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At least 1,099 records · Page 61Linked to original sources
PubMed2002

Antihyperalgesia effect of BmK AS, a scorpion toxin, in rat by intraplantar injection.

The antihyperalgesia effect of BmK AS, a novel sodium channel-specific polypeptide modulator from Chinese scorpion venom in rats was investigated in this study. PWLs (paw withdrawal latency) were increased to 150+/-28, 203+/-34 and 250+/-17% of the control by administration of BmK AS (10 microl) at the concentration of 0.001, 0.01 and 0.1 mg/ml in carrageenan-induced inflamed rats, respectively. Meanwhile, PWLs were enhanced to about 126+/-4, 132+/-4 and 140+/-6% of the control at the same applied concentration of BmK AS in normal rats. The results suggest that BmK AS can induce peripheral antihyperalgesia and antinociception, which probably by modulating the sodium channel on nociceptive afferent pathway.

Analgesics↗
PubMed1999

Effects of tachykinin NK1 or PAF receptor blockade on the lung injury induced by scorpion venom in rats.

In cases of severe human scorpion envenoming, lung injury is a common finding and frequently the cause of death. In the rat, two distinct mechanisms account for oedema following the intravenous injection of the venom -- acute left ventricular failure resulting from a massive release of catecholamines and an increase in pulmonary vascular permeability. In the present work, we investigated the effects of a tachykinin NK1 receptor antagonist (CP96,345, the dihydrochloride salt of (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)methyl)-1-az abicycol[2.2.2]octan-3-amine) and its 2 R-3 R inactive enantiomer (CP96,344) on the acute lung injury induced by the i.v. injection of Tityus serrulatus venom in rats. Lung injury was assessed by evaluating the extravasation of Evans blue dye in the bronchoalveolar lavage fluid and in the lung of venom-treated and control animals. The effects of the platelet-activating factor (PAF) receptor antagonist WEB2170 (2-methyl-1-phenylimidazol[4,5c]pyridine) were evaluated for comparison. The i.v. injection of the venom induced the extravasation of Evans blue in the bronchoalveolar lavage fluid and into the left lung. Pretreament with the tachykinin NK1 receptor antagonist CP96,345, but not CP96,344, inhibited Evans blue dye extravasation in the bronchoalveolar lavage fluid and in the lung by 96% and 86%, respectively. The PAF receptor antagonist WEB2170 inhibited the increase in vascular permeability in the bronchoalveolar lavage fluid by 60% and had no effect on the extravasation to the lung parenchyma of venom-injected animals. In addition to abrogating lung injury, pretreatment of rats with CP96,345, but not CP96,344 or WEB2170, decreased by 70% the mortality induced by the venom. This is the first study to show the relevance of the tachykinin NK1 receptor in mediating lung injury and mortality in animals injected with the neurotoxic T. serrulatus venom. Blockade of the tachykinin NK1 receptor may represent an important strategy in the treatment of patients with signs of severe envenoming and clearly deserves further studies.

Animals↗
PubMed2001

A new class of scorpion toxin binding sites related to an A-type K+ channel: pharmacological characterization and localization in rat brain.

A new scorpion toxin (3751.8 Da) was isolated from the Buthus martensi venom, sequenced and chemically synthesized (sBmTX3). The A-type current of striatum neurons in culture completely disappeared when 1 microM sBmTX3 was applied (Kd=54 nM), whereas the sustained K+ current was unaffected. 125I-sBmTX3 specifically bound to rat brain synaptosomes (maximum binding=14 fmol x mg(-1) of protein, Kd=0.21 nM). A panel of toxins yet described as specific ligands for K+ channels were unable to compete with 125I-sBmTX3. A high density of 125I-sBmTX3 binding sites was found in the striatum, hippocampus, superior colliculus, and cerebellum in the adult rat brain.

Amino Acid Sequence↗
PubMed2001

Slotoxin, alphaKTx1.11, a new scorpion peptide blocker of MaxiK channels that differentiates between alpha and alpha+beta (beta1 or beta4) complexes.

