Analogs of arachidonic acid methylated at C-7 and C-10 as inhibitors of leukotriene biosynthesis

Cohen, Noal; Weber, Giuseppe F.; Banner, Bruce L.; Welton, Ann F.; Hope, William C.; Crowley, Herman J.; Anderson, William A.; Simko, B.; O’Donnell, Margaret; Coffey, John W.; Fiedler‐Nagy, Christa; Batula-Bernardo, C.

doi:10.1016/0090-6980(84)90091-1

Cited by 22 publications

(5 citation statements)

References 32 publications

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“…DEDA is reported as a specific and competitive inhibitor of sPLA2 group II [ 35 ]. However, its effect on the expression of sPLA2 and the activity of other calcium-dependent PLA2s is not clear.…”

Section: Resultsmentioning

confidence: 99%

“…A selective inhibitor of sPLA2 IIA [ 35 ], 7,7-dimethyleicosadienoic acid (DEDA) is a non-toxic AA analog with IC 50 values in the range of 6–20 μM. DEDA has been documented to reduce sPLA2 activity significantly and decrease carotid artery ischemia-evoked release of glutamate and aspartate in the cerebral cortex when administered after injury in rats [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

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Reduction of lipoxidative load by secretory phospholipase A2 inhibition protects against neurovascular injury following experimental stroke in rat

Hoda

Singh

et al. 2009

J Neuroinflammation

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Background: In animal models, ischemia reperfusion (IR) injury triggers membrane lipid degradation and accumulation of lipoxidative exacerbations in neurovascular unit, leading to blood brain barrier (BBB) damage and neurologic deficits. In this study, we investigated whether impeding membrane lipid breakdown by inhibiting secretory phospholipase A2 (sPLA2) activity reduces BBB leakage, leading to neuroprotection and functional recovery.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduction of lipoxidative load by secretory phospholipase A2 inhibition protects against neurovascular injury following experimental stroke in rat

Hoda

Singh

et al. 2009

J Neuroinflammation

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“…Moreover, there is evidence suggesting that the ability to interact with nicotinic acetylcholine receptors may be a general property of several snakes PLA 2 from venoms [53,54]. To check the ability of the PLA 2 isolated from Micrurus lemniscatus (Mlx-8) to interact with mAChRs, the inhibitor of cobra venom phospholipases A 2 activity DEDA, an analogue of arachidonic acid that contains two cis double bonds as well as two methyl groups [55], was used in the present study. Indeed, the phospholipase A 2 enzymatic activity of Mlx-8 in the presence of DEDA decreased 51%.…”

Section: Discussionmentioning

confidence: 99%

Effects of Mlx-8, a phospholipase A2 from Brazilian coralsnake Micrurus lemniscatus venom, on muscarinic acetylcholine receptors in rat hippocampus

Santos

Silva

Porto

et al. 2020

J. Venom. Anim. Toxins incl. Trop. Dis

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Background: Here, we described the presence of a neurotoxin with phospholipase A 2 activity isolated from Micrurus lemniscatus venom (Mlx-8) with affinity for muscarinic acetylcholine receptors (mAChRs). Methods: The purification, molecular mass determination, partial amino acid sequencing, phospholipase A 2 activity determination, inhibition of the binding of the selective muscarinic ligand [ 3 H]QNB and inhibition of the total [ 3 H]inositol phosphate accumulation in rat hippocampus of the Mlx-8 were determined. Results: Thirty-one fractions were collected from HPLC chromatography, and the Mlx-8 toxin was used in this work. The molecular mass of Mlx-8 is 13.628 Da. Edman degradation yielded the following sequence: NLYQFKNMIQCTNTRSWL-DFADYG-CYCGRGGSGT. The Mlx-8 had phospholipase A 2 enzymatic activity. The pK i values were determined for Mlx-8 toxin and the M 1 selective muscarinic antagonist pirenzepine in hippocampus membranes via [ 3 H]QNB competition binding assays. The pK i values obtained from the analysis of Mlx-8 and pirenzepine displacement curves were 7.32 ± 0.15, n = 4 and 5.84 ± 0.18, n = 4, respectively. These results indicate that Mlx-8 has affinity for mAChRs. There was no effect on the inhibition ability of the [ 3 H]QNB binding in hippocampus membranes when 1 µM Mlx-8 was incubated with 200 µM DEDA, an inhibitor of phospholipase A 2. This suggests that the inhibition of the phospholipase A 2 activity of the venom did not alter its ability to bind to displace [ 3 H]QNB binding. In addition, the Mlx-8 toxin caused a blockade of 43.31 ± 8.86%, n = 3 and 97.42 ± 2.02%, n = 3 for 0.1 and 1 µM Mlx-8, respectively, on the total [ 3 H]inositol phosphate content induced by 10 µM carbachol. This suggests that Mlx-8 inhibits the intracellular

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“…Thus, it was possible that the effects of trifluoperazine shown in Figure 8 were unrelated to calmodulin. However, as shown in Table 2, the more specific inhibitor of arachidonic acid metabolism, DEDA (Cohen et al, 1984), was without an effect on receptor-independent increases in [Ca2+]i. Additionally, the calmodulin inhibitor W-7 (Hidaka et al, 1981) did inhibit the increase in [Ca2+]i seen in response to thapsigargin (Table 2). W-7 exerts its inhibitory actions in a manner entirely different from the phenothiazines.…”

Section: Calmodulinmentioning

confidence: 92%

Increased intracellular Ca2+ induces Ca2+ influx in human T lymphocytes.

Haverstick

Gray

1993

MBoC

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One current hypothesis for the initiation of Ca2+ entry into nonelectrically excitable cells proposes that Ca2+ entry is linked to the state of filling of intracellular Ca2+ stores. In the human T lymphocyte cell line Jurkat, stimulation of the antigen receptor leads to release of Ca2+ from internal stores and influx of extracellular Ca2+. Similarly, treatment of Jurkat cells with the tumor promoter thapsigargin induced release of Ca2+ from internal stores and also resulted in influx of extracellular Ca2+. Initiation of Ca2+ entry by thapsigargin was blocked by chelation of Ca2+ released from the internal storage pool. The Ca2+ entry pathway also could be initiated by an increase in the intracellular concentration of Ca2+ after photolysis of the Ca(2+)-cage, nitr-5. Thus, three separate treatments that caused an increase in the intracellular concentration of Ca2+ initiated Ca2+ influx in Jurkat cells. In all cases, Ca(2+)-initiated Ca2+ influx was blocked by treatment with any of three phenothiazines or W-7, suggesting that it is mediated by calmodulin. These data suggest that release of Ca2+ from internal stores is not linked capacitatively to Ca2+ entry but that initiation is linked instead by Ca2+ itself, perhaps via calmodulin.

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Analogs of arachidonic acid methylated at C-7 and C-10 as inhibitors of leukotriene biosynthesis

Cited by 22 publications

References 32 publications

Reduction of lipoxidative load by secretory phospholipase A2 inhibition protects against neurovascular injury following experimental stroke in rat

Reduction of lipoxidative load by secretory phospholipase A2 inhibition protects against neurovascular injury following experimental stroke in rat

Effects of Mlx-8, a phospholipase A2 from Brazilian coralsnake Micrurus lemniscatus venom, on muscarinic acetylcholine receptors in rat hippocampus

Increased intracellular Ca2+ induces Ca2+ influx in human T lymphocytes.

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