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Dalia Gordon - One of the best experts on this subject based on the ideXlab platform.
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Characterization of scorpion α‐like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus
FEBS Journal, 2002Co-Authors: Alain Hamon, Charles Kopeyan, Nicolas Gilles, Pierre Sautiere, Arlette Martinage, Chris Ulens, Jan Tytgat, Jeanmarc Lancelin, Dalia GordonAbstract:Two novel toxins, Lqh6 and Lqh7, isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus, have in their sequence a molecular signature (8Q/KPE10) associated with a recently defined group of α-toxins that target Na channels, namely the α-like toxins [reviewed in Gordon, D., Savarin, P., Gurevitz, M. & Zinn-Justin, S. (1998) J. Toxicol. Toxin Rev. 17, 131–159]. Lqh6 and Lqh7 are highly toxic to insects and mice, and inhibit the binding of α-toxins to cockroach neuronal membranes. Although they kill rodents by intracerebroventricular injection, they do not inhibit the binding of antimammal α-toxins (e.g. Lqh2) to rat brain synaptosomes, not even at high concentrations. Furthermore, in voltage-clamp experiments, rat brain Na channels IIA (rNav1.2A) expressed in Xenopus oocytes are not affected by Lqh6 nor by Lqh7 below 3 µm. In contrast, muscular Na channels (rNav1.4 and hNav1.5) expressed in the same cells respond to nanomolar concentrations of Lqh6 and Lqh7 by slowing of Na current inactivation and a leftward shift of the peak conductance–voltage curve. The structural and pharmacological properties of the new toxins are compared to those of other scorpion α-toxins in order to re-examine the hallmarks previously set for the α-like toxin group.
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characterization of scorpion α like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus
FEBS Journal, 2002Co-Authors: Alain Hamon, Charles Kopeyan, Nicolas Gilles, Pierre Sautiere, Arlette Martinage, Chris Ulens, Jan Tytgat, Jeanmarc Lancelin, Dalia GordonAbstract:Two novel toxins, Lqh6 and Lqh7, isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus, have in their sequence a molecular signature (8Q/KPE10) associated with a recently defined group of α-toxins that target Na channels, namely the α-like toxins [reviewed in Gordon, D., Savarin, P., Gurevitz, M. & Zinn-Justin, S. (1998) J. Toxicol. Toxin Rev. 17, 131–159]. Lqh6 and Lqh7 are highly toxic to insects and mice, and inhibit the binding of α-toxins to cockroach neuronal membranes. Although they kill rodents by intracerebroventricular injection, they do not inhibit the binding of antimammal α-toxins (e.g. Lqh2) to rat brain synaptosomes, not even at high concentrations. Furthermore, in voltage-clamp experiments, rat brain Na channels IIA (rNav1.2A) expressed in Xenopus oocytes are not affected by Lqh6 nor by Lqh7 below 3 µm. In contrast, muscular Na channels (rNav1.4 and hNav1.5) expressed in the same cells respond to nanomolar concentrations of Lqh6 and Lqh7 by slowing of Na current inactivation and a leftward shift of the peak conductance–voltage curve. The structural and pharmacological properties of the new toxins are compared to those of other scorpion α-toxins in order to re-examine the hallmarks previously set for the α-like toxin group.
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nmr structures and activity of a novel alpha like toxin from the scorpion Leiurus quinquestriatus hebraeus
Journal of Molecular Biology, 1999Co-Authors: Isabelle Krimm, Nicolas Gilles, Pierre Sautiere, Dalia Gordon, Maria Stankiewicz, M Pelhate, Jeanmarc LancelinAbstract:NMR structures of a new toxin from the scorpion Leiurus quinquestriatus hebraeus (Lqh III) have been investigated in conjunction with its pharmacological properties. This toxin is proposed to belong to a new group of scorpion toxins, the α-like toxins that target voltage-gated sodium channels with specific properties compared with the classical α-scorpion toxins. Electrophysiological analysis showed that Lqh III inhibits a sodium current inactivation in the cockroach axon, but induces in addition a resting depolarization due to a slowly decaying tail current atypical to other α-toxin action. Binding studies indicated that radiolabeled Lqh III binds with a high degree of affinity (Ki=2.2 nM) on cockroach sodium channels and that the α-toxin from L quinquestriatus hebraeus highly active on insects (LqhαIT) and α-like toxins compete at low concentration for its receptor binding site, suggesting that the α-like toxin receptor site is partially overlapping with the receptor site 3. Conversely, in rat brain, Lqh III competes for binding of the most potent anti-mammal α-toxin from Androctonus australis Hector venom (AaH II) only at very high concentration. The NMR structures were used for the scrutiny of the similarities and differences with representative scorpion α-toxins targeting the voltage-gated sodium channels of either mammals or insects. Three turn regions involved in the functional binding site of the anti-insect LqhαIT toxin reveal significant differences in the Lqh III structure. The electrostatic charge distribution in the Lqh III toxin is also surprisingly different when compared with the anti-mammal α-toxin AaH II. Similarities in the electrostatic charge distribution are, however, recognized between α-toxins highly active on insects and the α-like toxin Lqh III. This affords additional important elements to the definition of the new α-like group of scorpion toxins and the mammal versus insect scorpion toxin selectivities.