A novel peptide from Centruroides noxius Hoffmann scorpion venom was isolated and sequenced. The 37 amino acid peptide belongs to the charybdotoxin sub-family (alphaKTx1) and was numbered member 11. alphaKTx1.11 has 75% sequence identity with iberiotoxin and 54% with charybdotoxin. alphaKTx1.11 revealed specificity for mammalian MaxiK channels (hSlo), thus, was named slotoxin. Slotoxin blocks the MaxiK pore-forming alpha subunit reversibly (K(d)=1.5 nM). Slotoxin association with alpha+beta (beta1 or beta4) channels was approximately 10 times slower than iberiotoxin and charybdotoxin, leading to a lack of effect on alpha+beta4 when tested at 100 nM for 5 min. Thus, slotoxin is a better tool to distinguish MaxiK alpha+beta complexes.

Amino Acid Sequence↗
PubMed1997

Bot IT2: a new scorpion toxin to study receptor site on insect sodium channels.

The insect-specific Bothus occitanus tunetanus IT2 toxin is distinguishable from other scorpion toxins by its amino acid sequence and effects on sodium conductance. The present study reveals that Bot IT2 possesses in cockroach neuronal membranes a single class of high affinity (Kd = 0.3 +/- 0.1 nM) and low capacity (Bmax = 2.4 +/- 0.5 pmol/mg) binding sites. Competitive binding experiments with several known sodium channel neurotoxins reveal that the Bot IT2 binding site is in close proximity to the other toxins.

Animals↗
PubMed1998

Baculovirus-mediated expression of a scorpion depressant toxin improves the insecticidal efficacy achieved with excitatory toxins.

The insecticidal efficacy towards Helicoverpa armigera lepidopteran larvae of recombinant Autographa californica M nucleopolyhedroviruses, expressing depressant and excitatory scorpion anti-insect selective toxins, was investigated. The ET50 (effective paralysis time 50%) values obtained with the recombinant viruses expressing the depressant toxin, LqhIT2, and the excitatory toxin, LqhIT1, were 59 h and 66 h, respectively, whereas the ET50 value of the wild-type virus was longer, 87 h post infection. The insecticidal effects obtained when using two distinct temporally regulated viral promoters revealed advantage for the very late p10 promoter over the p35 early promoter. The higher insecticidity of the virus expressing the depressant toxin compared to the excitatory toxin suggests that pharmacokinetic factors and/or promoter efficiency may play a role during infection of insect pest larvae by recombinant baculoviruses.

Amino Acid Sequence↗
PubMed1999

A novel K+ channel blocking toxin from Tityus discrepans scorpion venom.

A novel toxin (TdK1) was purified from the venom of the scorpion Tityus discrepans, sequenced and functionally characterized. It contains 37 amino acid residues and blocks reversible the shakerB K+ channel expressed in SF9 cells with a Kd in the order of 280 nM. The proposed systematic nomenclature for this peptide is alpha-KTx4.3.

Amino Acid Sequence↗
PubMed1999

Monoclonal antibodies against the Androctonus australis hector scorpion neurotoxin I: characterisation and use for venom neutralisation.

A series of monoclonal antibodies (mAbs) specific for the alpha-neurotoxin I (Aah I) from the venom of the dangerous Androctonus australis hector scorpion were obtained using carrier protein-coupled toxin. Competitive RIA, receptor assays and mouse toxicity tests were performed to characterise mAbs in terms of affinity and neutralisation. Cross-reactivity studies and two-site ELISA results allowed some classification of mAbs into three groups. One mAb, 9C2, was particularly interesting since it recognised the parent toxin I with a K(D) of 0.15 nM and was also reactive with toxins of the same immunological group. Its ability to neutralise the toxic effect of the parent toxin and the venom fraction has been investigated. This anti-Aah I mAb 9C2, associated with anti-Aah II mAb 4C1, provides a valuable tool to neutralise the toxicity of the venom.

Amino Acid Sequence↗
PubMed2002

Brownian dynamics simulations of the recognition of the scorpion toxin P05 with the small-conductance calcium-activated potassium channels.

