensory neurons: role of phosphoinositide 3-kinase and mitogen activated protein kinase. J Neurosci Res 63:486–499[CrossRef][Medline]
- Ozdinler PH, Macklis JD 2006 IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci 9:1371–1381[CrossRef][Medline]
- Scolnick JA, Cui K, Duggan CD, Xuan S, Yuan XB, Efstratiadis A, Ngai J 2008 Role of IGF signaling in olfactory sensory map formation and axon guidance. Neuron 57:847–857[Medline]
- Caroni P, Schneider C, Kiefer MC, Zapf J 1994 Role of muscle insulin-like growth factors in nerve sprouting: suppression of terminal sprouting in paralyzed muscle by IGF-binding protein 4. J Cell Biol 125:893–902[Abstract/Free Full Text]
- Caroni P, Grandes P 1990 Nerve sprouting in innervated adult skeletal muscle induced by exposure to elevated levels of insulin-like growth factors. J Cell Biol 110:1307–1317[Abstract/Free Full Text]
- Yamada T, Placzek M, Tanaka H, Dodd J, Jessell TM 1991 Control of cell pattern in the developing nervous system: polarizing activity of the floor plate and notochord. Cell 64:635–647[CrossRef][Medline]
- Leventhal PS, Feldman EL 1997 Insulin-like growth factors as regulators of cell motility: signaling mechanisms. Trends Endocrinol Metab 8:1–6[Medline]
- Campana WM, Darin SJ, O'Brien JS Phosphatidylinositol 3-kinase and Akt protein kinase mediate IGF-I- and prosaptide-induced survival in Schwann cells. J Neurosci Res 57:332–341
- Delaney CL, Cheng HL, Feldman EL 1999 Insulin-like growth factor-I prevents caspase mediated apoptosis in Schwann cells. J Neurobiol 41:540–548[CrossRef][Medline]
- Cheng HL, Steinway M, Xin X, Feldman EL 2001 Insulin-like growth factor-I and Bcl-X L inhibit c-jun N-terminal kinase activation and rescue Schwann cells from apoptosis. J Neurochem 76:935–943[CrossRef][Medline]
- Vincent AM, Feldman EL 2002 Control of cell survival by IGF signaling pathways. Growth Horm IGF Res 12:193–197[CrossRef][Medline]
- Vincent AM, Mobley BC, Kim B, Feldman EL 2002 IGF-I signaling mechanisms in a cell culture model of ALS. Growth Horm IGF Res 12:253
- Leventhal PS, Shelden EA, Kim B, Feldman EL 1997 Tyrosine phosphorylation of paxillin and focal adhesion kinase during insulin-like growth factor-I-stimulated lamellipodial advance. J Biol Chem 272:5214–5218[Abstract/Free Full Text]
- Meyer GE, Shelden E, Kim B, Feldman EL 2001 Insulin-like growth factor I stimulates motility in human neuroblastoma cells. Oncogene 20:7542–7550[CrossRef][Medline]
- Meyer G, Kim B, van Golen C, Feldman EL 2005 Cofilin activity during insulin-like growth factor I-stimulated neuroblastoma cell motility. Cell Mol Life Sci 62:461–470[CrossRef][Medline]
- Salie R, Steeves JD 2005 IGF-1 and BDNF promote chick bulbospinal neurite outgrowth in vitro. Int J Dev Neurosci 23:587–598[CrossRef][Medline]
- Baker J, Liu JP, Robertson EJ, Efstratiadis A 1993 Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75:73–82[CrossRef][Medline]
- Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A 1993 Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59–72[Medline]
- Ye P, Li L, Richards RG, DiAugustine RP, D'Ercole AJ 2002 Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci 22:6041–6051[Abstract/Free Full Text]
- Beck KD, Powell-Braxton L, Widmer HR, Valverde J, Hefti F 1995 Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 14:717–730[CrossRef][Medline]
- Zochodne DW, Cheng C 2000 Neurotrophins and other growth factors in the regenerative milieu of proximal nerve stump tips. J Anat 196(Pt 2):279–283