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new toxins acting on sodium channels from the scorpion Leiurus quinquestriatus hebraeus suggest a clue to mammalian vs insect selectivity
Toxicon, 1998Co-Authors: Pierre Sautiere, Charles Kopeyan, Arlette Martinage, Sandrine Cestele, Herve Drobecq, Yvon Doljansky, Dalia GordonAbstract:Two new toxins were purified from Leiurus quinquestriatus hebraeus (Lqh) scorpion venom, Lqh II and Lqh III. Lqh II sequence reveals only two substitutions, as compared to AaH II, the most active scorpion α-toxin on mammals from Androctounus australis Hector. Lqh III shares 80% sequence identity with the α-like toxin Bom III, from Buthus occitanus mardochei. Using bioassays on mice and cockroach coupled with competitive binding studies with 125I-labeled scorpion α-toxins on rat brain and cockroach synaptosomes, the animal selectivity was examined. Lqh II has comparable activity to mammals as AaH II, but reveals significantly higher activity to insects attributed to its C-terminal substitution, and competes at low concentration for binding on both mammalian and cockroach sodium channels. Lqh II thus binds to receptor site 3 on sodium channels. Lqh III is active on both insects and mammals but competes for binding only on cockroach. The latter indicates that Lqh III binds to a distinct receptor site. Thus, Lqh II and Lqh III represent two different scorpion toxin groups, the α- and α-like toxins, respectively, according to the structural and pharmacological criteria. These new toxins may serve as a lead for clarification of the structural basis for insect vs mammal selectivity of scorpion toxins.
Charles Kopeyan - One of the best experts on this subject based on the ideXlab platform.
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Characterization of scorpion α‐like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus
FEBS Journal, 2002Co-Authors: Alain Hamon, Charles Kopeyan, Nicolas Gilles, Pierre Sautiere, Arlette Martinage, Chris Ulens, Jan Tytgat, Jeanmarc Lancelin, Dalia GordonAbstract:Two novel toxins, Lqh6 and Lqh7, isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus, have in their sequence a molecular signature (8Q/KPE10) associated with a recently defined group of α-toxins that target Na channels, namely the α-like toxins [reviewed in Gordon, D., Savarin, P., Gurevitz, M. & Zinn-Justin, S. (1998) J. Toxicol. Toxin Rev. 17, 131–159]. Lqh6 and Lqh7 are highly toxic to insects and mice, and inhibit the binding of α-toxins to cockroach neuronal membranes. Although they kill rodents by intracerebroventricular injection, they do not inhibit the binding of antimammal α-toxins (e.g. Lqh2) to rat brain synaptosomes, not even at high concentrations. Furthermore, in voltage-clamp experiments, rat brain Na channels IIA (rNav1.2A) expressed in Xenopus oocytes are not affected by Lqh6 nor by Lqh7 below 3 µm. In contrast, muscular Na channels (rNav1.4 and hNav1.5) expressed in the same cells respond to nanomolar concentrations of Lqh6 and Lqh7 by slowing of Na current inactivation and a leftward shift of the peak conductance–voltage curve. The structural and pharmacological properties of the new toxins are compared to those of other scorpion α-toxins in order to re-examine the hallmarks previously set for the α-like toxin group.
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characterization of scorpion α like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus
FEBS Journal, 2002Co-Authors: Alain Hamon, Charles Kopeyan, Nicolas Gilles, Pierre Sautiere, Arlette Martinage, Chris Ulens, Jan Tytgat, Jeanmarc Lancelin, Dalia GordonAbstract:Two novel toxins, Lqh6 and Lqh7, isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus, have in their sequence a molecular signature (8Q/KPE10) associated with a recently defined group of α-toxins that target Na channels, namely the α-like toxins [reviewed in Gordon, D., Savarin, P., Gurevitz, M. & Zinn-Justin, S. (1998) J. Toxicol. Toxin Rev. 17, 131–159]. Lqh6 and Lqh7 are highly toxic to insects and mice, and inhibit the binding of α-toxins to cockroach neuronal membranes. Although they kill rodents by intracerebroventricular injection, they do not inhibit the binding of antimammal α-toxins (e.g. Lqh2) to rat brain synaptosomes, not even at high concentrations. Furthermore, in voltage-clamp experiments, rat brain Na channels IIA (rNav1.2A) expressed in Xenopus oocytes are not affected by Lqh6 nor by Lqh7 below 3 µm. In contrast, muscular Na channels (rNav1.4 and hNav1.5) expressed in the same cells respond to nanomolar concentrations of Lqh6 and Lqh7 by slowing of Na current inactivation and a leftward shift of the peak conductance–voltage curve. The structural and pharmacological properties of the new toxins are compared to those of other scorpion α-toxins in order to re-examine the hallmarks previously set for the α-like toxin group.