The recognition of the scorpion toxin P05 and the small-conductance, calcium-activated potassium (SK) channels, rsk1, rsk2, and rsk3, has been studied by means of the Brownian dynamics (BD) method. All of the 25 available structures of P05 in the RCSB Protein Data Bank determined by NMR were considered during the simulation, which indicated that the conformation of P05 affects both the recognition and binding between the two proteins significantly. Comparing the top four high-frequency structures of P05 binding to the SK channels, we found that the rsk2 channel, with high frequencies and lowest electrostatic interaction energies (E (int)(ES)), is the most favorable for P05 binding, while rsk3 is intermediate, and rsk1 is the least favorable. Among the 25 structures of P05, the 13th structure docks into the binding site of the rsk2 channel with the highest probability and most favorable electrostatic interactions. From the P05-rsk2 channel binding model, we identified the residues critical for the recognition of these two proteins through triplet contact analyses. P05 locates around the extracellular mouth of the SK channels and contacts the SK channels using its alpha-helix rather than beta-sheets. The critical triplet contacts for recognition between P05 and the rsk2 channel are Arg6 (P05)-Asp364 (SK), Arg7 (P05)-Asn368 (SK), and Arg13 (P05)-Asp341 (SK). The structure of the P05-rsk2 complex with the most favorable electrostatic interaction energy was further refined by molecular mechanics, showing that six hydrogen bonding interactions exist between P05 and the rsk2 channel: one hydrogen bond is formed between Arg6 (P05) and Asp364(D) (rsk2); Arg7 (P05) forms three hydrogen bonds with Asp341(B) (rsk2)) and Asp364(C) (rsk2); two hydrogen bonds are formed by Arg13 (P05) with Asp341(A) (rsk2) and Asp364(B) (rsk2). The simulation results are in good agreement with the previous molecular biological experiments and can explain the binding phenomena between P05 and SK channels at the level of molecular structure. The consistency between the results of the BD simulations and the experimental data indicated that our 3D model of the P05-rsk2 channel complex is reasonable and can be employed in further biological studies, such as rational design of the novel therapeutic agents blocking the small-conductance, calcium-activated and apamin-sensitive potassium channels, and for mutagenesis studies in both toxins and SK channels. In particular, both the BD simulations and the molecular mechanics refinements indicate that residue Asp364 of the rsk2 channel is critical for its recognition and binding functionality towards P05. This phenomenon has not been appreciated in the previous mutagenesis experiments, indicating that this might be a new clue for further functional study of SK channels.

Amino Acid Sequence↗
PubMed2001

The inhibitory effects of BmK IT2, a scorpion neurotoxin on rat nociceptive flexion reflex and a possible mechanism for modulating voltage-gated Na(+) channels.

Buthus martensi Karsch IT2 (BmK IT2), a scorpion neurotoxin, was found to display a biphasic inhibitory effect on the C component of the rat nociceptive flexion reflex by subcutaneous injection in vivo, and also on the total Na(+) currents of rat dorsal root ganglion neurons using whole-cell patch clamping. BmK IT2 blocked the tetrodotoxin-resistant (TTX-R) component of the Na(+) currents with a degree of selectivity. The partial block of the TTX-R Na(+) currents, brought about by 0.01 microg/microl BmK IT2, reversed less rapidly and completely than the partial block of the tetrodotoxin-sensitive (TTX-S) current brought about by the same concentration of BmK IT2. These results suggest that the inhibition of the rat nociceptive flexion reflex by BmK IT2 may be attributed to modulation of the different voltage-gated Na(+) channels.

Animals↗
PubMed2000

The effects of lignocaine on actions of the venom from the yellow scorpion "Leiurus quinquestriatus" in vivo and in vitro.

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 microg kg(-1) min(-1)) significantly attenuated the majority of the venom-evoked effects and reduced mortality. Addition of LQQ venom (1, 3 and 10 microg 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 x 10(-4)-1.2 x 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.

Animals↗
PubMed2001

Effects of antivenom on Buthus occitanus tunetanus (Bot) scorpion venom pharmacokinetics: towards an optimization of antivenom immunotherapy in a rabbit model.

The pharmacokinetic parameters of Bot venom were determined in a rabbit model using a specific sandwich type ELISA. After intravenous injection, Bot venom seems to follow a three-compartment pharmacokinetic open model. However, after subcutaneous injection, the distribution and elimination kinetics of Bot venom are best characterized by a bi-compartment pharmacokinetic open model. Bot venom is completely absorbed from its SC injection site, since the absolute bioavailability is higher than 95%; the maximum plasma venom concentration is reached between 30 and 60 min after venom injection. Bot venom diffuses rapidly to tissues and is distributed in a high body volume. The total body clearance of Bot venom is relatively high in agreement with a low mean residence time. Antivenom immunotherapy experiments were carried out in the rabbit model, in order to select the most appropriate strategy for the adequate use of this treatment. The effects of the route, the dose and the delay of antivenom injection on Bot venom pharmacokinetic parameters and on the antivenom immunotherapy efficacy were then studied. These studies indicated in particular that: (1) the injection of a minimal neutralizing antivenom dose is required for a complete and permanent neutralization of circulating venom antigens; this dose is named minimal (threshold) efficacious antivenom dose; (2) the intramuscular route is not the most appropriate way for antivenom injection; and (3) a delayed antivenom immunotherapy remains efficacious especially on the neutralization of the remaining circulating venom. In short, these experimental studies show that early intravenous injection of an appropriate antivenom dose (at least the threshold efficacious dose) is the indicated way for a rapid and permanent neutralization of circulating scorpion venom toxins.