- Cheng HL, Randolph A, Yee D, Delafontaine P, Tennekoon G, Feldman EL 1996 Characterization of insulin-like growth factor-I (IGF-I), IGF-I receptor and binding proteins in transected nerves and cultured Schwann cells. J Neurochem 66:525–536[Medline]
- Hansson HA, Dahlin LB, Danielsen N, Fryklund L, Nachemson AK, Polleryd P, Rozell B, Skottner A, Stemme S, Lundborg G 1986 Evidence indicating trophic importance of IGF-I in regenerating peripheral nerves. Acta Physiol Scand 126:609–614[Medline]
- Nachemson AK, Lundborg G, Hansson HA 1990 Insulin-like growth factor I promotes nerve regeneration: an experimental study on rat sciatic nerve. Growth Factors 3:309–314[Medline]
- Hansson HA, Dahlin LB, Lowenadler B, Lundborg G, Paleus S, Skottner A 1988 Transient increase in insulin-like growth factor I immunoreactivity in rat peripheral nerves exposed to vibrations. Acta Physiol Scand 132:35–41[Medline]
- Glazner GW, Morrison AE, Ishii DN 1994 Elevated insulin-like growth factor (IGF) gene expression in sciatic nerves during IGF-supported nerve regeneration. Brain Res Mol Brain Res 25:265–272[Medline]
- Tam SL Gordon T 2003 Mechanisms controlling axonal sprouting at the neuromuscular junction. J Neurocytol 32:961–974[CrossRef][Medline]
- Kanje M, Skottner A, Sjoberg J, Lundborg G 1989 Insulin-like growth factor I (IGF-I) stimulates regeneration of the rat sciatic nerve. Brain Res 486:396–398[CrossRef][Medline]
- Streppel M, Azzolin N, Dohm S, Guntinas-Lichius O, Haas C, Grothe C, Wevers A, Neiss WF, Angelov DN 2002 Focal application of neutralizing antibodies to soluble neurotrophic factors reduces collateral axonal branching after peripheral nerve lesion. Eur J Neurosci 15:1327–1342[CrossRef][Medline]
- Kanje M, Skottner A, Lundborg G, Sjoberg J 1991 Does insulin-like growth factor I (IGF-1) trigger the cell body reaction in the rat sciatic nerve? Brain Res 563:285–287[CrossRef][Medline]
- Fortes WM, Noah EM, Liuzzi FJ, Terzis JK 1999 End-to-side neurorrhaphy: evaluation of axonal response and upregulation of IGF-I and IGF-II in a non-injury model. J Reconstr Microsurg 15:449–457[Medline]
- Caplan J, Tiangco DA, Terzis JK 1999 Effects of IGF-II in a new end-to-side model. J Reconstr Microsurg 15:351–358[Medline]
- Tiangco DA, Papakonstantinou KC, Mullinax KA, Terzis JK 2001 IGF-I and end-to-side nerve repair: a dose-response study. J Reconstr Microsurg 17:247–256[CrossRef][Medline]
- Thanos PK, Tiangco DA, Terzis JK 2001 Enhanced reinnervation of the paralyzed orbicularis oculi muscle after insulin-like growth factor-I (IGF-I) delivery to a nerve graft. J Reconstr Microsurg 17:357–362[CrossRef][Medline]
- Shiotani A, O'Malley Jr BW, Coleman ME, Flint PW Human insulinlike growth factor 1 gene transfer into paralyzed rat larynx: single vs multiple injection. Arch Otolaryngol Head Neck Surg 125:555–560
- Shiotani A, O'Malley Jr BW, Coleman ME, Alila HW, Flint PW 1998 Reinnervation of motor endplates and increased muscle fiber size after human insulin-like growth factor I gene transfer into the paralyzed larynx. Hum Gene Ther 9:2039–2047[Medline]
- Kerns JM, Shott S, Brubaker L, Sakamoto K, Benson JT, Fleischer AE, Coleman ME 2003 Effects of IGF-I gene therapy on the injured rat pudendal nerve. Int Urogynecol J Pelvic Floor Dysfunc 14:2–7; discussion 8
- Kanje M, Skottner A, Lundborg G 1988 Effects of growth hormone treatment on the regeneration of rat sciatic nerve. Brain Res 475:254–258[CrossRef][Medline]
- Lutz BS, Wei FC, Ma SF, Chuang DC 1999 Effects of insulin-like growth factor-1 in motor nerve regeneration after nerve transection and repair vs. nerve crushing injury in the rat. Acta Neurochirurg 141:1101–1106