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new toxins acting on sodium channels from the scorpion Leiurus quinquestriatus hebraeus suggest a clue to mammalian vs insect selectivity
Toxicon, 1998Co-Authors: Pierre Sautiere, Charles Kopeyan, Arlette Martinage, Sandrine Cestele, Herve Drobecq, Yvon Doljansky, Dalia GordonAbstract:Two new toxins were purified from Leiurus quinquestriatus hebraeus (Lqh) scorpion venom, Lqh II and Lqh III. Lqh II sequence reveals only two substitutions, as compared to AaH II, the most active scorpion α-toxin on mammals from Androctounus australis Hector. Lqh III shares 80% sequence identity with the α-like toxin Bom III, from Buthus occitanus mardochei. Using bioassays on mice and cockroach coupled with competitive binding studies with 125I-labeled scorpion α-toxins on rat brain and cockroach synaptosomes, the animal selectivity was examined. Lqh II has comparable activity to mammals as AaH II, but reveals significantly higher activity to insects attributed to its C-terminal substitution, and competes at low concentration for binding on both mammalian and cockroach sodium channels. Lqh II thus binds to receptor site 3 on sodium channels. Lqh III is active on both insects and mammals but competes for binding only on cockroach. The latter indicates that Lqh III binds to a distinct receptor site. Thus, Lqh II and Lqh III represent two different scorpion toxin groups, the α- and α-like toxins, respectively, according to the structural and pharmacological criteria. These new toxins may serve as a lead for clarification of the structural basis for insect vs mammal selectivity of scorpion toxins.
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1h nmr derived secondary structure and the overall fold of the potent anti mammal and anti insect toxin iii from the scorpion Leiurus quinquestriatus quinquestriatus
FEBS Journal, 1996Co-Authors: Celine Landon, Charles Kopeyan, H Rochat, Bruno Cornet, Jeanmarc Bonmatin, Francoise Vovelle, Marius PtakAbstract:We describe the secondary structure and the overall fold of toxin III from the venom of the scorpion Leiurus quinquestriatus quinquestriatus determined using two-dimensional-1H-NMR spectroscopy. This protein, which contains 64 amino acids and 4 disulfide bridges, belongs to the long-chain toxin category and is highly toxic to both mammals and insects. The overall fold was determined on the basis of 1208 inter-proton-distance restraints derived from NOE measurements and 90 Ψ, Φ dihedral-angle restraints derived from NOE connectivities and 3JNH-αH coupling constants using the HABAS program. This fold, which mainly consists of an α-helix packed against a small antiparallel three-stranded β-sheet, and of several turns and loops, is similar to that of other long-chain scorpion toxins. Aromatic and non-polar residues form several patches on the surface of the protein which alternate with patches of charged and polar residues. Such a topology should be important in the interactions of toxin III with sodium channels in membranes. Two weakly constrained loops introduce some flexibility to the structure which could be related to the activity of this toxin. The central core of toxin III is compared with the cysteine-stabilized αβ motif (an α-helix connected to a β-sheet through two disulfide bridges) found in insect defensins and plant thionins. Defensins and thionins are small proteins (≈40–50 amino acid residues) containing three or four disulfide bridges, respectively. This comparison confirms that the cysteine-stabilized αβ motif is a common core to a number of small proteins from different origins and having different activities.
