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PubMed1994

Purification, N-terminal sequence and structural characterization of a toxic protein from the Indian scorpion venom Buthus tamulus.

A toxic protein component (Bt-II) was isolated from the venom of the Indian scorpion, Buthus tamulus, by ion-exchange chromatography on Biorex-70 and reverse phase high pressure liquid chromatography (RP-HPLC). This 7800 mol. wt protein was found to have an LD50 value of 2.25 mg/kg body weight in mice by subcutaneous injection. Amino acid composition of the protein revealed the presence of aromatic and basic amino acids; the N-terminal amino acid sequence was also determined. Structural characterization of Bt-II, based on circular dichroic and fluorescent quenching studies, has also been reported.

Amino Acid Sequence↗
PubMed1996

New procedures and parameters for better evaluation of Androctonus australis garzonii (Aag) and Buthus occitanus tunetanus (Bot) scorpion envenomations and specific serotherapy treatment.

New procedures describing intoxication with variable amounts of scorpion venoms (from 1 to 5 LD50) allowed us to introduce new parameters to evaluate Aag and Bot envenomations. Significant differences between the fatal limit time (FLT) and the last mortality time (LMT) were observed when the amount of Aag and Bot venom injected was equal to 1 LD50 and equal to or higher than 2 LD50. For Aag and Bot, the percentage of the fast mortality (FM) and the delayed mortality (DM) varied conversely when the amount of injected venom increased from 1 to 5 LD50. The relationship between the venom LD50 (from 2 to 20), the median protective dose (PD50) and the neutralizing activity of specific antivenom have been established. PD50 increased in a parallel manner with LD50. The neutralizing titres (LD50/ml) of Aag antivenom decreased from 74 +/- 3 to 44 +/- 2 and that of Bot antivenom from 52 +/- 2 to 36 +/- 1 when the number of LD50 injected increased from 2 to 20. Antivenom potency was evaluated using different protocols based on the presence or the absence of preincubation of the venom with the antivenom. In experiments where venom and antivenom were simultaneously but immediately injected, PD50 were twice as high as those found when venom and antivenom were preincubated (30 min at 37 degrees C). On the contrary, the corresponding neutralizing titres were two times lower. In an attempt to simulate accidental envenomations and subsequent serotherapy, Aag and Bot venom (4 LD50) were subcutaneously injected and the appropriate PD50S of antivenom were intravenously administered at different time intervals after envenomation. When the time of antivenom administration was shorter than the FLT, all envenomed mice might be protected by increasing volume of antivenom. However, when the antivenom is injected closer to the FLT only 50 to 60% of mice envenomed, respectively, by Aag and Bot could be saved even when more than 5 PD50 were injected.

Animals↗
PubMed1993

Fine molecular analysis of the antigenicity of the Androctonus australis hector scorpion neurotoxin II: a new antigenic epitope disclosed by the Pepscan method.

A set of 58 overlapping rod-bound peptides was used to map the antigenic reactivity pattern of a 64-residue neurotoxin (AaH II) from the venom of the scorpion Androctonus australis hector. Five anti-toxin rabbit antisera were assayed serially for their capacity to bind to each peptide in the set. Six regions of antigenic reactivity were thus identified (sequences: 1-8, 4-12, 27-35, 39-45, 52-58 and 55-61). When positioned on a 3-D model of the toxin, these regions appeared to correspond to either beta-turn or extended parts of the molecule. The antigenic regions revealed by this technique agree fairly well with those previously mapped on the same toxin by different methods. One discrepancy was, however, that the present study shows the N-terminus to be strongly reactive with anti-toxin antibodies. The antigenicity of this region was confirmed, since rabbit antibodies raised against a synthetic peptide mimicking the sequence 1-8 of the toxin were found to bind the toxin with high efficiency. A fine analysis of the recognition of this region was performed. Alanine-containing analogs of the sequence 1-7 and peptides mimicking the N-terminal of the four main toxins of AaH were probed with anti-toxin and anti-peptide antibodies. Lysine 2, aspartic acid 3 and glycine 4 were shown to be key residues in the recognition of the N-terminal region of the AaH II toxin by anti-toxin antibodies. In contrast, a loose specificity of recognition was shown by one anti-peptide serum which was, in addition, able to recognize the N-termini of all four AaH toxins.

