Chronic Insulin-like Growth Factor-1 Research Articles

Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability.

Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and non-neuronal cells. IGF-1 provides trophic support for many neurons of both the central and peripheral nervous systems. In the central nervous system (CNS), IGF-1R signaling regulates brain development, increases neuronal firing and modulates synaptic transmission. IGF-1 and IGF-IR are not only expressed in CNS neurons but also in sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain signals. DRG nociceptive neurons express a variety of receptors and ion channels that are essential players of neuronal excitability, notably the ligand-gated cation channel TRPV1 and the voltage-gated M-type K+ channel, which, respectively, triggers and dampens sensory neuron excitability. Although many lines of evidence suggest that IGF-IR signaling contributes to pain sensitivity, its possible modulation of TRPV1 and M-type K+ channel remains largely unexplored. In this study, we examined the impact of IGF-1R signaling on DRG neuron excitability and its modulation of TRPV1 and M-type K+ channel activities in cultured rat DRG neurons. Acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection. These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin. Surprisingly, acute exposure to IGF-1 profoundly inhibited both the TRPV1 current and the spike burst evoked by capsaicin. The Src kinase inhibitor PP2 potently depressed the capsaicin-evoked spike burst but did not alter the IGF-1 inhibition of the hyperexcitability triggered by capsaicin. Chronic IGF-1 treatment (24 h) reduced the spike firing evoked by depolarizing current injection and upregulated the M-current density. In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures.

Antidepressant-like effects of insulin and IGF-1 are mediated by IGF-1 receptors in the brain

Depression is associated with uncontrolled diabetes, which indicates a lack of insulin effect, yet the role of the insulin receptor in mediating depression is not clearly established because insulin receptors are not required for glucose entry into the brain. However, insulin receptors are important for brain function since insulin receptor knockout mice have depressive-like activity. Depression and cognitive problems are also associated with low insulin-like growth factor-1 (IGF-1) in the elderly. Rodent studies showed chronic IGF-1 administration had antidepressant-like (AD) activity. We asked if insulin in the brain might act through the IGF-1 receptor, as it does in some tissues. We used acute insulin or IGF-1 infusions into the 3rd ventricle (icv) in rats and tested animals in a forced swim test. We found that antidepressive-like behavior is mediated by insulin and IGF-1. Further, administration of the IGF-1 receptor antagonist JB-1 blocked the antidepressive-like activity of the insulin and IGF-1, indicating a strong relationship between insulin, IGF-1 and depression. Insulin acts at least partially through the IGF-1 receptor and is responsive to receptor antagonism. The model offers promise for future studies of the mechanism of depression, and therapy to increase insulin sensitivity and IGF-1 action including exercise and nutrition.

A Novel Role of IGF1 in Apo2L/TRAIL-Mediated Apoptosis of Ewing Tumor Cells

Insulin-like growth factor 1 (IGF1) reputedly opposes chemotoxicity in Ewing sarcoma family of tumor (ESFT) cells. However, the effect of IGF1 on apoptosis induced by apoptosis ligand 2 (Apo2L)/tumor necrosis factor (TNF-) related apoptosis-inducing ligand (TRAIL) remains to be established. We find that opposite to the partial survival effect of short-term IGF1 treatment, long-term IGF1 treatment amplified Apo2L/TRAIL-induced apoptosis in Apo2L/TRAIL-sensitive but not resistant ESFT cell lines. Remarkably, the specific IGF1 receptor (IGF1R) antibody α-IR3 was functionally equivalent to IGF1. Short-term IGF1 incubation of cells stimulated survival kinase AKT and increased X-linked inhibitor of apoptosis (XIAP) protein which was associated with Apo2L/TRAIL resistance. In contrast, long-term IGF1 incubation resulted in repression of XIAP protein through ceramide (Cer) formation derived from de novo synthesis which was associated with Apo2L/TRAIL sensitization. Addition of ceramide synthase (CerS) inhibitor fumonisin B1 during long-term IGF1 treatment reduced XIAP repression and Apo2L/TRAIL-induced apoptosis. Noteworthy, the resistance to conventional chemotherapeutic agents was maintained in cells following chronic IGF1 treatment. Overall, the results suggest that chronic IGF1 treatment renders ESFT cells susceptible to Apo2L/TRAIL-induced apoptosis and may have important implications for the biology as well as the clinical management of refractory ESFT.

Transcriptional up-regulation of cell surface NaV1.7 sodium channels by insulin-like growth factor-1 via inhibition of glycogen synthase kinase-3β in adrenal chromaffin cells: enhancement of 22Na+ influx, 45Ca2+ influx and catecholamine secretion