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1H‐NMR‐Derived Secondary Structure and the Overall Fold of the Potent Anti‐Mammal and Anti‐Insect Toxin III from the Scorpion Leiurus quinquestriatus quinquestriatus
FEBS Journal, 1996Co-Authors: Celine Landon, Charles Kopeyan, Herve Rochat, Bruno Cornet, Jeanmarc Bonmatin, Francoise Vovelle, Marius PtakAbstract:We describe the secondary structure and the overall fold of toxin III from the venom of the scorpion Leiurus quinquestriatus quinquestriatus determined using two-dimensional-1H-NMR spectroscopy. This protein, which contains 64 amino acids and 4 disulfide bridges, belongs to the long-chain toxin category and is highly toxic to both mammals and insects. The overall fold was determined on the basis of 1208 inter-proton-distance restraints derived from NOE measurements and 90 Ψ, Φ dihedral-angle restraints derived from NOE connectivities and 3JNH-αH coupling constants using the HABAS program. This fold, which mainly consists of an α-helix packed against a small antiparallel three-stranded β-sheet, and of several turns and loops, is similar to that of other long-chain scorpion toxins. Aromatic and non-polar residues form several patches on the surface of the protein which alternate with patches of charged and polar residues. Such a topology should be important in the interactions of toxin III with sodium channels in membranes. Two weakly constrained loops introduce some flexibility to the structure which could be related to the activity of this toxin. The central core of toxin III is compared with the cysteine-stabilized αβ motif (an α-helix connected to a β-sheet through two disulfide bridges) found in insect defensins and plant thionins. Defensins and thionins are small proteins (≈40–50 amino acid residues) containing three or four disulfide bridges, respectively. This comparison confirms that the cysteine-stabilized αβ motif is a common core to a number of small proteins from different origins and having different activities.
Pierre Sautiere - One of the best experts on this subject based on the ideXlab platform.
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characterization of a new family of toxin like peptides from the venom of the scorpion Leiurus quinquestriatus hebraeus nmr structure of leiuropeptide ii
Journal of Peptide Research, 2009Co-Authors: Eric Buisine, Jeanmichel Wieruszeski, Guy Lippens, Daniele Wouters, Andre Tartar, Pierre SautiereAbstract:To extend our knowledge about the structural features of short scorpion toxins, the ion-exchange fractions obtained from Leiurus quinquestriatus hebraeus venom were investigated by plasma desorption mass spectrometry in order to select low molecular mass polypeptides. Three toxin-like peptides with molecular mass close to 3 kDa, named leiuropeptides I, II and III, were purified and found devoid of any significant toxicity against mammals and insects. Their amino acid sequences revealed a cysteine pattern analogous to that of short-chain scorpion toxins. The solution structure of leiuropeptide II was determined by 2D H-NMR spectroscopy and indicated the presence of a helix accomodating a proline, connected to a two-stranded β-sheet by three disulfide bonds. The overall fold of leiuropeptide II is found to be similar to that of leiurotoxin I, a 31-residue toxin present in the same scorpion venom which acts on K+ channels. In order to rationalize the absence of toxicity, the electrostatic potential of leiuropeptide II was compared to that of leiurotoxin I. The peptide is characterized by a large negative zone around Glu4, Asp5 and Asp8 residues, beginning in the neighbourhood of the β-turn and extending along the helix. In the same area, leiurotoxin I exhibits a positive surface, around Arg6 and Argl3 basic residues, which are essential for its receptor affinity. © Munksgaard 1997.
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Characterization of a new family of toxin‐like peptides from the venom of the scorpion Leiurus quinquestriatus hebraeus‐NMR structure of leiuropeptide II
Journal of Peptide Research, 2009Co-Authors: Eric Buisine, Jeanmichel Wieruszeski, Guy Lippens, Daniele Wouters, Andre Tartar, Pierre SautiereAbstract:To extend our knowledge about the structural features of short scorpion toxins, the ion-exchange fractions obtained from Leiurus quinquestriatus hebraeus venom were investigated by plasma desorption mass spectrometry in order to select low molecular mass polypeptides. Three toxin-like peptides with molecular mass close to 3 kDa, named leiuropeptides I, II and III, were purified and found devoid of any significant toxicity against mammals and insects. Their amino acid sequences revealed a cysteine pattern analogous to that of short-chain scorpion toxins. The solution structure of leiuropeptide II was determined by 2D H-NMR spectroscopy and indicated the presence of a helix accomodating a proline, connected to a two-stranded β-sheet by three disulfide bonds. The overall fold of leiuropeptide II is found to be similar to that of leiurotoxin I, a 31-residue toxin present in the same scorpion venom which acts on K+ channels. In order to rationalize the absence of toxicity, the electrostatic potential of leiuropeptide II was compared to that of leiurotoxin I. The peptide is characterized by a large negative zone around Glu4, Asp5 and Asp8 residues, beginning in the neighbourhood of the β-turn and extending along the helix. In the same area, leiurotoxin I exhibits a positive surface, around Arg6 and Argl3 basic residues, which are essential for its receptor affinity. © Munksgaard 1997.
