IGF-I protects cortical neurons against ceramide-induced apoptosis via activation of the PI-3K/Akt and ERK pathways; is this protection independent of CREB and Bcl-2?

Willaime‐Morawek, Sandrine; Arbez, Nicolas; Mariani, Jean; Brugg, Bernard

doi:10.1016/j.molbrainres.2005.09.020

Cited by 37 publications

(31 citation statements)

References 62 publications

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“…In our studies the IL-1 preincubation time was 2 h. Under specific conditions CREB can play a critical role in promoting the survival of various types of cells, including neurons [27,31,45,74,75]. Recently, Willaime-Morawek et al have shown that CREB is not involved in the IGF-1-mediated attenuation of neuron loss induced by ceramide treatment [79]. However, in addition to their role in promoting neuron survival under specific conditions, CREB and the Ras/MAPK pathway play essential roles in synaptic plasticity, including learning and memory processes [1,62,66].…”

Section: Discussionmentioning

confidence: 63%

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Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

196

142

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The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1β renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1β compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ ERK, but not PLCγ, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1β. As the cytokine did not influence TrkB receptor and PLCγ activation, IL-1β might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1β suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1β places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. Keywords IL-1β; BDNF; signal transduction; cortical neuronsInterleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral ischemia and trauma, and circumstantial evidence is consistent with a similar role in chronic neurological diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease (AD) [48]. Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the a...

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Section: Discussionmentioning

confidence: 63%

“…This may be related to the summation of the IL-1-induced decrease of BDNF signaling through various pathways, including PI3-K/Akt and Ras/ERK (e.g. [79]), which converge at this transcription factor. Under our experimental conditions, IL-1 alone had no effect on the basal level of P-CREB.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

196

142

View full text Add to dashboard Cite

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“…IGF-1 plays an important role in the nervous system, stimulating postnatal brain growth (46), promoting neuron survival and growth (47,48), increasing the rate of axon regeneration in crush-injured sciatic nerve (49) and increasing the proliferation of oligodendrocytes (50). Lack of IGF-1 in knockout mice severely affects survival and maturation of neurons (51).…”

Section: Discussionmentioning

confidence: 99%

IPLEX Administration Improves Motor Neuron Survival and Ameliorates Motor Functions in a Severe Mouse Model of Spinal Muscular Atrophy

Murdocca¹,

Malgieri²,

Luchetti³

et al. 2012

Mol Med

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Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder and the first genetic cause of death in childhood. SMA is caused by low levels of survival motor neuron (SMN) protein that induce selective loss of α-motor neurons (MNs) in the spinal cord, resulting in progressive muscle atrophy and consequent respiratory failure. To date, no effective treatment is available to counteract the course of the disease. Among the different therapeutic strategies with potential clinical applications, the evaluation of trophic and/or protective agents able to antagonize MNs degeneration represents an attractive opportunity to develop valid therapies. Here we investigated the effects of IPLEX (recombinant human insulinlike growth factor 1 [rhIGF-1] complexed with recombinant human IGF-1 binding protein 3 [rhIGFBP-3]) on a severe mouse model of SMA. Interestingly, molecular and biochemical analyses of IGF-1 carried out in SMA mice before drug administration revealed marked reductions of IGF-1 circulating levels and hepatic mRNA expression. In this study, we found that perinatal administration of IPLEX, even if does not influence survival and body weight of mice, results in reduced degeneration of MNs, increased muscle fiber size and in amelioration of motor functions in SMA mice. Additionally, we show that phenotypic changes observed are not SMN-dependent, since no significant SMN modification was addressed in treated mice. Collectively, our data indicate IPLEX as a good therapeutic candidate to hinder the progression of the neurodegenerative process in SMA.

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“…This family of kinases has a well-demonstrated role regulating proliferation and differentiation, and its involvement in cell death is emerging (Johnson and Lapadat, 2002;Cheung and Slack, 2004;Wada and Penninger, 2004). In contrast to numerous studies demonstrating that, in the nervous system, insulinrelated growth factors can prevent apoptosis via PI3K activation (Varela-Nieto et al, 2003), there are only a few showing that IGF-I effects in the nervous system are mediated by ERK activation (Subramaniam et al, 2005;Willaime-Morawek et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Differential, age‐dependent MEK‐ERK and PI3K‐Akt activation by insulin acting as a survival factor during embryonic retinal development

Chavarría

Valenciano

Mayordomo

et al. 2007

Developmental Neurobiology

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Programmed cell death is a genuine developmental process of the nervous system, affecting not only projecting neurons but also proliferative neuroepithelial cells and young neuroblasts. The embryonic chick retina has been employed to correlate in vivo and in vitro studies on cell death regulation. We characterize here the role of two major signaling pathways, PI3K-Akt and MEK-ERK, in controlled retinal organotypic cultures from embryonic day 5 (E5) and E9, when cell death preferentially affects proliferating neuroepithelial cells and ganglion cell neurons, respectively. The relative density of programmed cell death in vivo was much higher in the proliferative and early neurogenic stages of retinal development (E3-E5) than during neuronal maturation and synaptogenesis (E8-E19). In organotypic cultures from E5 and E9 retinas, insulin, as the only growth factor added, was able to completely prevent cell death induced by growth factor deprivation. Insulin activated both the PI3K-Akt and the MEK-ERK pathways. Insulin survival effect, however, was differentially blocked at the two stages. At E5, the effect was blocked by MEK inhibitors, whereas at E9 it was blocked by PI3K inhibitors. The cells which were found to be dependent on insulin activation of the MEK-ERK pathway at E5 were mostly proliferative neuroepithelial cells. These observations support a remarkable specificity in the regulation of early neural cell death.

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IGF-I protects cortical neurons against ceramide-induced apoptosis via activation of the PI-3K/Akt and ERK pathways; is this protection independent of CREB and Bcl-2?

Cited by 37 publications

References 62 publications

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

IPLEX Administration Improves Motor Neuron Survival and Ameliorates Motor Functions in a Severe Mouse Model of Spinal Muscular Atrophy

Differential, age‐dependent MEK‐ERK and PI3K‐Akt activation by insulin acting as a survival factor during embryonic retinal development

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