Sesquiterpene lactone from Wunderlichia crulsiana inhibits the respiratory burst of leukocytes triggered by distinct biochemical pathways

Núñez, Cecília Veronica; Zacheu, Fabı́ola Maria; Pinto, Ernani; Roque, Nı́dia Franca; Colepicolo, Pio; Brigagão, Maı́sa Ribeiro Pereira Lima

doi:10.1016/s0024-3205(03)00600-3

Cited by 8 publications

(2 citation statements)

References 33 publications

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“…Similar differential effects between PMA and OPZ-triggered signaling have been observed with other natural products [62]. Furthermore, the current data suggest the following on the as yet undefined mechanism of action of MZA: Firstly, that the MZA molecular target plays a critical role in O 2 - and TXB 2 generation initiated by PMA upon binding to PKC [63,64] and activation of the p44/42 mitogen-activated protein kinase signaling pathway [43]; Secondly, that the MZA molecular target probably plays a less critical role in O 2 - and TXB 2 release elicited by OPZ, a ligand of the microglial cell surface complement receptor 3 shown to activate the p38 mitogen-activated protein kinase signaling pathway [43].…”

Section: Discussionsupporting

confidence: 73%

Differential modulation of microglia superoxide anion and thromboxane B2 generation by the marine manzamines

et al. 2005

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BackgroundThromboxane B2 (TXB2) and superoxide anion (O2-) are neuroinflammatory mediators that appear to be involved in the pathogenesis of several neurodegenerative diseases. Because activated-microglia are the main source of TXB2 and O2- in these disorders, modulation of their synthesis has been hypothesized as a potential therapeutic approach for neuroinflammatory disorders. Marine natural products have become a source of novel agents that modulate eicosanoids and O2- generation from activated murine and human leukocytes. With the exception of manzamine C, all other manzamines tested are characterized by a complex pentacyclic diamine linked to C-1 of the β-carboline moiety. These marine-derived alkaloids have been reported to possess a diverse range of bioactivities including anticancer, immunostimulatory, insecticidal, antibacterial, antimalarial and antituberculosis activities. The purpose of this investigation was to conduct a structure-activity relationship study with manzamines (MZ) A, B, C, D, E and F on agonist-stimulated release of TXB2 and O2- from E. coli LPS-activated rat neonatal microglia in vitro.ResultsThe manzamines differentially attenuated PMA (phorbol 12-myristate 13-acetate)-stimulated TXB2 generation in the following order of decreasing potency: MZA (IC50 <0.016 μM) >MZD (IC50 = 0.23 μM) >MZB (IC50 = 1.6 μM) >MZC (IC50 = 2.98 μM) >MZE and F (IC50 >10 μM). In contrast, there was less effect on OPZ (opsonized zymosan)-stimulated TXB2 generation: MZB (IC50 = 1.44 μM) >MZA (IC50 = 3.16 μM) >MZC (IC50 = 3.34 μM) >MZD, MZE and MZF (IC50 >10 μM). Similarly, PMA-stimulated O2- generation was affected differentially as follows: MZD (apparent IC50<0.1 μM) >MZA (IC50 = 0.1 μM) >MZB (IC50 = 3.16 μM) >MZC (IC50 = 3.43 μM) >MZE and MZF (IC50 >10 μM). In contrast, OPZ-stimulated O2- generation was minimally affected: MZB (IC50 = 4.17 μM) >MZC (IC50 = 9.3 μM) >MZA, MZD, MZE and MZF (IC50 > 10 μM). From the structure-activity relationship perspective, contributing factors to the observed differential bioactivity on TXB2 and O2- generation are the solubility or ionic forms of MZA and D as well as changes such as saturation or oxidation of the β carboline or 8-membered amine ring. In contrast, the fused 13-membered macrocyclic and isoquinoline ring system, and any substitutions in these rings would not appear to be factors contributing to bioactivity.ConclusionTo our knowledge, this is the first experimental study that demonstrates that MZA, at in vitro concentrations that are non toxic to E. coli LPS-activated rat neonatal microglia, potently modulates PMA-stimulated TXB2 and O2- generation. MZA may thus be a lead candidate for the development of novel therapeutic agents for the modulation of TXB2 and O2- release in neuroinflammatory diseases. Marine natural products provide a novel and rich source of chemical diversity that can contribute to the design and development of new and potentially useful anti-inflammatory agents to treat neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 73%

Differential modulation of microglia superoxide anion and thromboxane B2 generation by the marine manzamines

et al. 2005

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“…Recently, Siedle et al (2002) also reported inhibition of the catalytic activity and release of human PMNL elastase by low concentrations of STLs. Previous investigations reported a ROS scavenger effect in-vitro (Seitembetova et al 1995;Jodynis-Liebert et al 1999) and inhibition of PMNL respiratory burst associated with the inflammatory process (Pe´rez-Garcia et al 1996;Nun˜ez et al 2003).…”

Section: Introductionmentioning

confidence: 96%

Sesquiterpene lactones fromLychnophora pohlii: neutrophil chemiluminescence inhibition and free radical scavenger activity

Kanashiro

Kabeya

Grael

et al. 2006

Journal of Pharmacy and Pharmacology

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Excessive production of reactive oxygen species (ROS) by polymorphonuclear leucocytes (PMNLs) is thought to contribute to the pathology of many inflammatory diseases. Sesquiterpene lactones (STLs) seem to be important contributors to the anti-inflammatory activity of many species of Lychnophora (Asteraceae), which have been widely used in Brazilian folk medicine because of this pharmacological property. In this study, the inhibitory effects of three STLs isolated from Lychnophora pohlii (lychnopholide, centratherin and goyazensolide) on rabbit PMNL oxidative burst were evaluated by the luminol-enhanced chemiluminescence (CL-lum) assay. All STLs tested showed concentration-dependent inhibitory activity on CL-lum but were not cytotoxic to PMNLs (evaluated by lactate dehydrogenase release) under the assessed conditions. Moreover, goyazensolide, the most active STL, had no free radical scavenger property, as assessed by 1,1-diphenyl-2picrylhydrazyl radical assay, and had no inhibitory effect on the luminol-horseradish peroxidase-hydrogen peroxide chemiluminescence. Taken together, the results of this investigation suggest that the concomitant presence of methacrylate ester and hydroxyl groups contributes to a high inhibitory effect on PMNL oxidative metabolism. This effect was not mediated by free radical scavenger or cytotoxic effects, but probably by inhibition of enzymes involved in the signal transduction pathways of the ROS generation process.

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Modulation of human neutrophil oxidative metabolism and degranulation by extract of Tamarindus indica L. fruit pulp

Paula

Kabeya

Kanashiro

et al. 2009

Food and Chemical Toxicology

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Sesquiterpene lactone from Wunderlichia crulsiana inhibits the respiratory burst of leukocytes triggered by distinct biochemical pathways

Cited by 8 publications

References 33 publications

Differential modulation of microglia superoxide anion and thromboxane B2 generation by the marine manzamines

Differential modulation of microglia superoxide anion and thromboxane B2 generation by the marine manzamines

Sesquiterpene lactones fromLychnophora pohlii: neutrophil chemiluminescence inhibition and free radical scavenger activity

Modulation of human neutrophil oxidative metabolism and degranulation by extract of Tamarindus indica L. fruit pulp

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