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Characterization of scorpion α‐like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus
FEBS Journal, 2002Co-Authors: Alain Hamon, Charles Kopeyan, Nicolas Gilles, Pierre Sautiere, Arlette Martinage, Chris Ulens, Jan Tytgat, Jeanmarc Lancelin, Dalia GordonAbstract:Two novel toxins, Lqh6 and Lqh7, isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus, have in their sequence a molecular signature (8Q/KPE10) associated with a recently defined group of α-toxins that target Na channels, namely the α-like toxins [reviewed in Gordon, D., Savarin, P., Gurevitz, M. & Zinn-Justin, S. (1998) J. Toxicol. Toxin Rev. 17, 131–159]. Lqh6 and Lqh7 are highly toxic to insects and mice, and inhibit the binding of α-toxins to cockroach neuronal membranes. Although they kill rodents by intracerebroventricular injection, they do not inhibit the binding of antimammal α-toxins (e.g. Lqh2) to rat brain synaptosomes, not even at high concentrations. Furthermore, in voltage-clamp experiments, rat brain Na channels IIA (rNav1.2A) expressed in Xenopus oocytes are not affected by Lqh6 nor by Lqh7 below 3 µm. In contrast, muscular Na channels (rNav1.4 and hNav1.5) expressed in the same cells respond to nanomolar concentrations of Lqh6 and Lqh7 by slowing of Na current inactivation and a leftward shift of the peak conductance–voltage curve. The structural and pharmacological properties of the new toxins are compared to those of other scorpion α-toxins in order to re-examine the hallmarks previously set for the α-like toxin group.
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characterization of scorpion α like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus
FEBS Journal, 2002Co-Authors: Alain Hamon, Charles Kopeyan, Nicolas Gilles, Pierre Sautiere, Arlette Martinage, Chris Ulens, Jan Tytgat, Jeanmarc Lancelin, Dalia GordonAbstract:Two novel toxins, Lqh6 and Lqh7, isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus, have in their sequence a molecular signature (8Q/KPE10) associated with a recently defined group of α-toxins that target Na channels, namely the α-like toxins [reviewed in Gordon, D., Savarin, P., Gurevitz, M. & Zinn-Justin, S. (1998) J. Toxicol. Toxin Rev. 17, 131–159]. Lqh6 and Lqh7 are highly toxic to insects and mice, and inhibit the binding of α-toxins to cockroach neuronal membranes. Although they kill rodents by intracerebroventricular injection, they do not inhibit the binding of antimammal α-toxins (e.g. Lqh2) to rat brain synaptosomes, not even at high concentrations. Furthermore, in voltage-clamp experiments, rat brain Na channels IIA (rNav1.2A) expressed in Xenopus oocytes are not affected by Lqh6 nor by Lqh7 below 3 µm. In contrast, muscular Na channels (rNav1.4 and hNav1.5) expressed in the same cells respond to nanomolar concentrations of Lqh6 and Lqh7 by slowing of Na current inactivation and a leftward shift of the peak conductance–voltage curve. The structural and pharmacological properties of the new toxins are compared to those of other scorpion α-toxins in order to re-examine the hallmarks previously set for the α-like toxin group.
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nmr structures and activity of a novel alpha like toxin from the scorpion Leiurus quinquestriatus hebraeus
Journal of Molecular Biology, 1999Co-Authors: Isabelle Krimm, Nicolas Gilles, Pierre Sautiere, Dalia Gordon, Maria Stankiewicz, M Pelhate, Jeanmarc LancelinAbstract:NMR structures of a new toxin from the scorpion Leiurus quinquestriatus hebraeus (Lqh III) have been investigated in conjunction with its pharmacological properties. This toxin is proposed to belong to a new group of scorpion toxins, the α-like toxins that target voltage-gated sodium channels with specific properties compared with the classical α-scorpion toxins. Electrophysiological analysis showed that Lqh III inhibits a sodium current inactivation in the cockroach axon, but induces in addition a resting depolarization due to a slowly decaying tail current atypical to other α-toxin action. Binding studies indicated that radiolabeled Lqh III binds with a high degree of affinity (Ki=2.2 nM) on cockroach sodium channels and that the α-toxin from L quinquestriatus hebraeus highly active on insects (LqhαIT) and α-like toxins compete at low concentration for its receptor binding site, suggesting that the α-like toxin receptor site is partially overlapping with the receptor site 3. Conversely, in rat brain, Lqh III competes for binding of the most potent anti-mammal α-toxin from Androctonus australis Hector venom (AaH II) only at very high concentration. The NMR structures were used for the scrutiny of the similarities and differences with representative scorpion α-toxins targeting the voltage-gated sodium channels of either mammals or insects. Three turn regions involved in the functional binding site of the anti-insect LqhαIT toxin reveal significant differences in the Lqh III structure. The electrostatic charge distribution in the Lqh III toxin is also surprisingly different when compared with the anti-mammal α-toxin AaH II. Similarities in the electrostatic charge distribution are, however, recognized between α-toxins highly active on insects and the α-like toxin Lqh III. This affords additional important elements to the definition of the new α-like group of scorpion toxins and the mammal versus insect scorpion toxin selectivities.
