The enzymology and pharmacology of 5-lipoxygenase and 5-lipoxygenase activating protein

Bell, Randy L.; Harris, Richard R.

doi:10.1007/bf02737599

Cited by 10 publications

(4 citation statements)

References 97 publications

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“…The concentrations of the specific inhibitors of 5-LOX and FLAP required to inhibit monocytic and microglial toxicity were above their reported inhibitory concentration (IC 50 ) values as inhibitors of 5-LOX enzymatic activity. These values have been reported to be 0.7 M for zilueton [3], 0.12 M for REV 5901 [59], and 0.1 M for MK-886 [60]. However, concentrations in the range of 1-10 M of these inhibitors have been required to achieve biological effects in various in vitro assays (e.g., refs.…”

Section: Discussionmentioning

confidence: 99%

“…Selective 5-LOX inhibitors and CysLT 1 antagonists are already available for clinical use and are prescribed for asthma treatment (see refs. [1,3,15,38]). The data from this study suggest that there may be a role for 5-LOX inhibitors in neuroinflammatory disorders possibly as a part of multitarget therapy.…”

Section: Discussionmentioning

confidence: 99%

“…They also have other proinflammatory properties (for reviews, see refs. [3][4][5][6]) as well as possible roles in intracellular and intranuclear signaling [7]. 5-LOX is primarily localized in leukocytes.…”

Section: Introductionmentioning

confidence: 99%

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Toxicity of human monocytic THP-1 cells and microglia toward SH-SY5Y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein FLAP

Klegeris

McGeer

2003

Journal of Leukocyte Biology

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To explore whether the proinflammatory products of the 5-lipoxygenase (5-LOX) pathway are involved in microglia-mediated toxicity toward neuronal cells, we evaluated the effects of 5-LOX inhibitors using an in vitro assay system where human neuronal SH-SY5Y cells are exposed to toxic secretions from THP-1 monocytic cells or human microglia. The specific 5-LOX inhibitors, REV 5901, zileuton, and 5-hydroxyeicosatetraenoic acid lactone; the nonselective LOX inhibitors, phenidone and dapsone; the dual 5-LOX/cyclooxygenase inhibitor, tepoxalin; and the selective inhibitor of the 5-LOX-activating protein (FLAP), MK-886, inhibited such toxicity. The toxicity was enhanced by the 5-LOX product leukotriene (LT)D(4) and reduced by the selective cysteinyl LT receptor (CysLT(1)) antagonist MK-571. The mRNAs for 5-LOX and FLAP were detected in THP-1 cells and human microglia but not in SH-SY5Y cells. The data suggest that inhibition of proinflammatory LT production by 5-LOX inhibition could selectively reduce toxicity of microglial cells and thus be beneficial in neuroinflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Toxicity of human monocytic THP-1 cells and microglia toward SH-SY5Y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein FLAP

Klegeris

McGeer

2003

Journal of Leukocyte Biology

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“…SP‐induced stimulation of endothelial cells, mast cells and/or neutrophils may trigger the release of arachidonic acid metabolites by these cyclo‐oxygenase (COX) and lipoxygenase (LOX) rich cells ( Bell & Harris, 1999 ; Pairet & Engelhardt, 1996 ). Arachidonic acid derivatives are important inflammatory mediators in several models of acute and chronic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Cyclo‐oxygenase and lipoxygenase pathways in mast cell dependent‐neurogenic inflammation induced by electrical stimulation of the rat saphenous nerve

Filliatre

Sayah

Latournerie

et al. 2001

British J Pharmacology

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1 We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic in¯ammation in rat paw skin. We compared the eect of lipoxygenase (LOX) and cyclo-oxygenase (COX) inhibitors on oedema induced by saphenous nerve stimulation, substance P (SP), and compound 48/80. 2 Intravenous (i.v.) pre-treatment with a dual COX/LOX inhibitor (RWJ 63556), a dual LOX inhibitor/cysteinyl-leukotriene (CysLt) receptor antagonist (Rev 5901), a LOX inhibitor (AA 861), a ®ve-lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S-transferase inhibitor (ethacrynic acid) signi®cantly inhibited (40 to 60%) the development of neurogenic oedema, but did not aect cutaneous blood¯ow. Intradermal (i.d.) injection of LOX inhibitors reduced SP-induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating eect. 3 Indomethacin and rofecoxib, a highly selective COX-2 inhibitor, did not aect neurogenic and SP-induced oedema. Surprisingly, the structurally related COX-2 inhibitors, NS 398 and nimesulide, signi®cantly reduced both neurogenic and SP-induced oedema (70% and 42% for neurogenic oedema, respectively; 49% and 46% for SP-induced oedema, respectively). 4 COX-2 mRNA was undetectable in saphenous nerves and paw skin biopsy samples, before and after saphenous nerve stimulation. 5 A mast cell stabilizer, cromolyn, and a H 1 receptor antagonist, mepyramine, signi®cantly inhibited neurogenic (51% and 43%, respectively) and SP-induced oedema (67% and 63%, respectively). 6 The co-injection of LOX inhibitors and compound 48/80 did not alter the eects of compound 48/80. Conversely, ethacrynic acid had a signi®cant potentiating eect. The pharmacological pro®le of the eect of COX inhibitors on compound 48/80-induced oedema was similar to that of neurogenic and SP-induced oedema. 7 The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not aect neurogenic or SPinduced oedema. 8 Thus, (i) SP-induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene-mediated plasma extravasation might be independent of mast cell activation and/or of the adhesion of leukocytes to the endothelium; (iii) COX did not appear to play a signi®cant role in this process.

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Arachidonate 5-lipoxygenase

Springer Handbook of Enzymes

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The enzymology and pharmacology of 5-lipoxygenase and 5-lipoxygenase activating protein

Cited by 10 publications

References 97 publications

Toxicity of human monocytic THP-1 cells and microglia toward SH-SY5Y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein FLAP

Toxicity of human monocytic THP-1 cells and microglia toward SH-SY5Y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein FLAP

Cyclo‐oxygenase and lipoxygenase pathways in mast cell dependent‐neurogenic inflammation induced by electrical stimulation of the rat saphenous nerve

Arachidonate 5-lipoxygenase

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