Lethal forebrain ischemia stimulates sphingomyelin hydrolysis and ceramide generation in the gerbil hippocampus

Nakane, Makoto; Kubota, Masaru; Nakagomi, Tadayoshi; Tamura, Akira; Hisaki, Harumi; Shimasaki, Hiroyuki; Ueta, Nobuo

doi:10.1016/s0304-3940(00)01655-4

Cited by 72 publications

(66 citation statements)

References 19 publications

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“…Mammalian cells utilize two separate forms of sphingomyelinase, an acidic and a neutral isoform, for ceramide generation (55). It was reported that sphingomyelinase activation and sphingomyelin hydrolysis led to endogenous ceramide accumulation following severe and lethal cerebral ischemia reperfusion (56,57). Sphingomyelinases appear to play a role in ischemic neuronal cell death as a knock out in acid sphingomyelinase decreased I/R-induced brain tissue damage (24).…”

Section: Discussionmentioning

confidence: 99%

Ceramide Generated by Sphingomyelin Hydrolysis and the Salvage Pathway Is Involved in Hypoxia/Reoxygenation-induced Bax Redistribution to Mitochondria in NT-2 Cells

Jin¹,

Hou

Mullen³

et al. 2008

Journal of Biological Chemistry

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Ceramide functions as an important second messenger in apoptosis signaling pathways. In this report, we show that treatment of NT-2 neuronal precursor cells with hypoxia/reoxygenation (H/R) resulted in ceramide up-regulation. This elevation in ceramide was primarily due to the actions of acid sphingomyelinase and ceramide synthase LASS 5, demonstrating the action of the salvage pathway. Hypoxia/reoxygenation treatment led to Bax translocation from the cytoplasm to mitochondria and cytochrome c release from mitochondria. Down-regulation of either acid sphingomyelinase or LASS 5-attenuated ceramide accumulation and H/R-induced Bax translocation to mitochondria. Overall, we have demonstrated that ceramide upregulation following H/R is pertinent to Bax activation to promote cell death.

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Section: Discussionmentioning

confidence: 99%

Ceramide Generated by Sphingomyelin Hydrolysis and the Salvage Pathway Is Involved in Hypoxia/Reoxygenation-induced Bax Redistribution to Mitochondria in NT-2 Cells

Jin¹,

Hou

Mullen³

et al. 2008

Journal of Biological Chemistry

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“…2). Ceramide generation and JNK activation could also be correlated in vivo in animal models of ischemia, as data show that ceramide levels increase (Nakane et al, 2000) and JNK1 has been shown to activate and translocate to the nuclei (Mizukami et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…creased during developmental neuronal death in rat brain (Spence and Burgess, 1978). Secondly, increased ceramide levels are observed during apoptosis induced by growth factor withdrawal in PC12 cells (Lambeng et al, 1999) and after lethal ischemia in the gerbil hippocampus (Nakane et al, 2000). Furthermore, apoptosis can be induced by exogenous ceramide treatment of PC12 cells (France-Lanord et al, 1997;Hartfield et al, 1997), mesencephalic (Brugg et al, 1996), hippocampal (Mitoma et al, 1998) or cortical neurons (Willaime et al, 2001).…”

mentioning

confidence: 99%

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

Willaime‐Morawek¹,

Brami‐Cherrier²,

Mariani³

et al. 2003

Neuroscience

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“…Sphingomyelinase activity is strongly increased during developmental neuronal death in rat brain [54]. Increased ceramide levels are observed during apoptosis induced by growth factor-withdrawal in neuronally differentiated PC12 cells [32] or cortical neurons [62] and after ischemia in the gerbil hippocampus [41]. Furthermore, apoptosis can be induced by exogenous ceramide treatment of PC12 cells [20,24], mesencephalic [7], hippocampal [40] or cortical neurons [60].…”

Section: Introductionmentioning

confidence: 99%

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

Arbez

Mariani

et al. 2005

Molecular Brain Research

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Current understanding of IGF-I-mediated neuroprotection implies the activation of phosphatidylinositol-3-kinase (PI-3K), which leads to the activation of Akt/Protein Kinase B. In non-neuronal cells, Akt phosphorylates and activates the transcription factor CREB, implicated in the transcription of the anti-apoptotic bcl-2 gene. This paper further analyses the anti-apoptotic IGF-I action in neurons. We show that IGF-I protects cortical neurons against ceramide-induced apoptosis. Ceramide decreases Akt phosphorylation during apoptotic process whereas a simultaneous treatment with IGF-I increases Akt phosphorylation. Analysis of the signal transduction pathways revealed that IGF-I induces CREB phosphorylation via PI-3K and ERK, whereas simultaneous ceramide and IGF-I treatment decreases CREB phosphorylation. Although an overexpression of Bcl-2 protects cortical neurons against ceramide-induced apoptosis, our data indicate that the Bcl-2 protein level is not modulated during IGF-I, ceramide and/or LY294002 treatment. In consequence, we demonstrated that IGF protects neurons against ceramide-induced apoptosis and that IGF-I protection involves the PI-3K/Akt and ERK pathways; this protection may be independent of CREB and Bcl-2. D

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Lethal forebrain ischemia stimulates sphingomyelin hydrolysis and ceramide generation in the gerbil hippocampus

Cited by 72 publications

References 19 publications

Ceramide Generated by Sphingomyelin Hydrolysis and the Salvage Pathway Is Involved in Hypoxia/Reoxygenation-induced Bax Redistribution to Mitochondria in NT-2 Cells

Ceramide Generated by Sphingomyelin Hydrolysis and the Salvage Pathway Is Involved in Hypoxia/Reoxygenation-induced Bax Redistribution to Mitochondria in NT-2 Cells

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

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?

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