The 5‐lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages

Rossi, Antonietta; Pergola, Carlo; Koeberle, Andreas; Hoffmann, Marika; Dehm, Friederike; Bramantı, Placido; Cuzzocrea, Salvatore; Werz, Oliver; Sautebin, Lidia

doi:10.1111/j.1476-5381.2010.00930.x

Cited by 117 publications

(93 citation statements)

References 38 publications

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“…4F and Supplementary Fig. S3E), but by zileuton-a phenomenon that may be explained by the known effect of zileuton on arachidonic acid release (31). Both NO 2 -FA and zileuton decreased PGE 2 levels in the plasma ( Supplementary Fig.…”

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confidence: 88%

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

Awwad

Steinbrink²,

Frömel³

et al. 2014

Antioxidants & Redox Signaling

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Aims: The reaction of nitric oxide and nitrite-derived species with polyunsaturated fatty acids yields electrophilic fatty acid nitroalkene derivatives (NO 2 -FA), which display anti-inflammatory properties. Given that the 5-lipoxygenase (5-LO, ALOX5) possesses critical nucleophilic amino acids, which are potentially sensitive to electrophilic modifications, we determined the consequences of NO 2 -FA on 5-LO activity in vitro and on 5-LOmediated inflammation in vivo. Results: Stimulation of human polymorphonuclear leukocytes (PMNL) with nitro-oleic (NO 2 -OA) or nitro-linoleic acid (NO 2 -LA) (but not the parent lipids) resulted in the concentrationdependent and irreversible inhibition of 5-LO activity. Similar effects were observed in cell lysates and using the recombinant human protein, indicating a direct reaction with 5-LO. NO 2 -FAs did not affect the activity of the platelet-type 12-LO (ALOX12) or 15-LO-1 (ALOX15) in intact cells or the recombinant protein. The NO 2 -FAinduced inhibition of 5-LO was attributed to the alkylation of Cys418, and the exchange of Cys418 to serine rendered 5-LO insensitive to NO 2 -FA. In vivo, the systemic administration of NO 2 -OA to mice decreased neutrophil and monocyte mobilization in response to lipopolysaccharide (LPS), attenuated the formation of the 5-LO product 5-hydroxyeicosatetraenoic acid (5-HETE), and inhibited lung injury. The administration of NO 2 -OA to 5-LO knockout mice had no effect on LPS-induced neutrophil or monocyte mobilization as well as on lung injury. Innovation: Prophylactic administration of NO 2 -OA to septic mice inhibits inflammation and promotes its resolution by interfering in 5-LO-mediated inflammatory processes. Conclusion: NO 2 -FAs directly and irreversibly inhibit 5-LO and attenuate downstream acute inflammatory responses. Antioxid. Redox Signal. 20, 2667Signal. 20, -2680

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confidence: 88%

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

Awwad

Steinbrink²,

Frömel³

et al. 2014

Antioxidants & Redox Signaling

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“…Zileuton, the only approved 5-LOX inhibitor as a treatment for asthma, is wildly utilized as a selective tool to evaluate the role of 5-LOX. 13) By using the model of oxidative glutamate toxicity in HT22 cells, we investigated if zileuton conferred direct neuroprotection against oxidative toxicity.…”

Section: )mentioning

confidence: 99%

The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis

Yang

Wang

et al. 2015

Biological & Pharmaceutical Bulletin

150

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5-Lipoxygenase (5-LOX) inhibitors have been shown to be protective in several neurodegenerative disease models; however, the underlying mechanisms remain unclear. We investigated whether 5-LOX inhibitor zileuton conferred direct neuroprotection against glutamate oxidative toxicity by inhibiting ferroptosis, a newly identified iron-dependent programmed cell death. Treatment of HT22 mouse neuronal cell line with glutamate resulted in significant cell death, which was inhibited by zileuton in a dose-dependent manner. Consistently, zileuton decreased glutamate-induced production of reactive oxygen species but did not restore glutamate-induced depletion of glutathione. Moreover, the pan-caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (ZVAD-fmk) neither prevented HT22 cell death induced by glutamate nor affected zileuton protection against glutamate oxidative toxicity, suggesting that zileuton did not confer neuroprotection by inhibiting caspase-dependent apoptosis. Interestingly, glutamate-induced HT22 cell death was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. Moreover, zileuton protected HT22 neuronal cells from erastin-induced ferroptosis. However, we did not observe synergic protective effects of zileuton and ferrostatin-1 on glutamate-induced cell death. These results suggested that both the 5-LOX inhibitor zileuton and the ferropotosis inhibitor ferrostatin-1 acted through the same cascade to protect against glutamate oxidative toxicity. In conclusion, our results suggested that zileuton protected neurons from glutamate-induced oxidative stress at least in part by inhibiting ferroptosis.Key words 5-lipoxygenase inhibitor; neuroprotection; glutamate oxidative toxicity; ferroptosis Glutamate, an important excitatory transmitter in the central nervous system, essentially contributed to the pathogenesis of a variety of neurological diseases. When excessively released, glutamate induces both receptor-dependent excitotoxicity and non-receptor-mediated oxidative toxicity, which are implicated in a number of neurodegeneration diseases, such as stroke.1-6) Thus, targeting glutamate-induced oxidative toxicity is a promising strategy for treating neurological diseases.

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“…The choice of these drugs was based upon the COX-1/2 non-selective [16] behavior of first three, COX-2 selective mode of action of celecoxib [17] and 5-LOX selectivity of zileuton. [18] Mass spectra of the respective solutions of these drugs with COX-1, COX-2 and 5-LOX were recorded. As evident from the stoichiometry and association constant data of aspirin with COX-1 and COX-2 (entries 6-9, Table 1; entry 2, Table 2), its affinity as well as association constants for COX-1 and COX-2 are higher than that of AA (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Arachidonic acid metabolic pathway: Appraisal of differential availability of arachidonic acid and anti-inflammatory drugs to COX-1, COX-2 and 5-LOX enzymes

2014

Inflamm Cell Signal

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Arachidonic acid metabolic pathway has remarkable contribution in the working of biological systems. Having arachidonic acid as the common substrate; the COX-1, COX-2 and 5-LOX channels of this metabolic pathway produce different metabolites which play a significant role in homeostasis, blood clotting, gastrointestinal protection, inflammation and vasoconstriction. The quantity of metabolite produced from the three channels depends upon the expression of each enzyme as well as the affinity of the enzymes for arachidonic acid (the substrate). Here, it is found that the relative affinity of the three enzymes for AA follows the order 5-LOX, COX-1 and COX-2. Based on this trend, the metabolic significance of each channel is rationalized. Moreover, examining the relative interactions of anti-inflammatory drugs like aspirin, diclofenac, indomethacin, celecoxib, zileuton with the three enzymes, the possibility of side effects associated with these drugs was also revisited.

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The 5‐lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages

Cited by 117 publications

References 38 publications

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis

Arachidonic acid metabolic pathway: Appraisal of differential availability of arachidonic acid and anti-inflammatory drugs to COX-1, COX-2 and 5-LOX enzymes

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