Amino Acid Sequence↗
PubMed1988

Synthesis of a gene coding for an insect-specific scorpion neurotoxin and attempts to express it using baculovirus vectors.

We have explored the possibility of improving baculovirus pesticides by incorporating an insect-specific neurotoxin gene into a baculovirus genome. A 112-bp gene (BeIt) encoding insectotoxin-1 of the scorpion Buthus eupeus was synthesized and cloned in Escherichia coli. For expression, BeIt was transferred to the DNA genome of Autographa californica nuclear polyhedrosis virus (AcMNPV). Three different recombinant AcMNPVs, carrying BeIt under the control of the strong AcMNPV polyhedrin promoter, were constructed and expression of BeIt was monitored upon infection of Spodoptera frugiperda (Sf) cells. Toxin expression was low using a recombinant virus in which BeIt was inserted 6 nucleotides (nt) downstream from the intact polyhedrin mRNA leader. More expression was observed when a signal-peptide was attached in-frame to the N terminus of BeIt. The highest level of expression was observed with a fusion gene comprised of the 58 N-terminal codons of polyhedrin fused to BeIt; however, the level of expression was ten- to twenty-fold below that for polyhedrin. Polyhedrin promoter-directed transcripts of all three recombinants accumulated to levels similar to those of wild-type polyhedrin transcripts, indicating that the limitation to expression of unfused BeIt was not at the level of transcription but rather at the posttranscriptional level including translation or protein stability. Paralytic activity of the toxin products was not detected.

Amino Acid Sequence↗
PubMed2004

Discrepin, a new peptide of the sub-family alpha-ktx15, isolated from the scorpion Tityus discrepans irreversibly blocks K+ -channels (IA currents) of cerebellum granular cells.

A new peptide was purified from the venom of the Venezuelan scorpion Tityus discrepans, by high-performance liquid chromatography and its amino acid sequence was completed by Edman degradation and mass spectrometry analysis. It contains 38 amino acid residues with a molecular weight of 4177.7 atomic mass units, tightly folded by three disulfide bridges, and has a pyroglutamic acid at the N-terminal region. This peptide, named Discrepin, was shown to block preferentially the IA currents of the voltage-dependent K+ -channel of rat cerebellum granular cells in culture. The K+ -currents are inhibited in an apparently irreversible manner, whose 50% inhibitory effect is reached with a 190 nM toxin concentration. The systematic nomenclature proposed for this toxin is alpha-KTx15.6.

Amino Acid Sequence↗
PubMed2005

Diversity of long-chain toxins in Tityus zulianus and Tityus discrepans venoms (Scorpiones, Buthidae): molecular, immunological, and mass spectral analyses.

In Venezuela, stings by Tityus zulianus scorpions produce cardiorespiratory arrest, whereas envenoming by Tityus discrepans involves gastrointestinal/pancreatic complications, suggesting structural and/or functional differences. We sought to compare their toxin repertoires through immunological, molecular, and mass spectral analyses. First, in vivo tests showed that neutralization of T. zulianus venom toxicity by the anti-T. discrepans antivenom was not complete. To compare T. discrepans and T. zulianus long-chain (sodium channel-active) toxins, their most toxic Sephadex G-50 fractions, TdII and TzII, were subjected to acid-urea PAGE, which showed differences in composition. Amplification of toxin-encoding mRNAs using a leader peptide-based oligonucleotide rendered cDNAs representing twelve T. discrepans and two T. zulianus distinct toxin transcripts, including only one shared component, indicating divergence between T. zulianus and T. discrepans 5' region-encoded, toxin signal peptides. A 3'-UTR polymorphism was also noticed among the transcripts encoding shared components Tz1 and Td4. MALDI-TOF MS profiling of TdII and TzII produced species-specific spectra, with seven of the individual masses matching those predicted by cDNA sequencing. Phylogenetic analysis showed that the unique T. zulianus transcript-encoded sequence, Tz2, is structurally related to Tityus serrulatus and Centruroides toxins. Together with previous reports, this work indicates that T. zulianus and T. discrepans toxin repertoires differ structurally and functionally.

