Lipoxygenase metabolites of arachidonic acid in neuronal transmembrane signalling

Piomelli, Daniele; Greengard, Paul

doi:10.1016/0165-6147(90)90182-8

Cited by 190 publications

(103 citation statements)

References 24 publications

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“…Finally, 12-HETE, the main downstream metabolite of 12-HPETE without GC activation capacity, did not induce cell death in control or BSO-treated cultures. Although the reduction of 12-HPETE to 12-HETE is very rapid, and it has long been known to be a major metabolite of AA in brain (28), the 12-HPETE metabolism is not limited to its reduction and, therefore, the participation of other derived compounds such as hepoxilins in cell death may not be formally discarded.…”

Section: Discussionmentioning

confidence: 99%

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Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase

Canals¹,

Casarejos

Bernardo

et al. 2003

Journal of Biological Chemistry

100

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Glutathione (GSH) depletion is the earliest biochemical alteration shown to date in brains ofHere we demonstrate that arachidonic acid (AA) metabolism through the 12-lipoxygenase (12-LOX) pathway is also central for this GSH-NO interaction. LOX inhibitors (nordihydroguaiaretic acid and baicalein), but not cyclooxygenase (indomethacin) or epoxygenase (clotrimazole) ones, prevent cell death in the culture, even when added 10 h after NO treatment. Furthermore, the addition of AA to GSH-depleted cultures precipitates a cell death process that is indistinguishable from that initiated by NO in its morphology, time course, and 12-LOX, GC, and PKG dependence. The first AA metabolite through the 12-LOX enzyme, 12-hydroperoxyeicosatetraenoic acid, induces cell death in the culture, and its toxicity is greatly enhanced by GSH depletion. In addition we show that if GSH synthesis inhibition persists for up to 4 days without any additional treatment, it will induce a cell death process that also depends on 12-LOX, GC, and PKG activation. In this study, therefore, we show that the signaling pathway AA/12-LOX/12-HPETE/GC/ PKG may be important in several pathologies in which GSH decrease has been documented, such as Parkinson's disease. The potentiating effect of NO over such a signaling pathway may be of relevance as part of the cascade of events leading to and sustaining nerve cell death.

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Section: Discussionmentioning

confidence: 99%

“…The last hypothesis is based on the fact that GSH depletion potentiates 12-HPETE toxicity and on data showing that the GSH system participates in the reduction of lipid hydroperoxides into hydroxy acids (28). But another important function of GSH may be directly related to NO.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase

Canals¹,

Casarejos

Bernardo

et al. 2003

Journal of Biological Chemistry

100

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“…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%

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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“…After all, some of the most effec tive and widely used drugs are directed at intracellular messenger pathways. Aspirin and all other nonsteroi dal antiinflammatory agents inhibit cyclo-oxygenase, the fIrst enzyme in the generation of prostaglandin, leu kotriene, and endoperoxide intracellular messengers (Piomelli and Greengard 1990). FK-506 and related im munosuppressive agents bind to a newly discovered class of protein, the immunophilins (also present at high levels in brain), that regulate the activity of specific pro tein phosphatases (see Steiner et al 1992).…”

Section: Contributions Of Intracellular Messenger Proteins To Drug Dementioning

confidence: 99%

Molecular Neurobiology of Drug Addiction

Nestler

1994

Neuropsychopharmacol

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The purpose of this review is to illustrate the ways in which molecular neurobiological investigations will contribute to an improved understanding of drug addiction and, ultimately, to the development of more effective treatments. Such molecular studies of drug addiction are needed to establish two general types of in formation: (1) mechanisms of pathophysiology, identification of the changes that drugs of abuse produce KEY WORDS: Synaptic transmission; Drug addiction; G proteins; Ventral tegmental area; Cyclic AMP; Nucleus accumbens EVOLVING MODELS OF SYNAPTIC TRANSMISSIONThe most important area where molecular neurobiolog ical investigations have contributed to drug addiction, and to biological psychiatry in general, is the increas ingly complete and sophisticated picture of synaptic transmission these studies have provided. Figure 1 shows a working model of synaptic transmission around the time (1968)(1969)(1970)(1971)(1972)(1973)(1974)(1975)(1976)

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Lipoxygenase metabolites of arachidonic acid in neuronal transmembrane signalling

Cited by 190 publications

References 24 publications

Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase

Nitric Oxide Triggers the Toxicity due to Glutathione Depletion in Midbrain Cultures through 12-Lipoxygenase

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

Molecular Neurobiology of Drug Addiction

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