Amal J Fatani - One of the best experts on this subject based on the ideXlab platform.
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comparative study between peripherally and centrally acting sublethal and lethal doses of Leiurus quinquestriatus scorpion venom in rabbits the usefulness of the sodium channel blocker lidocaine
Journal of The Saudi Pharmaceutical Society, 2010Co-Authors: Amal J FataniAbstract:Abstract Background Scorpion envenomation is common among desert dwellers, affecting several systems and resulting in multiple organ dysfunction (MOD) or failure (MOF), mainly due to their action on Na+ channels. Although scorpion venoms toxins do not pass the blood brain barrier, their CNS effects are prominent, occurring in conjunction with, or as an aftermath of peripheral actions of the venom. Objective To determine the ability of venom of the common scorpion Leiurus quinquestriatus (LQQ) to induce MOD or MOF when injected into rabbits in micro quantities centrally (intracerebroventricularly, i.c.v.) or macro amounts peripherally (s.c. or i.v.). Also, to assess if the Na+ channel blocker lidocaine can protect rabbits from the resultant manifestations. Methods Rabbits were injected with LQQ venom centrally or peripherally, in either sublethal or lethal doses, and MOD or MOF determined by assessing: cardiac output (CO), estimated hepatic blood flow (EHBF), biochemical parameters indicative of cardiac/hepatic/renal and pancreatic functions, blood pressure (BP), survival, lung/body index (LBI, indicative of pulmonary edema), and/or histological changes in hearts, lungs, livers plus kidneys. In pre-treatment experiments, lidocaine was injected 40 min before venom and protective ability examined. Results LQQ venom in sublethal doses caused comparable significant reductions (vs control) in CO and EHBF when injected i.c.v. (2 μg kg−1) or s.c. (0.2 mg kg−1). Both routes caused gradual dose-related enhanced levels of creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, creatinine, glucose and amylase, indicating MOD. Also, characteristic venom-induced changes in BP were evident after lethal doses of venom i.v. (0.5 mg kg−1) or i.c.v. (3 μg kg−1). Histological changes in the organs plus LBI were comparable after i.c.v. and i.v. venom injection, with animals ultimately exhibiting MOF. Lidocaine (1 mg kg−1 i.v., then infusion 50 μg kg−1 min−1, 30 min before venom), protected the animals from MOF evoked by lethal doses of the venom (whether injected centrally or peripherally), as evidenced by the amelioration of the venom’s effects on blood pressure, LBI, survival and multiple organ histopathological manifestations. Conclusion LQQ venom, whether injected centrally or peripherally caused comparable systemic dose-dependent MOD or MOF, with the latter attenuated by the Na+ channel blocker lidocaine, indicating a role for Na+ channels.
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comparative study between the protective effects of saudi and egyptian antivenoms alone or in combination with ion channel modulators against deleterious actions of Leiurus quinquestriatus scorpion venom
Toxicon, 2010Co-Authors: Amal J Fatani, Amany A E Ahmed, Rabab M Abdelhalim, Nozha A Abdoon, Amal Q DarweeshAbstract:Abstract This study compared efficacy of two polyvalent antivenoms (Saudi Arabian and Egyptian), against lethality and pathophysiological changes of Leiurus quinquestriatus quinquestriatus ( LQQ ) scorpion venom in mice. Additionally, the study examined whether treatment with selected ion channel modulators, lidocaine, nimodipine or amiodarone would be effective, alone or combined with the antivenoms. The protein concentration of the Saudi antivenom was 1/3 of Egyptian, indicating lesser immunogenicity, while both preservative contents were within limits. In immunodiffusion experiments, both exhibited prominent precipitin bands indicating high concentrations of specific antibodies. Neutralizing capacities (60–70 LD 50 ) stated on labels were confirmed. Both antivenoms significantly ( P + channel blocker lidocaine and the Ca 2+ channel blocker nimodipine on their own significantly protected the animals ( P The two antivenoms, significantly ameliorated the venom-evoked changes in serum LDH ( P P P In Conclusion both Saudi and Egyptian antivenoms protected mice from the pathological and lethal effects of LQQ scorpion. Sodium and calcium channel blockers, lidocaine and nimodipine, may be useful when antivenoms are not available.