- Gao WQ, Shinsky N, Ingle G, Beck K, Elias KA, Powell-Braxton L 1999 IGF-I deficient mice show reduced peripheral nerve conduction velocities and decreased axonal diameters and respond to exogenous IGF-I treatment. J Neurobiol 39:142–152[CrossRef][Medline]
- Ekstrom AR, Kanje M, Skottner A 1989 Nerve regeneration and serum levels of insulin-like growth factor-I in rats with streptozotocin-induced insulin deficiency. Brain Res 496:141–147[CrossRef][Medline]
- Brussee V, Cunningham FA, Zochodne DW 2004 Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes 53:1824–1830[Abstract/Free Full Text]
- Wuarin L, Guertin DM, Ishii DN 1994 Early reduction in insulin-like growth factor gene expression in diabetic nerve. Exp Neurol 130:106–114[CrossRef][Medline]
- Ishii DN 1995 Implication of insulin-like growth factors in the pathogenesis of diabetic neuropathy. Brain Res Brain Res Rev 20:47–67[CrossRef][Medline]
- Bitar MS, Pilcher CW, Khan I, Waldbillig RJ 1997 Diabetes-induced suppression of IGF-1 and its receptor mRNA levels in rat superior cervical ganglia. Diabetes Res Clin Pract 38:73–80[CrossRef][Medline]
- Kamiya H, Zhang W, Sima AA 2006 Degeneration of the Golgi and neuronal loss in dorsal root ganglia in diabetic BioBreeding/Worcester rats. Diabetologia 49:2763–2774[Medline]
- Ishii DN, Guertin DM, Whalen LR 1994 Reduced insulin-like growth factor-I mRNA content in liver, adrenal glands and spinal cord of diabetic rats. Diabetologia 37:1037–1081
- Bitar MS, Pilcher CW 1998 Attenuation of IGF-1 antinociceptive action and a reduction in spinal cord gene expression of its receptor in experimental diabetes. Pain 75:69–74[Medline]
- Xu G, Sima AA 2001 Altered immediate early gene expression in injured diabetic nerve: implications in regeneration. J Neuropathol Exp Neurol 60:972–983[Medline]
- Zhuang HX, Synder CK, Pu SF, Ishii DN 1996 Insulin-like growth factors reverse or arrest diabetic neuropathy: Effects on hyperalgesia and impaired nerve regeneration in rats. Exp Neurol 140:198–205[CrossRef][Medline]
- Russell JW, Rout P, van Golen CM, Feldman EL, IGF-I prevents hyperglycemic induction of oxidative stress, loss of mitochondrial membrane integrity and caspase cleavage in models of diabetic neuronal programmed cell death. Program of the 81st Annual Meeting of The Endocrine Society, San Diego, CA, p. 70 (Abstract OR6-5)
- Schmidt RE, Dorsey DA, Beaudet LN, Plurad SB, Parvin CA, Miller MS 1999 Insulin-like growth factor I reverses experimental diabetic autonomic neuropathy. Am J Pathol 155:1651–1660[Abstract/Free Full Text]
- Migdalis IN, Kalogeropoulou K, Kalantzis L, Nounopoulos C, Bouloukos A, Samartzis M 1995 Insulin-like growth factor-I and IGF-I receptors in diabetic patients with neuropathy. Diabetes Med 12:823–827[Medline]
- Grandis M, Nobbio L, Abbruzzese M, Banchi L, Minuto F, Barreca A, Garrone S, Mancardi GL, Schenone A 2001 Insulin treatment enhances expression of IGF-I in sural nerves of diabetic patients. Muscle Nerve 24:622–629[CrossRef][Medline]
- Windebank AJ, Sorenson EJ, Civil R, O'Brien PC 2004 Role of insulin-like growth factor-I in the treatment of painful small fiber predominant neuropathy. J Peripher Nerv Syst 9:183–189[Medline]
- Fernyhough P, Willars GB, Lindsay RM, Tomlinson DR 1993 Insulin and insulin-like growth factor I enhance regeneration in cultured adult rat sensory neurones. Brain Res 607:117–124[CrossRef][Medline]