Animals↗
PubMed2002

Asian scorpion BmK venom induces plasma extravasation and thermal hyperalgesia in the rat.

In the present study, the effects of scorpion Buthus martensi Karsch (BmK) venom on plasma extravasation and paw withdrawal latency (PWL) to radiant heat have been investigated in rats. BmK venom (20-200 microg/kg) by subcutaneous injection under the surface of the rat hindpaw causes dose-dependant increased plasma extravasation that could be partially inhibited by intraperitoneal (i.p.) injected morphine (6 mg/kg). Peak plasma extravasation was reached at 10 min and persisted for 60 min at a dose of 200 microg/kg. BmK venom induced cutaneous hyperalgesia as indicated by decreased PWL to radiant heat in the ipsilateral paw following subcutaneous injection of 20 microg/kg BmK venom without effect on PWL of the contralateral hindpaw. Meanwhile, it was found that i.p. morphine injection could inhibit this decreased ipsilateral PWL. The results thus suggest that BmK venom could induce peripheral inflammation in rat by subcutaneous injection, and may prove a valuable animal model for investigating the pathophysiology of a number of inflammatory diseases and identifying potential anti-inflammatory and analgesic drugs.

Animals↗
PubMed2003

Experimental envenoming of mice with venom from the scorpion Centruroides limpidus limpidus: differences in mortality and symptoms with and without antibody therapy relating to differences in age, sex and strain of mouse.

C57Bl/6J and BALB/cAnN inbred strains of mice differed significantly in mortality and symptoms when intoxicated subcutaneously with one LD(50) of venom from Centruroides limpidus limpidus. Higher mortality was observed in C57Bl/6J than in BALB/cAnN. Also, C57Bl/6J mice more quickly developed muscular and respiratory collapse whilst BALB/cAnN mice were hyperactive before dying. Also, the symptoms in the survivors lasted for 24 h in C57Bl/6J and for 2 h in BALB/cAnN. The age and sex of mice were also related to mortality: younger mice were more resistant than older mice and females were more susceptible than males, especially in the younger groups. Antivenom (horse F(ab')(2)) administration 5-10 min after envenoming of mice with one LD(50) rescued 60% of BALB/cAnN and 52% of C57Bl/6J mice, respectively. Results indicate that genetic background, gender and age differences are of consequence in the pathogenesis of C. limpidus scorpion envenomation in mice, and that timely treatment with active antivenom F(ab')(2) saves a significant fraction of intoxicated mice without statistically significant distinction of strains.

Age Factors↗
PubMed1997

Molecular characterization, antigenicity and immunogenicity of anatoxic polymeric forms conferring protection against scorpion venoms.

Two polymeric forms of Buthus occitamus tunetanus (Bot) G-50 and Androctonus australis hector (Aah) G-50 were obtained by controlled polymerization with glutaraldehyde. Their mol. wts, determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and exclusion high-performance liquid chromatography using radiolabelled toxin, ranged from 14,000 to 90,000 and 90,000 to 100,000 for Aah G-50 and Bot G-50, respectively. Modification of about 20% of the lysine residues yielded completely detoxified Bot G-50 fractions which retained the antigenic cross-reactivity with the native G-50 fraction, venom and toxins. High levels of specific antibodies against venoms and toxins were generated by immunization with prepared polymeric forms because absorbance values higher than 3 units were regularly observed by enzyme-linked immunosorbent assay with immune sera dilutions of 1/10,000. In vitro protection experiments demonstrated that immune sera from mice, horse and monkeys efficiently neutralized either Aah or Bot venom. Depending on the adjuvant and animal model species used, the neutralizing titre estimated by subcutaneous injection in mice varied between 20 and 40 LD50/ml. The in vivo protection assays showed that immunized mice could resist the challenge by six times the LD50 amounts of the toxic fraction. This protection was found to be long-lived. It was concluded that G-50 polymeric forms are highly detoxified and immunogenic, and should be useful for the production of potent polyvalent antivenom against scorpion toxins. They could also be considered for further studies towards the development of vaccine candidates.