Amino Acid Sequence↗
PubMed2006

Rat pain-related responses induced by experimental scorpion BmK sting.

The developmental and pharmacological characteristics of pain responses induced by the experimental scorpion BmK (Buthus martensi Karsch) sting were detailed in this study. Following the unilateral intraplantar injection of BmK venom into rat hind paw, it was found: 1) BmK venom induced an edematogenic response, spontaneous pain and pain hypersensitivity in a dose-dependent manner; 2) the paw edema and flare were induced rapidly and restricted at the injected paw for about 24-48 h; 3) the monophasic tonic spontaneous pain manifested as continuous paw flinching and lifting/licking of the injected paw and lasted for more than 2 h; 4) the detectable thermal hypersensitivity to radiant heat stimuli was just at the injected side for about 72-96 h; 5) the mechanical hypersensitivity to von Frey filaments was evoked surprisingly to be the bilateral and mirror-like for about 2-3 weeks; 6) morphine, indomethacin and bupivacaine could suppress BmK venom-induced pain responses with different intensity and time courses. The results indicated that the experimental BmK sting could evoke the prolonged paw inflammation, tonic spontaneous behaviors, unilateral thermal and bilateral mechanical hypersensitivity. The distinct time development of pain responses induced by experimental BmK sting might be involved in different nervous and/or tissue mechanisms. The experimental BmK sting test thus may be an available tissue injury-induced tonic inflammatory pain model for understanding the mechanisms underlying clinical spontaneous pain, thermal and mirror-imaged bilateral mechanical pain hypersensitivity.

Analgesics, Opioid↗
PubMed2005

OD1, the first toxin isolated from the venom of the scorpion Odonthobuthus doriae active on voltage-gated Na+ channels.

In this study, we isolated and pharmacologically characterized the first alpha-like toxin from the venom of the scarcely studied Iranian scorpion Odonthobuthus doriae. The toxin was termed OD1 and its primary sequence was determined: GVRDAYIADDKNCVYTCASNGYCNTECTKNGAESGYCQWIGRYGNACWCIKLPDEVPIRIPGKCR. Using the two-electrode voltage clamp technique, the pharmacological effects of OD1 were studied on three cloned voltage-gated Na+ channels expressed in Xenopus laevis oocytes (Na(v)1.2/beta1, Na(v)1.5/beta1, para/tipE). The inactivation process of the insect channel, para/tipE, was severely hampered by 200 nM of OD1 (EC50 = 80+/-14 nM) while Na(v)1.2/beta1 still was not affected at concentrations up to 5 microM. Na(v)1.5/beta1 was influenced at micromolar concentrations.

Amino Acid Sequence↗
PubMed2006

A novel toxin from the venom of the scorpion Tityus trivittatus, is the first member of a new alpha-KTX subfamily.

The first example of a new sub-family of toxins (alpha-KTx20.1) from the scorpion Tityus trivittatus was purified, sequenced and characterized physiologically. It has 29 amino acid residues, three disulfide bridges assumed to adopt the cysteine-stabilized alpha/beta scaffold with a pI value of 8.98. The sequence identities with all the other known alpha-KTx are less than 40%. Its effects were verified using seven different cloned K(+) channels (vertebrate Kv1.1-1.5, Shaker IR and hERG) expressed in Xenopus leavis oocytes. The toxin-induced effects show large differences among the different K(+) channels and a preference towards Kv1.3 (EC50=7.9+/-1.4 nM).