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correlation between blood pressure cytokines and nitric oxide in conscious rabbits injected with Leiurus quinquestriatus quinquestriatus scorpion venom
Toxicon, 2009Co-Authors: Nuzha A Abdoon, Amal J FataniAbstract:Activation of the inflammatory response with the release and activation of pro-inflammatory cytokines is among the factors thought to be important in the pathogenesis of many deleterious inflammatory effects seen in case of scorpion envenomation. The released inflammatory mediators interact in the body with a large number of proteins and receptors; this interaction determines the eventual inflammatory effect of the venom. Thus, in the present study an attempt was made to map the time course of scorpion envenomation and correlate the effects observed on the cardiovascular and respiratory systems with the changes that could take place in the levels of selected cytokines and nitric oxide during the course of experimental envenomation. New Zealand white male conscious rabbits were prepared for blood pressure recording. Arterial blood pressure was measured from the left central ear artery while a cannula was inserted into the right central ear artery and blood samples collected at different time interval after venom injection for biochemical and hematological analyses. In general, subcutaneous injection of Leiurus quinquestriatus quinquestriatus venom caused a significant (P � 0.05) triphasic effect on BP consisting of an initial transient reduction, followed by an increase that peaked 2 h after venom injection, and a gradual terminal hypotensive phase. The significantly high serum level of IL8, TNF a (P < 0.001) and nitric oxide (P < 0.0001) observed in the present study supports the evidence for the role of these potent vasodilators in the terminal hypotension that is usually observed in humans and animals after envenomation. 2009 Published by Elsevier Ltd.
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amelioration of the cardiovascular manifestations of the yellow scorpion Leiurus quinquestriatus envenomation in rats by red grape seeds proanthocyanidins
Toxicon, 2008Co-Authors: Abir T Elalfy, Amany A E Ahmed, Amal J Fatani, Farida KaderAbstract:Abstract The study attempts to determine the involvement of oxidative stress in cardiovascular manifestations during Leiurus quinquestriatus quinquestriatus (LQQ) scorpion envenomation and to examine the possible protective role of red grape seed proanthocyanidins (GSP) against such effects. Lethality studies conducted in mice demonstrated a significant (p
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the effects of lignocaine on actions of the venom from the yellow scorpion Leiurus quinquestriatus in vivo and in vitro
Toxicon, 2000Co-Authors: Amal J Fatani, Alan L Harvey, B L Furman, E G RowanAbstract:Abstract Fatani, A.J., Harvey, A.L., Furman, B.L., and Rowan, E.G. The effects of lignocaine on actions of the venom from the yellow scorpion, Leiurus quinquestriatus, in vivo and in vitro. Toxicon, 19. Many toxins from scorpion venoms activate sodium channels, thereby enhancing neurotransmitter release. The aim of the present work was to determine if the in vivo and in vitro effects of Leiurus quinquestriatus venom (LQQ) could be ameliorated by lignocaine, a sodium channel blocker. In urethane anaesthetised rabbits, LQQ venom (0.5 mg kg−1, i.v.) caused initial hypotension and bradycardia followed by hypertension, pulmonary oedema, electrocardiographic changes indicating conduction defects, ischaemia, infarction, and then hypotension and death. Lignocaine (1 mg kg−1 i.v. bolus initially, followed by i.v. infusion of 50 μg kg−1 min−1) significantly attenuated the majority of the venom-evoked effects and reduced mortality. Addition of LQQ venom (1, 3 and 10 μg ml−1) to chick biventer cervicis, guinea pig ileum, and rat vas deferens preparations, increased the height of electrically-induced twitches, elevated resting tension, and caused autorhythmic oscillations. Lignocaine (3 × 10−4–1.2 × 10−3 M) greatly attenuated these venom-evoked actions in the three preparations. Antagonists of appropriate neurotransmitters were also tested to determine the contribution of released transmitters to LQQ effects. Atropine significantly decreased the venom-elicited effects on guinea pig ileum preparations, while prazosin and guanethidine significantly reduced the venom’s actions on rat vas deferens. In chick biventer cervicis preparations, tubocurarine and hexamethonium significantly attenuated the venom-induced effects. This study supports the hypothesis that many effects of LQQ venom involve the release of neurotransmitters and may be ameliorated by treatment with lignocaine.
