A Role for 12-lipoxygenase in Nerve Cell Death Caused by Glutathione Depletion

Li, Yonghong; Maher, Pamela; Schubert, David

doi:10.1016/s0896-6273(00)80953-8

Cited by 464 publications

(479 citation statements)

References 59 publications

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“…[24][25][26] Moreover, a few studies suggested the involvement of 5-or 12-LOX in pathways leading to neuronal death, such as kainic acid excitotoxicity, 27 apoptosis induced by prion peptide 28 and oxidative glutamate toxicity. 23 In this work, we show that blockade of 12-LOX expression protects cortical neurons from Ab-induced apoptosis, through disruption of a c-Jun-dependent apoptosis pathway. These findings suggest that 12-LOX might be considered as a new target for the treatment of AD.…”

Section: Introductionmentioning

confidence: 64%

“…A similar doublet pattern was already observed in previous studies on these cultures. 23 As shown in Figure 1a, pretreatment of cortical cells for 48 h with the antisense 12-LOX oligonucleotide induced an important decrease in the expression of 12-LOX protein. When normalized to corresponding actin levels, the effect of the oligonucleotide represented an 85% decrease in 12-LOX protein levels.…”

Section: Resultsmentioning

confidence: 85%

“…23 Alteration of glutathione metabolism is one of the events triggered by Ab 29 and was reported to occur in AD, 30 which suggested that this LOX might also participate in Ab-induced apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies 23,37 indicated that the 12-LOX isoform present in primary cultures of rat cortical neurons was the 12-LOX cloned from rat brain, 38 belonging to the family of leukocyte-type 12-LOXs. Like other members of this family, rat brain 12-LOX presented high similarity with 15-LOX.…”

Section: Resultsmentioning

confidence: 99%

“…21 Both 12-and 5-LOX are expressed in the brain and especially in neurons. 22,23 LOXs represent important regulators of cell proliferation and death in different cell types. [24][25][26] Moreover, a few studies suggested the involvement of 5-or 12-LOX in pathways leading to neuronal death, such as kainic acid excitotoxicity, 27 apoptosis induced by prion peptide 28 and oxidative glutamate toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

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The cyclo-oxygenase (COX) and lipoxygenase (LOX) pathways belong to the eicosanoid synthesis pathway, a major component of the chronic inflammatory process occurring in Alzheimer's disease (AD). Clinical studies reported beneficial effects of COX inhibitors, but little is known about the involvement of LOXs in AD pathogenesis. b-amyloid peptide (Ab) accumulation contributes to neurodegeneration in AD, but mechanisms underlying Ab toxicity have not been fully elucidated yet. Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both Ab-induced apoptosis and overexpression of c-Jun, a factor required for the apoptotic process, in cortical neurons. Conversely, the 12-LOX metabolite, 12(S)-HETE (12(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraenoic acid), promoted c-Jun-dependent apoptosis. Specificity of the 12-LOX involvement was further supported by the observed lack of contribution of 5-LOX in this process. These data indicate that blockade of 12-LOX expression disrupts a c-Jun-dependent apoptosis pathway, and suggest that 12-LOX may represent a new target for the treatment of AD.

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Section: Introductionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

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Evidence that increased 12-lipoxygenase activity induces apoptosis in fibroblasts

Liu²,

Wen

et al. 2001

J. Cell. Physiol.

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The 12-lipoxygenase (LO) enzyme has been implicated in playing a role in pancreatic beta cell inflammatory damage and atherosclerosis. 12-LO reacts with fatty acids to form hydroperoxides which may alter cellular growth. In this study we investigated the direct effect of mouse leukocyte type 12-LO cDNA overexpression on apoptosis in Chinese hamster ovary fibroblast cells that also stably overexpress the angiotensin II type 1a receptor. CHO-AT1a cells expressing background levels of 12-LO exhibited clear increases in growth in response to angiotensin II. In contrast, the new 12-LO transfected cells (CHO-AT1a/ML12-LO cells) displayed reduced basal and angiotensin Il-induced growth compared to CHO-AT1a cells. Furthermore, serum-deprivation resulted in a significantly greater number of non-viable cells in clones having the greatest magnitude of 12-LO overexpression. These results suggested that reduction of the proliferation rate of CHO-AT1a/ML12-LO cells was due to an increasing rate of cell death. To determine whether the increase in cell death was due to apoptosis, we evaluated nuclear DNA fragmentation, cell morphologic changes, and activation of caspase-3. Cells overexpressing 12-LO cDNA displayed all these changes characteristic of apoptosis. In addition the 12-LO product, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), directly induced apoptosis in CHO-AT1a cells. These results demonstrate for the first time that 12-LO activation can lead to apoptosis in fibroblasts, suggesting a role of 12-LO in leading to inflammatory mediated cellular damage.

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Designed Prostaglandins with Neurotrophic Activities

et al. 2000

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283and FcB1-Columbia are chloroquine-resistant (CI 50 of chloroquine > 100 nM). [14, 15] Biological activities were measured by the method of Desjardins et al. [16] Assays were performed in triplicate in 96microplates, cultures being at 1 % of hematocrite and with 0.5 ± 1 % of parasitemia.For each assay, parasites were incubated with decreasing concentrations of drugs during 32 h (data not shown) or 72 h (four wells contained chloroquine as reference). The initial drug dilutions were made at 10 mg mL À1 in dimethylsulfoxide and the next ones with RPMI 1640. The parasite growth was measured by incorporation of tritiated hypoxanthine and compared with the incorporation in the absence of drug (used as 100 % value). [17] IC 50 values were determined by tracing the percentage of inhibition as function of the drug concentration. The IC 50 values measured at 32 h correspond to the action of the drug on the trophozoite stage and IC 50 values measured at 72 h (time for 1.5 parasite life cycles) indicate a possible effect on the liberation and reinvasion steps of the erythrocytes by the parasites.We are grateful to the CNRS (Programme Physique et Chimie du Vivant) for financial support.[1] a) P. Newton, N. White, Annu. Rev. Med. 1999, 50, 179 ± 192; T. Bradley, University of Leicester, http://www-micro.msb.le.ac.uk/224/Bradley/Bradley.html. [2] N.

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A Role for 12-lipoxygenase in Nerve Cell Death Caused by Glutathione Depletion

Cited by 464 publications

References 59 publications

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Evidence that increased 12-lipoxygenase activity induces apoptosis in fibroblasts

Designed Prostaglandins with Neurotrophic Activities

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