Amino Acid Sequence↗
PubMed2004

Identification and functional characterization of novel scorpion venom peptides with no disulfide bridge from Buthus martensii Karsch.

The scorpion venom peptides with no disulfide bridge are rarely identified and poorly characterized so far. Here, we report the identification and characterization of four novel disulfide-bridge-free venom peptides (BmKa1, BmKa2, BmKb1 and BmKn2) from Buthus martensii Kasch. BmKa1 and BmKa2 are very acidic and hydrophilic, showing no any similarity to other proteins, whereas BmKb1 and BmKn2 both are basic, alpha-helical peptide with an amidated C-terminus, showing a little homology with other peptides. Functional tests with synthetic peptide showed that BmKn2 has strong antimicrobial activity against both Gram-positive and Gram-negative bacteria, whereas BmKb1 has weak activity in inhibiting the growth of these bacteria.

Amino Acid Sequence↗
PubMed2005

Expression of functional scorpion neurotoxin Lqq-V in E.coli.

We report the results on the expression in Escherichia coli of a functional neurotoxin LqqV from the scorpion Leiurus quinquestriatus quinquestriatus. The gene for LqqV was synthesized using recursive PCR and expressed as a poly-histidine-tagged fusion protein in thioredoxin mutant E. coli strain [AD494(DE3)pLysS], thus permitting disulfide-bond formation. When cultured at 37 degrees C, about 50% of the expressed protein is contained as a monomer in the soluble fraction of the E. coli extract. The fusion protein from the soluble fraction was purified and the His-tag was cleaved by thrombin, resulting in a yield of about 1.5 mg/liter. The globular structure of the purified protein was confirmed by NMR and CD spectroscopy. Patch-clamp measurements using native sodium channels in guinea pig ventricular myocytes reveal (1) a slowing of inactivation and (2) a decrease in peak current upon application of toxin, thus confirming the alpha-toxin activity of the purified recombinant protein.

Amino Acid Sequence↗
PubMed2006

The anti-nociceptive effect of BmK AS, a scorpion active polypeptide, and the possible mechanism on specifically modulating voltage-gated Na+ currents in primary afferent neurons.

In the present study, we investigated the anti-nociceptive effect and the underlying mechanism of BmK AS, an active peptide purified from scorpion Buthus martensi Karsch. The results showed that BmK AS can significantly relieve formalin-induced two-phase spontaneous flinching response and carrageenan-induced mechanical hyperalgesia. Using the whole-cell patch-clamp recording, exposure of acutely isolated sensory neurons to 500 nM BmK AS produced a one-fold decrease in the number of action potentials (APs) evoked by a ramp of depolarizing current. To investigate the mechanism of action of BmK AS, isolated membrane current and Ca2+ influx on rat primary sensory neurons were examined. BmK AS produced insignificant effect on voltage-dependent I(K) and KCl or caffeine-induced Ca2+ influx, but caused remarkable suppressive effect on tetrodotoxin-resistant (TTX-R) and tetrodotoxin-sensitive (TTX-S) I(Na). Further experiments showed that BmK AS reduced the peak TTX-R and TTX-S Na+ conductance in a dose-dependent manner, prompted the voltage-dependent activation, and caused a negative shift of the steady-state inactivation of TTX-R and TTX-S I(Na). Thus, the present results indicate the anti-nociceptive response of BmK AS may be ascribed to its specific modulation of voltage-gated Na+ channels of sensory neurons.

Action Potentials↗
PubMed2005

ANEPIII, a new recombinant neurotoxic polypeptide derived from scorpion peptide, inhibits delayed rectifier, but not A-type potassium currents in rat primary cultured hippocampal and cortical neurons.