- Karagiannis SN, King RH, Thomas PK 1997 Colocalisation of insulin and IGF-1 receptors in cultured rat sensory and sympathetic ganglion cells. J Anat 191(Pt 3):431–440
- Craner MJ, Klein JP, Black JA, Waxman SG 2002 Preferential expression of IGF-I in small DRG neurons and down-regulation following injury. Neuroreport 13:1649–1652[CrossRef][Medline]
- Russell JW, Sullivan KA, Windebank AJ, Herrmann DN, Feldman EL 1999 Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis 6:347–363[CrossRef][Medline]
- Russell JW, Windebank AJ, Schenone A, Feldman EL 1998 Insulin-like growth factor-I prevents apoptosis in neurons after nerve growth factor withdrawal. J Neurobiol 36:455–467[CrossRef][Medline]
- Vincent AM, Olzmann JA, Brownlee M, Sivitz WI, Russell JW 2004 Uncoupling proteins prevent glucose-induced neuronal oxidative stress and programmed cell death. Diabetes 53:726–734[Abstract/Free Full Text]
- Russell JW, Golovoy D, Vincent AM, Mahendru P, Olzmann JA, Mentzer A, Feldman EL 2002 High glucose induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 16:1738–1748[Abstract/Free Full Text]
- Leinninger GM, Backus C, Uhler MD, Lentz SI, Feldman EL 2004 Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. FASEB J 18:1544–1546[Abstract/Free Full Text]
- Leinninger GM, Backus C, Sastry AM, Yi YB, Wang CW, Feldman EL 2006 Mitochondria in DRG neurons undergo hyperglycemic mediated injury through Bim, Bax and the fission protein Drp1. Neurobiol Dis 23:11–22[CrossRef][Medline]
- Schumacher M, Jung-Testas I, Robel P, Baulieu EE 1993 Insulin-like growth factor I: a mitogen for rat Schwann cells in the presence of elevated levels of cyclic AMP. Glia 8:232–240[CrossRef][Medline]
- Stewart HJS, Bradke F, Tabernero A, Morrell D, Jessen KR, Mirsky R 1996 Regulation of rat Schwann cell Po expression and DNA synthesis by insulin-like growth factors in vitro. Eur J Neurosci 8:553–564[CrossRef][Medline]
- Cheng HL, Feldman EL 1997 Insulin-like growth factor-I (IGF-I) and IGF binding protein-5 in Schwann cell differentiation. J Cell Physiol 171:161–167[CrossRef][Medline]
- Svenningsen AF, Kanje M 1996 Insulin and the insulin-like growth factors I and II are mitogenic to cultured rat sciatic nerve segments and stimulate [3H]thymidine incorporation through their respective receptors. Glia 18:68–72[CrossRef][Medline]
- Syroid DE, Zorick TS, Arbet-Engels C, Kilpatrick TJ, Eckhart W, Lemke G 1999 A role for insulin-like growth factor-I in the regulation of Schwann cell survival. J Neurosci 19:2059–2068[Abstract/Free Full Text]
- Liang G, Cline GW, Macica CM 2007 IGF-1 stimulates de novo fatty acid biosynthesis by Schwann cells during myelination. Glia 55:632–641[CrossRef][Medline]
- Cheng HL, Steinway M, Russell JW, Feldman EL 2000 GTPases and phosphatidylinositol-3 kinase are critical for insulin-like growth factor-I mediated Schwann cell motility. J Biol Chem 275:27197–27204[Abstract/Free Full Text]
- Russell JW, Cheng HL, Golovoy D 2000 Insulin-like growth factor-I promotes myelination of peripheral sensory axons. J Neuropathol Exp Neurol 59:575–584[Medline]
- Delbono O 2003 Neural control of aging skeletal muscle. Aging Cell 2:21–29[CrossRef][Medline]
- Caroni P, Becker M 1992 The downregulation of growth-associated proteins in motoneurons at the onset of synapse elimination is controlled by muscle activity and IGF1. J Neurosci 12:3849–3861[Abstract]
- Messi ML, Delbono O 2003 Target-derived trophic effect on skeletal muscle innervation in senescent mice. J Neurosci 23:1351–1359[Abstract/Free Full Text]