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Characterization of scorpion α‐like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus
FEBS Journal, 2002Co-Authors: Alain Hamon, Charles Kopeyan, Nicolas Gilles, Pierre Sautiere, Arlette Martinage, Chris Ulens, Jan Tytgat, Jeanmarc Lancelin, Dalia GordonAbstract:Two novel toxins, Lqh6 and Lqh7, isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus, have in their sequence a molecular signature (8Q/KPE10) associated with a recently defined group of α-toxins that target Na channels, namely the α-like toxins [reviewed in Gordon, D., Savarin, P., Gurevitz, M. & Zinn-Justin, S. (1998) J. Toxicol. Toxin Rev. 17, 131–159]. Lqh6 and Lqh7 are highly toxic to insects and mice, and inhibit the binding of α-toxins to cockroach neuronal membranes. Although they kill rodents by intracerebroventricular injection, they do not inhibit the binding of antimammal α-toxins (e.g. Lqh2) to rat brain synaptosomes, not even at high concentrations. Furthermore, in voltage-clamp experiments, rat brain Na channels IIA (rNav1.2A) expressed in Xenopus oocytes are not affected by Lqh6 nor by Lqh7 below 3 µm. In contrast, muscular Na channels (rNav1.4 and hNav1.5) expressed in the same cells respond to nanomolar concentrations of Lqh6 and Lqh7 by slowing of Na current inactivation and a leftward shift of the peak conductance–voltage curve. The structural and pharmacological properties of the new toxins are compared to those of other scorpion α-toxins in order to re-examine the hallmarks previously set for the α-like toxin group.
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characterization of scorpion α like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus
FEBS Journal, 2002Co-Authors: Alain Hamon, Charles Kopeyan, Nicolas Gilles, Pierre Sautiere, Arlette Martinage, Chris Ulens, Jan Tytgat, Jeanmarc Lancelin, Dalia GordonAbstract:Two novel toxins, Lqh6 and Lqh7, isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus, have in their sequence a molecular signature (8Q/KPE10) associated with a recently defined group of α-toxins that target Na channels, namely the α-like toxins [reviewed in Gordon, D., Savarin, P., Gurevitz, M. & Zinn-Justin, S. (1998) J. Toxicol. Toxin Rev. 17, 131–159]. Lqh6 and Lqh7 are highly toxic to insects and mice, and inhibit the binding of α-toxins to cockroach neuronal membranes. Although they kill rodents by intracerebroventricular injection, they do not inhibit the binding of antimammal α-toxins (e.g. Lqh2) to rat brain synaptosomes, not even at high concentrations. Furthermore, in voltage-clamp experiments, rat brain Na channels IIA (rNav1.2A) expressed in Xenopus oocytes are not affected by Lqh6 nor by Lqh7 below 3 µm. In contrast, muscular Na channels (rNav1.4 and hNav1.5) expressed in the same cells respond to nanomolar concentrations of Lqh6 and Lqh7 by slowing of Na current inactivation and a leftward shift of the peak conductance–voltage curve. The structural and pharmacological properties of the new toxins are compared to those of other scorpion α-toxins in order to re-examine the hallmarks previously set for the α-like toxin group.
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nmr structures and activity of a novel alpha like toxin from the scorpion Leiurus quinquestriatus hebraeus
Journal of Molecular Biology, 1999Co-Authors: Isabelle Krimm, Nicolas Gilles, Pierre Sautiere, Dalia Gordon, Maria Stankiewicz, M Pelhate, Jeanmarc LancelinAbstract:NMR structures of a new toxin from the scorpion Leiurus quinquestriatus hebraeus (Lqh III) have been investigated in conjunction with its pharmacological properties. This toxin is proposed to belong to a new group of scorpion toxins, the α-like toxins that target voltage-gated sodium channels with specific properties compared with the classical α-scorpion toxins. Electrophysiological analysis showed that Lqh III inhibits a sodium current inactivation in the cockroach axon, but induces in addition a resting depolarization due to a slowly decaying tail current atypical to other α-toxin action. Binding studies indicated that radiolabeled Lqh III binds with a high degree of affinity (Ki=2.2 nM) on cockroach sodium channels and that the α-toxin from L quinquestriatus hebraeus highly active on insects (LqhαIT) and α-like toxins compete at low concentration for its receptor binding site, suggesting that the α-like toxin receptor site is partially overlapping with the receptor site 3. Conversely, in rat brain, Lqh III competes for binding of the most potent anti-mammal α-toxin from Androctonus australis Hector venom (AaH II) only at very high concentration. The NMR structures were used for the scrutiny of the similarities and differences with representative scorpion α-toxins targeting the voltage-gated sodium channels of either mammals or insects. Three turn regions involved in the functional binding site of the anti-insect LqhαIT toxin reveal significant differences in the Lqh III structure. The electrostatic charge distribution in the Lqh III toxin is also surprisingly different when compared with the anti-mammal α-toxin AaH II. Similarities in the electrostatic charge distribution are, however, recognized between α-toxins highly active on insects and the α-like toxin Lqh III. This affords additional important elements to the definition of the new α-like group of scorpion toxins and the mammal versus insect scorpion toxin selectivities.