A new recombinant neurotoxic polypeptide ANEPIII (BmK ANEPIII) derived from Scorpion peptide, which was demonstrated with antineuroexcitation properties in animal models, was examined for its action on K+ currents in primary cultured rat hippocampal and cortical neurons using the patch clamp technique in the whole-cell configuration. The delayed rectifier K+ current (I(k)) was inhibited by externally applied recombinant BmK ANEPIII, while the transient A-current (I(A)) remained virtually unaffected. BmK ANEPIII 3 microM, reduced the delayed rectifier current by 28.2% and 23.6% in cultured rat hippocampal and cortical neurons, respectively. The concentration of half-maximal block was 155.1 nM for hippocampal neurons and 227.2 nM for cortical neurons, respectively. These results suggest that BmK ANEPIII affect K+ currents, which may lead to a reduction in neuronal excitability.

Animals↗
PubMed2004

Molecular characterization of protective antibodies raised in mice by Tityus serrulatus scorpion venom toxins conjugated to bovine serum albumin.

The possibility of raising a humoral immune response capable of inducing in vivo protection against the lethal effects of Tityus serrulatus (Ts) scorpion venom was evaluated in the mouse model. An immunogen was prepared that consists of a toxic fraction (TstFG(50)) of the Tityus venom (this G(50) chromatography fraction represents most of the toxicity of the crude venom) conjugated to bovine serum albumin (BSA) with glutaraldehyde. TstFG(50) coupled to BSA yielded a thoroughly detoxified immunogen. BALB/c and C57BL/10 mice were immunized with this preparation and all developed an antibody response. In vivo protection assays one week after the last immunization showed that vaccinated mice could resist the challenge by twice the LD(50) of the TstFG(50), a dose which killed all control non-immune mice. The protective effect persisted nine weeks after the end of the immunization protocol. To characterize epitopes of protective antibodies we used the Spot method of multiple peptide synthesis to prepare sets of immobilized 15 mer overlapping peptides, covering the complete amino acid sequences of the main Tityus toxins, TsII and TsVII (both beta-type toxins) and TsIV, an alpha-type toxin that is the major lethal component of the venom. Antibody binding to peptides, revealed one major antigenic region in the C-terminal part of the three toxins and another region in the helical part of TsII and TsIV toxins. It is likely that these epitopes correspond to neutralizing epitopes since they correspond to regions of the toxins that are known to be involved in the active site of the toxins.

Amino Acid Sequence↗
PubMed2004

Dantrolene protects hippocampal cells from damage induced by TsTX, an alpha-scorpion toxin from Tityus serrulatus.

We examined the effects of dantrolene, an inhibitor of intracellular calcium release, on alterations associated with the intrahippocampal injection of the TsTX scorpion toxin. Male Wistar rats (230-250 g) were injected with Ringer solution (1 microl; n = 6); TsTX toxin (1 microg/microl; n = 8); and dantrolene (10.0 mg/kg) plus TsTX toxin (1 microg/microl; n = 6). After injection, electroencephalographic (EEG) recordings and observation of animals behaviour were performed continuously for 4 h. One week later, animals were submitted to histopathological analysis. TsTX caused electrographic seizure expressed by moderate or intense discharges and neuronal loss in hippocampal areas in all injected animals (n = 8). Dantrolene reduced the effect of TsTX. Thus, 67% of rats (four out of six) treated with toxin and dantrolene had electrographic convulsions, but only for 30 min after injection and none of them presented neuronal damage. Dantrolene or Ringer had no effects on the EEG.

Animals↗
PubMed2004

Modelling Tityus scorpion venom and antivenom pharmacokinetics. Evidence of active immunoglobulin G's F(ab')2 extrusion mechanism from blood to tissues.