- Suliman IA, Lindgren JU, Gillberg PG, Elhassan AM, Monneron C, Adem A 1999 Alteration of spinal cord IGF-I receptors and skeletal muscle IGF-I after hind-limb immobilization in the rat. Neuroreport 10:1195–1199[Medline]
- Suliman IA, Lindgren JU, Elhassan AM, Diab KM, Adem A 2001 Effects of short- and long-term rat hind limb immobilization on spinal cord insulin-like growth factor-I and its receptor. Brain Res 912:17–23[CrossRef][Medline]
- Alila H, Coleman M, Nitta H, French M, Anwer K, Liu Q, Meyer T, Wang J, Mumper R, Oubari D, Long S, Nordstrom J, Rolland A 1997 Expression of biologically active human insulin-like growth factor-I following intramuscular injection of a formulated plasmid in rats. Hum Gene Ther 8:1785–1795[Medline]
- Payne AM, Zheng Z, Messi ML, Milligan CE, Gonzalez E, Delbono O 2006 Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle. J Physiol 570:283–294[Abstract/Free Full Text]
- Day CS, Riano F, Tomaino MM, Buranatanitkit B, Somogyi G, Sotereanos D, Huard J 2001 Growth factor may decrease muscle atrophy secondary to denervation. J Reconstr Microsurg 17:51–57[Medline]
- Eustache I, Seyfritz N, Gueritaud JP 1994 Effects of insulin-like growth factors on organotypic cocultures of embryonic rat brainstem slices and skeletal muscle fibres. Brain Res Dev Brain Res 81:284–292[Medline]
- Glazner GW, Ishii DN 1995 Insulinlike growth factor gene expression in rat muscle during reinnervation. Muscle Nerve 18:1433–1442[CrossRef][Medline]
- Li L, Oppenheim RW, Lei M, Houenou LJ 1994 Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse. J Neurobiol 25:759–766[CrossRef][Medline]
- Vergani L, Di Giulio AM, Losa M, Rossoni G, Muller EE, Gorio A 1998 Systemic administration of insulin-like growth factor decreases motor neuron cell death and promotes muscle reinnervation. J Neurosci Res 54:840–847[CrossRef][Medline]
- Iwasaki Y, Ikeda K 1999 Prevention by insulin-like growth factor-I and riluzole in motor neuron death after neonatal axotomy. J Neurol Sci 169:148–155[Medline]
- Pulford BE, Whalen LR, Ishii DN 1999 Peripherally administered insulin-like growth factor-I preserves hindlimb reflex and spinal cord noradrenergic circuitry following a central nervous system lesion in rats. Exp Neurol 159:114–123[CrossRef][Medline]
- Bitar MS, Francis IM, Pilcher CW 2000 Insulin-like growth factor 1-induced alterations in lumbospinal monoamine dynamics. Horm Metab Res 32:207–215[Medline]
- Bilak MM, Corse AM, Kuncl RW 2001 Additivity and potentiation of IGF-I and GDNF in the complete rescue of postnatal motor neurons. Amyotroph Lateral Scler Other Motor Neuron Disord 2:83–91[CrossRef][Medline]
- Bilak MM, Kuncl RW 2001 Delayed application of IGF-I and GDNF can rescue already injured postnatal motor neurons. Neuroreport 12:2531–2535[CrossRef][Medline]
- Vincent AM, Mobley BC, Hiller A, Feldman EL 2004 IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis 16:407–416[CrossRef][Medline]
- Nakao Y, Otani H, Yamamura T, Hattori R, Osako M, Imamura H 2001 Insulin-like growth factor 1 prevents neuronal cell death and paraplegia in the rabbit model of spinal cord ischemia. J Thorac Cardiovasc Surg 122:136–143[Abstract/Free Full Text]
- Yamauchi T, Sakurai M, Abe K, Takano H, Sawa Y 2006 Neuroprotective effects of activated protein C through induction of insulin-like growth factor-1 (IGF-1), IGF-1 receptor, and its downstream signal phosphorylated serine-threonine kinase after spinal cord ischemia in rabbits. Stroke 37:1081–1086[Abstract/Free Full Text]
- Hung KS, Tsai SH, Lee TC, Lin JW, Chang CK, Chiu WT 2007 Gene transfer of insulin-like growth factor-I providing neuroprotection after spinal cord injury in rats. J Neurosurg Spine 6:35–46[Medline]
