ملخص
Abstract. Background: Using molecular modeling simulations and Albino mice model ,accumulating evidence indicates a role for Ciguatoxins (CTXs) in protecting from many neurological problems mainly pathognomonic features of postingestion paraesthesiae, dysaesthesiae, heightened nociperception pruritis, arthralgia, myalgia, cerebellar dysfunction, neuropathy and polymyositis. Evidence shows that Echium angustifolium Mill constituents can be used to prevent CTX toxicity. Further chemical synthesis of analogues and in vivo studies, were necessary to substantiate the obtained results. The aim of the study is to explore the effect of Echium angustifolium Mill constituents on ciguatoxins toxicity produced by microalgae (dinoflagellate, Gambierdiscus spp) using molecular modelling strategy and in vivo mice model. Methods: A total of 30 adult male Swiss albino mice (2 to 2.6 months old, N=6) were randomly divided into five groups and treated orally as follows. The first five group received only 200 ?l (0. 2 g/ml) of the CTXs extract (LD50 0.45?g/ kg, in mice). Groups 2 -5 were given an equivalent amount of extract with 100 ?l, 200?l, 300?l and 400?l of aqueous Echium angustifolium Mill extract orally (0.043 g/ml), respectively. The number of deaths was recorded within twenty-four hours. Similar experiments were conducted with liver, brain and viscera extracts using groups 6 to 20. Molecular modeling as a tool was used to aid the understanding of the fundamental concepts of structure-activity relationships, and to elucidate the mechanism of action of experimental Echium angustifolium Mill constituents with the ciguatoxins toxicity. The physico-chemical properties as well as three-dimensional visualization of electronic and steric molecular properties elucidation of the interaction between Echium angustifolium Mill constituents and macromolecules target sodium (Na+ ) and potassium (K+ ) voltage-gated channels can be calculated and/or suggested by molecular modeling programs. Molecular dockings of Echium angustifolium Mill components with (sodium (Na+ ) and potassium (K+ ) voltage-gated channels) were accomplished by Auto Dock 4.2 software. Results: The Sarpa salpa toxin introduced to the experimental mice, caused different histopathological effects on the four different tissues and different LD50 values. The mice affected by the toxin exhibited typical signs of neurotoxin disorders including hypothermia, considerably reduced locomotors activity during the first three hours and eventually breathing failure showing a significant difference in toxicity between the four extracts. Clearly, the concentrations of toxins in organs were different and can be ranked in ascending order; flesh, brain, liver, and lastly the viscera extract. The Echium angustifolium Mill aqueous extract significantly increases mean survival time up to 5±1 days and protects animals from death if compared with the control. Echium angustifolium Mill aqueous extract if used at a higher dose was found to be more effective against Sarpa salpa toxin. The binding energies of Echium angustifolium Mill constituents to voltage-gated Na+ (6AGF) and K+ (1BL8) channels obtained by the molecular docking strategy are significant. The modeling studies show that there are van der Waals, hydrogen bonding and electrostatic interactions between Echium angustifolium Mill constituents with voltage-gated channels.