Modelling Tityus scorpion venom and antivenom pharmacokinetics. Evidence of active immunoglobulin G's F(ab')(2) extrusion mechanism from blood to tissues. We measured pharmacokinetic parameters for T. discrepans venom in rams. Forty, 75 or 100 microg/kg venom were injected subcutaneously in the inner side of the thigh. Plasma venom content (venenemia) was determined by enzyme-linked immunosorbent assay (ELISA) from 0 to 300 min after injecting venom. Venenemia was fit to a three-compartment model (inoculation site, plasma and extra vascular extracellular space), it was assumed that the venom may also be irreversibly removed from plasma. Calculated time course of venom content shows that at any time no more that 30% of the venom is present in plasma. Venenemia peaks at 1h and decays afterwards. Fluorescently labelled antivenom [horse anti-TityusF(ab')(2) or fraction antigen binding, immuglobulin without Fc chain covalently bound to fluorescine or fluorescamine] pharmacokinetics was determined. Although F(ab')(2) molecular weight is >/=10 times bigger that toxin's, the rate of outflow of F(ab')(2) from blood to tissues was approximately 4 times faster than the venom's outflow. Venom content in the injection site decays exponentially for >6h, this prediction was confirmed immunohistochemically. Only approximately 5% of the venom is eliminated in 10h; approximately 80% of the venom is in the tissues after 2h and remains there for >10h.

Animals↗
PubMed2005

Localization of epitopes in the toxins of Tityus serrulatus scorpions and neutralizing potential of therapeutic antivenoms.

Overlapping pentadecapeptides covering the complete amino acid sequence of TsII, TsVII and TsIV toxins from the venom of scorpion Tityus serrulatus (Ts), were prepared by use of the Spot method of multiple peptide synthesis. Horse anti-Ts antisera for therapeutic use were tested for their binding to peptides. All nine antisera tested showed reactivity with several peptides from the three toxins. Three antigenic regions, one in the very N-terminal, the second in the central part and the other in the C-terminal part of the three toxins were frequently, but not constantly recognized, with an intensity that seemed to be related to the neutralizing potency of the tested antivenom. Thus the corresponding peptides (residues 1-15 and 48-62 of TsII; residues 1-15, 16-30 and 48-62 of TsIV and residues 1-15 and 47-61 of TsVII) were synthesized, coupled to KLH and used as antigens to coat the microtitration plates to determine any relationship between their ELISA reactivity with therapeutic horse antivenoms and the neutralizing potential of these antivenoms. The mixture of the N-terminal peptide of TsII, of the N-terminal TsVII peptide and of the C-terminal of TsIV was found to give a linear relationship with the neutralizing titer of horse serum of low neutralizing potency (< or =1 mg/ml). However, high neutralizing antivenoms did not show the expected response in peptide ELISA. This observation is discussed in the context of the occurrence of continuous and discontinuous epitopes on toxins.

Amino Acid Sequence↗
PubMed2005

Pharmacokinetics of a F(ab')2 scorpion antivenom in healthy human volunteers.

This paper presents the first study of F(ab')2 scorpion antivenom pharmacokinetics in humans. We have studied the pharmacokinetics of an antiscorpion venom preparation (Alacramyn) in eight human healthy volunteers. The fabotherapic was administered as a 47.5 mg i.v. bolus. Blood samples were drawn at 0, 5, 15, 30, 45, 60, 90, 120, 180 and 360 min after antivenom administration. Subsequently, the volunteers made seven visits to the hospital. Four of them at 24 h intervals, one at day 10, and one at day 21. We measured antivenom plasmatic concentrations using a specific high sensitivity ELISA method for F(ab')2. The time course of F(ab')2 in serum of seven subjects was well described by a lineal combination of three exponential components; a four exponential component model was necessary to fit the eighth subject. The most significant antivenom pharmacokinetic parameters determined were: AUC(infinity)=596.9 (369.3, 891.2) mg h l(-1); V(c) = 3.1 (2.3, 4.3)l; V(ss) = 15.4 (12.8, 39.9)l; MRT = 250.0 (218.8, 310.2) h; CL = 96.6 (58.0, 139.2) ml h(-1); t(1/2,tau1) (also called t(1/2,alpha)) = 0.25 (0.13, 0.37) h; t(1/2,tau(z)) (corresponding to the slowest component) = 161.3 (141.0, 212.0) h.

Adolescent↗