- Vaught JL, Contreras PC, Glicksman MA, Neff NT 1996 Potential utility of rhIGF-1 in neuromuscular and/or degenerative disease. CIBA Found Symp 196:18–27[Medline]
- Kerkhoff H, Hassan SM, Troost D, Van Etten RW, Veldman H, Jennekens FGI 1994 Insulin-like and fibroblast growth factors in spinal cords, nerve roots and skeletal muscle of human controls and patients with amyotrophic lateral sclerosis. Acta Neuropathol 87:411–421[Medline]
- Dore S, Krieger C, Kar S, Quirion R 1996 Distribution and levels of insulin-like growth factor (IGF-I and IGF-II) and insulin receptor binding sites in the spinal cords of amyotrophic lateral sclerosis (ALS) patients. Brain Res Mol Brain Res 41:128–133[Medline]
- Wilczak N, de Vos RA, De Keyser J 2003 Free insulin-like growth factor (IGF)-I and IGF binding proteins 2, 5, and 6 in spinal motor neurons in amyotrophic lateral sclerosis. Lancet 361:1007–1011[CrossRef][Medline]
- Chung YH, Joo KM, Shin CM, Lee YJ, Shin DH, Lee KH, Cha CI 2003 Immunohistochemical study on the distribution of insulin-like growth factor I (IGF-I) receptor in the central nervous system of SOD1(G93A) mutant transgenic mice. Brain Res 994:253–259[Medline]
- Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH 2003 Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301:839–842[Abstract/Free Full Text]
- Nagano I, Ilieva H, Shiote M, Murakami T, Yokoyama M, Shoji M, Abe K 2005 Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of amyotrophic lateral sclerosis. J Neurol Sci 235:61–68[CrossRef][Medline]
- Narai H, Nagano I, Ilieva H, Shiote M, Nagata T, Hayashi T, Shoji M, Abe K 2005 Prevention of spinal motor neuron death by insulin-like growth factor-1 associating with the signal transduction systems in SODG93A transgenic mice. J Neurosci Res 82:452–457[Medline]
- Vincent AM, Feldman EL, Song DK, Jung V, Schild A, Zhang W, Imperiale MJ, Boulis NM 2004 Adeno-associated viral-mediated insulin-like growth factor delivery protects motor neurons in vitro. Neuromol Med 6:79–86[CrossRef]
- Teng Q, Garrity-Moses M, Federici T, Tanase D, Liu JK, Mazarakis ND, Azzouz M, Walmsley LE, Carlton E, Boulis NM 2005 Trophic activity of rabies G protein-pseudotyped equine infectious anemia viral vector mediated IGF-I motor neuron gene transfer in vitro. Neurobiol Dis 20:694–700[Medline]
- Lepore AC, Bakshi A, Swanger SA, Rao MS, Fischer I 2005 Neural precursor cells can be delivered into the injured cervical spinal cord by intrathecal injection at the lumbar cord. Brain Res 1045:206–216[Medline]
- Dobrowolny G, Giacinti C, Pelosi L, Nicoletti C, Winn N, Barberi L, Molinaro M, Rosenthal N, Musaro A 2005 Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model. J Cell Biol 168:193–199[Abstract/Free Full Text]
- Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery C, Schwartz RJ 1995 Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice. J Biol Chem 270:12109–12116[Abstract/Free Full Text]
- Renganathan M, Messi ML, Delbono O 1998 Overexpression of IGF-1 exclusively in skeletal muscle prevents age-related decline in the number of dihydropyridine receptors. J Biol Chem 273:28845–28851[Abstract/Free Full Text]
- Renganathan M, Messi ML, Schwartz R, Delbono O 1997 Overexpression of hIGF-1 exclusively in skeletal muscle increases the number of dihydropyridine receptors in adult transgenic mice. FEBS Lett 417:13–16[CrossRef][Medline]