Animals↗
PubMed1997

Biochemical and histopathological alterations induced in rats by Tityus serrulatus scorpion venom and its major neurotoxin tityustoxin-I.

Intravenous injection into the rat of sublethal doses of Tityus serrulatus scorpion venom (100 micrograms protein/kg) or its major neurotoxin tityustoxin-I (TsTX-I, 20 micrograms/kg) caused, 30-180 min after injection, statistically significant increases in the serum levels of aspartate aminotransferase, amylase, creatine kinase and lactate dehydrogenase, as well as hyperglycemia, a high level of plasma free fatty acids and a low level of liver glycogen. The in vitro serum levels of the above enzymes did not change. For alanine aminotransferase, gamma-glutamyl transferase and alkaline phosphatase, neither in vitro nor in vivo alterations were observed. The whole venom and TsTX-I caused hepatic congestion with hemolysis and hydropic degeneration. Other histological lesions included edema and congestion with subpleural hemorrhage in the lungs, hypertrophy of fibers with degeneration areas in the heart, and congestion and hemorrhage in the kidneys. In the salivary glands, alterations to the acini and ductules were visible. In the adrenal glands no morphological alterations could be detected at the studied doses. The results suggest that the in vivo enzymatic and histopathological alterations are due to tissue lesions evoked by the whole venom and TsTX-I. An indirect effect, however, induced by stimulation of acetylcholine and catecholamine release in the postganglionic nerve terminals, cannot be excluded.

Animals↗
PubMed1997

Action of babycurus-toxin 1 from the east African scorpion Babycurus centrurimorphus on the isolated cockroach giant axon.

A toxin named babycurus-toxin 1 (mol. wt 8191), from telson extracts of the scorpion Babycurus centrurimorphus, was found to depolarize the cockroach giant axon. It progressively blocked the evoked action potentials after a short period of limited repetitive activity and after 30 min of toxin action it became impossible to evoke responses to current stimulations. Voltage-clamp experiments on the sodium current indicated that the toxin in micromolar concentrations progressively decreased the transient inward peak sodium current, but also slowed the activation phase of this sodium current and maintained an inward current during the voltage pulses, which deactivated slowly. The toxin also induced in the insect axon a slowly activating-deactivating component of the sodium current. This suggests that the toxin modifies both activation and inactivation mechanisms of sodium channels. Thus there is some similarity in the electrophysiological effects between BcTx1 and the beta-toxins active on mammals.

Amino Acid Sequence↗
PubMed1998

Two similar peptides from the venom of the scorpion Pandinus imperator, one highly effective blocker and the other inactive on K+ channels.

Two novel peptides, named Pi4 and Pi7, were purified from the venom of the scorpion Pandinus imperator, and their primary structures were determined. These peptides have 38 amino acids residues, compacted by four disulfide bridges, instead of the normal three found in most K+-channel specific toxins. Both peptides contain 25 identical amino acid residues in equivalent positions (about 66% identity), including all eight half-cystines. Despite the fact that their C-terminal sequence comprising amino acid residues 27 to 37 are highly conserved (10 out of 11 amino acids are identical), Pi4 blocks completely and reversibly Shaker B K+ -channels (a Kv1.1 sub-family type of channel) at 100nM concentration, whereas Pi7 is absolutely inactive at this concentration. Similar effects were observed in binding and displacement experiments to rat brain synaptosomal membranes using 125I-Noxiustoxin, a well known K+-channel specific toxin. In this preparation Pi4 displaces the binding of radiolabeled Noxiustoxin with Ic50 in the order of 10 nM, whereas Pi7 is ineffective at same concentration. Comparative analysis of Pi4 and Pi7 sequences with those obtained by site directed mutagenesis of Charybdotoxin, another very well studied K -channel blocking toxin, shows that the substitution of lysine (in Pi4) for arginine (in Pi7) at position 26, might be one of the important 'point mutations' responsible for such impressive variation in blocking properties of both toxins, here described.

Amino Acid Sequence↗