Insulin-like growth factor-1 (IGF-1) plays important roles in the regulation of neuronal development. The electrical activity of Na+ channels is crucial for the regulation of synaptic formation and maintenance/repair of neuronal circuits. Here, we examined the effects of chronic IGF-1 treatment on cell surface expression and function of Na+ channels. In cultured bovine adrenal chromaffin cells expressing NaV1.7 isoform of voltage-dependent Na+ channels, chronic IGF-1 treatment increased cell surface [3H]saxitoxin binding by 31%, without altering the Kd value. In cells treated with IGF-1, veratridine-induced 22Na+ influx, and subsequent 45Ca2+ influx and catecholamine secretion were augmented by 35%, 33%, 31%, respectively. Pharmacological properties of Na+ channels characterized by neurotoxins were similar between nontreated and IGF-1-treated cells. IGF-1-induced up-regulation of [3H]saxitoxin binding was prevented by phosphatydil inositol-3 kinase inhibitors (LY204002 or wortmannin), or Akt inhibitor (Akt inhibitor IV). Glycogen synthase kinase-3 (GSK-3) inhibitors (LiCl, valproic acid, SB216763 or SB415286) also increased cell surface [3H]saxitoxin binding by ∼33%, whereas simultaneous treatment of IGF-1 with GSK-3 inhibitors did not produce additive increasing effect on [3H]saxitoxin binding. IGF-1 (100nM) increased Ser437-phosphorylated Akt and Ser9-phosphorylated GSK-3β, and inhibited GSK-3β activity. Treatment with IGF-1, LiCl or SB216763 increased protein level of Na+ channel α-subunit; it was prevented by cycloheximide. Either treatment increased α-subunit mRNA level by ∼48% and accelerated α-subunit gene transcription by ∼30% without altering α-subunit mRNA stability. Thus, inhibition of GSK-3β caused by IGF-1 up-regulates cell surface expression of functional Na+ channels via acceleration of α-subunit gene transcription.

IGF-1 Partially Reproduces Beneficial Effect of Exercise Training on Glucose Tolerance in Normal Rats

Exercise transiently elevates the IGF-1 (insulin-like growth factor 1) level, but whether exogenous IGF-1 administration can reproduce exercise training benefit in glycemic control is currently unknown. This study compared the effect of IGF-1 administration and exercise training on glycogen storage, glucose tolerance, and muscle glucose transporter 4 (GLUT4) protein expression in normal rats. Forty rats were weight matched and evenly assigned to the following 4 groups: control (C), exercise trained (E), IGF-1 treated (I), and exercise-trained + IGF-1 (EI). Same volume of saline or IGF-1 (2 μg/kg BW) was injected daily to the rats. Exercise training consisted of daily 90 min of swimming for the first week and gradually increased to 180 min, twice for the third week. Oral glucose tolerance test (OGTT) was performed in all rats under fasted condition. Muscle tissues were removed at the end of the 3-week treatments (3 days after OGTT). The levels of GLUT4 protein and mRNA were determined in red and white portions of the quadriceps muscle (RQ and WQ). Both exercise training and chronic IGF-1 administration increased GLUT4 expression and improved glucose tolerance without an observed additive effect. Exercise training increased glycogen level in RQ and WQ above control level. Despites chronic IGF-1 administration increased muscle GLUT4 expression above control level, glycogen increase was not observed. Our data suggest that IGF-1 can partially reproduce exercise training effect on improving glycemic control.

Insulin-like growth factor 1 reduces age-related disorders induced by prenatal stress in female rats

Stress during the prenatal period can induce permanent abnormalities in adult life such as increased anxiety-like behavior and hyperactivity of hypothalamo-pituitary–adrenal (HPA) axis system. The present study was designed to investigate whether prenatal stress could induce spatial learning impairment in aged female rats. Furthermore, since it has been recently reported that insulin-like growth factor 1 (IGF-1) attenuates spatial learning deficits in aged rats and promotes neurogenesis in the hippocampus, we assessed the impact of a chronic infusion of IGF-1 on age-related disorders. Our results show that females stressed during prenatal life exhibit learning impairments in the water maze task. Chronic IGF-1 treatment restores their spatial abilities, reduces their HPA axis dysfunction and increases plasma estradiol levels. Parallel to these effects, chronic IGF-1 up-regulates neural proliferation in the dentate gyrus of the hippocampus. These findings support the hypothesis of an early programming of the vulnerability to some neurological diseases during senescence and reinforce the potential therapeutic interest of IGF-1 during brain aging.

Age and insulin-like growth factor-1 modulate N-methyl-D-aspartate receptor subtype expression in rats

N-Methyl-D-aspartate (NMDA) receptors have been reported to have an important role in synaptic plasticity and neurodegeneration. Two major subtypes of these receptors, NMDAR1 and NMDAR2, are present in brain and heterogeneity of these receptors have been reported to define specific functional responses. In this study, the effects of age and chronic insulin-like growth factor-1 (IGF-1) administration on NMDA receptor density and subtype expression were investigated in frontal cortex, CA1, CA2/3 and the dentate gyrus of the hippocampus of young (10 months), middle-aged (21 months) and old (30 months) male Fisher 344xBrown Norway (F1) rats. No age-related changes in 125I-MK-801 binding or NMDAR1 protein expression were observed in hippocampus or frontal cortex. However, analysis of NMDAR2A and NMDAR2B protein expression in hippocampus indicated a significant decrease between 21 and 30 months of age and administration of IGF-1 increased these receptor subtypes. In cortex, NMDAR2A and NMDAR2B protein expression were not influenced by age or IGF-1 treatment, although NMDAR2C protein expression decreased with age and this decline was not ameliorated by IGF-1 administration. These data demonstrate that NMDA receptor subtypes are altered with age in a regional and subtype specific manner. We conclude that both age and IGF-1 regulate the expression of NMDA receptor subtypes and suggest that age-related changes in NMDA receptor heterogeneity may result in functional changes in the receptor that have relevance for aging.