- Ye P, Xing Y, Dai Z, D'Ercole AJ 1996 In vivo actions of insulin-like growth factor-I (IGF-I) on cerebellum development in transgenic mice: evidence that IGF-I increases proliferation of granule cell progenitors. Brain Res Dev Brain Res 95:44–54[Medline]
- Messi ML, Clark HM, Prevette DM, Oppenheim RW, Delbono O 2007 The lack of effect of specific overexpression of IGF-1 in the central nervous system or skeletal muscle on pathophysiology in the G93A SOD-1 mouse model of ALS. Exp Neurol 207:52–63[Medline]
- Lai EC, Felice KJ, Festoff BW, Gawel MJ, Gelinas DF, Kratz R, Murphy MF, Natter HM, Norris FH, Rudnicki SA 1997 Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology 49:1621–1630[Abstract/Free Full Text]
- Borasio GD, Robberecht W, Leigh PN, Emile J, Guiloff RJ, Jerusalem F, Silani V, Vos PE, Wokke JH, Dobbins T 1998 A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology 51:583–586[Abstract/Free Full Text]
- Nagano I, Shiote M, Murakami T, Kamada H, Hamakawa Y, Matsubara E, Yokoyama M, Moritaz K, Shoji M, Abe K 2005 Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis. Neurol Res 27:768–772[CrossRef][Medline]
- Mitchell JD, Wokke JH, Borasio GD 2002 Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev:CD002064
- Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N 2001 Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27:195–200[CrossRef][Medline]
- Hatton J, Rapp RP, Kudsk KA, Brown RO, Luer MS, Bukar JG, Chen SA, McClain CJ, Gesundheit N, Dempsey RJ, Young B 1997 Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a phase II safety and efficacy trial. J Neurosurg 86:779–786[Medline]
- Apfel SC, Kessler JA 1995 Neurotrophic factors in the therapy of peripheral neuropathy. Baillieres Clin Neurol 4:593–606[Medline]
- Apfel SC, Kessler JA 1996 Neurotrophic factors in the treatment of peripheral neuropathy. CIBA Found Symp 196:98–108[Medline]
- Leinninger GM, Meyer GE, Feldman EL 2003 IGFs and the nervous system. In: LeRoith D, Zumkeller W, Baxter R, eds. Insulin-like growth factors. London: Eurekah.com/Landes Bioscience and Kluwer Academic/Plenum Publishers; 158–187
- Cavaletti G, Zanna C 2002 Current status and future prospects for the treatment of chemotherapy-induced peripheral neurotoxicity. Eur J Cancer 38:1832–1837[Medline]
- Holly J, Perks C 2006 The role of insulin-like growth factor binding proteins. Neuroendocrinology 83:154–160[CrossRef][Medline]
- Clemmons DR 2007 IGF-I assays: current assay methodologies and their limitations. Pituitary 10:121–128[CrossRef][Medline]
- Clemmons DR, Thissen JP, Maes M, Ketelslegers JM, Underwood LE 1989 Insulin-like growth factor-I (IGF-I) infusion into hypophysectomized or protein-deprived rats induces specific IGF-binding proteins in serum. Endocrinology 125:2967–2972[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
Y.-M. Chang, W.-H. Kuo, T.-Y. Lai, Y.-T. Shih, F.-J. Tsai, C.-H. Tsai, W.-T. Shu, Y.-Y. Chen, Y.-S. Chen, W.-W. Kuo, et al.
RSC96 Schwann Cell Proliferation and Survival Induced by Dilong through PI3K/Akt Signaling Mediated by IGF-I
Evid. Based Complement. Altern. Med.,
December 29, 2009;
(2009)
nep216v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. A. R. White, J. T. Kyle, and A. W. Wood
Targeted Gene Knockdown in Zebrafish Reveals Distinct Intraembryonic Functions for Insulin-Like Growth Factor II Signaling
Endocrinology,
September 1, 2009;
150(9):
4366 - 4375.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. LeRoith
Insulin-Like Growth Factors and the Brain
Endocrinology,
December 1, 2008;
149(12):
5951 - 5951.
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
