The Experts below are selected from a list of 197574 Experts worldwide ranked by ideXlab platform
Wayne Clarence Hodgson - One of the best experts on this subject based on the ideXlab platform.
-
isolation and pharmacological characterization of α elapitoxin ot1a a short chain postsynaptic neurotoxin from the venom of the western desert taipan oxyuranus temporalis
Toxins, 2016Co-Authors: Carmel M Barber, Muhamad Rusdi Ahmad Rusmili, Wayne Clarence HodgsonAbstract:Taipans (Oxyuranus spp.) are elapids with highly potent venoms containing presynaptic (β) and postsynaptic (α) neurotoxins. O. temporalis (Western Desert taipan), a newly discovered member of this genus, has been shown to possess venom which displays marked in vitro Neurotoxicity. No components have been isolated from this venom. We describe the characterization of α-elapitoxin-Ot1a (α-EPTX-Ot1a; 6712 Da), a short-chain postsynaptic neurotoxin, which accounts for approximately 30% of O. temporalis venom. α-Elapitoxin-Ot1a (0.1–1 µM) produced concentration-dependent inhibition of indirect-twitches, and abolished contractile responses to exogenous acetylcholine and carbachol, in the chick biventer cervicis nerve-muscle preparation. The inhibition of indirect twitches by α-elapitoxin-Ot1a (1 µM) was not reversed by washing the tissue. Prior addition of taipan antivenom (10 U/mL) delayed the Neurotoxic effects of α-elapitoxin-Ot1a (1 µM) and markedly attenuated the Neurotoxic effects of α-elapitoxin-Ot1a (0.1 µM). α-Elapitoxin-Ot1a displayed pseudo-irreversible antagonism of concentration-response curves to carbachol with a pA2 value of 8.02 ± 0.05. De novo sequencing revealed the main sequence of the short-chain postsynaptic neurotoxin (i.e., α-elapitoxin-Ot1a) as well as three other isoforms found in O. temporalis venom. α-Elapitoxin-Ot1a shows high sequence similarity (i.e., >87%) with other taipan short-chain postsynaptic neurotoxins.
-
inhibition of presynaptic neurotoxins in taipan venom by suramin
Neurotoxicity Research, 2014Co-Authors: Sanjaya Kuruppu, Janeyuth Chaisakul, Ian A Smith, Wayne Clarence HodgsonAbstract:Taipans are amongst the most venomous snakes in the world, and Neurotoxicity is a major life-threatening symptom of envenoming by these snakes. Three species of taipans exist, and the venom from each species contains a presynaptic neurotoxin which accounts for much of the Neurotoxicity observed following human envenoming. The high cost of antivenom used to treat Neurotoxicity has resulted in the need to develop alternative but effective therapies. Therefore, in this study, we examined the ability of the P2Y receptor antagonist suramin to prevent the in vitro Neurotoxic effects of the three presynaptic neurotoxins in taipan venoms: taipoxin, paradoxin and cannitoxin. Toxins were purchased from commercial sources or purified in house, using multiple steps of gel filtration chromatography. All three toxins (11 nM) inhibited nerve-mediated twitches in the chick biventer cervicis nerve–muscle preparation within 300 min. The presence of suramin (0.3 mM) completely blocked the taipoxin and cannitoxin-mediated inhibition of nerve-mediated twitches within the course of the experiment (P < 0.0001). However, paradoxin induced a 32 % decrease in twitch height even in the presence of suramin within 360 min. This was significantly different compared to toxin alone (P < 0.0001). We also examined the effect of suramin on the Neurotoxic effects of textilotoxin and the products of phospholipase A2 action. Each toxin alone or in the presence of suramin failed to inhibit the responses to exogenous agonists ACh, CCh or KCl. Our results warrant clinical studies aimed determining the efficacy of suramin in preventing the onset of Neurotoxicity following taipan envenoming.
-
Inhibition of Presynaptic Neurotoxins in Taipan Venom by Suramin
Neurotoxicity Research, 2014Co-Authors: Sanjaya Kuruppu, Janeyuth Chaisakul, A. Ian Smith, Wayne Clarence HodgsonAbstract:Taipans are amongst the most venomous snakes in the world, and Neurotoxicity is a major life-threatening symptom of envenoming by these snakes. Three species of taipans exist, and the venom from each species contains a presynaptic neurotoxin which accounts for much of the Neurotoxicity observed following human envenoming. The high cost of antivenom used to treat Neurotoxicity has resulted in the need to develop alternative but effective therapies. Therefore, in this study, we examined the ability of the P2Y receptor antagonist suramin to prevent the in vitro Neurotoxic effects of the three presynaptic neurotoxins in taipan venoms: taipoxin, paradoxin and cannitoxin. Toxins were purchased from commercial sources or purified in house, using multiple steps of gel filtration chromatography. All three toxins (11 nM) inhibited nerve-mediated twitches in the chick biventer cervicis nerve–muscle preparation within 300 min. The presence of suramin (0.3 mM) completely blocked the taipoxin and cannitoxin-mediated inhibition of nerve-mediated twitches within the course of the experiment ( P
-
intersexual variations in the pharmacological properties of coremiocnemis tropix araneae theraphosidae spider venom
Toxicon, 2009Co-Authors: Volker Herzig, Wayne Clarence HodgsonAbstract:Abstract This study aimed to determine the biochemical, insecticidal and Neurotoxic properties of venom from both sexes of the Australian spider Coremiocnemis tropix (Araneae, Theraphosidae). Insecticidal properties were tested in crickets, while in vitro Neurotoxicity was determined in an avian skeletal muscle preparation. Some intersexual differences in venom composition were identified by rp-HPLC and by LC–MS, but the majority of components were found in venoms of both sexes. Injecting the venom into crickets revealed that venom from male specimens was slightly more potent, while female venom induced more prominent effects in the chick biventer cervicis nerve–muscle preparation. The results from the chick assay suggest the presence of at least two vertebrate-active neurotoxins. A pre-synaptic neurotoxin may explain the reversible inhibition of muscle twitches and the unaffected response to nicotinic agonists at medium concentrations of female and medium to high concentrations of male venom. In addition, the presence of a neurotoxin that blocks post-synaptic nicotinic receptors might explain the irreversible inhibition of muscle twitches and the reduced response to nicotinic agonists at high concentrations (5–10 μg/ml) of venom from female specimens only.
-
oxylepitoxin 1 a reversible neurotoxin from the venom of the inland taipan oxyuranus microlepidotus
Peptides, 2006Co-Authors: Carol Clarke, Ian A Smith, Shane Reeve, Sanjaya Kuruppu, Wayne Clarence HodgsonAbstract:Abstract This study describes the characterization of oxylepitoxin-1 (MW 6789), the first postsynaptic neurotoxin isolated from the venom of the Inland taipan ( Oxyuranus microlepidotus ), which is the most venomous snake in the world. Oxylepitoxin-1, purified using successive steps of size-exclusion and reverse phase-high performance liquid chromatography, produced concentration-dependent (0.3–1.0 μM) inhibition of nerve-mediated (0.1 Hz, 0.2 ms, supramaximal V) twitches of the chick biventer cervicis nerve-muscle preparation. Taipan antivenom (5 units/ml) prevented the Neurotoxic activity of whole venom (10 μg/ml), but had no significant effect on oxylepitoxin-1 (1 μM). The toxin-induced inhibition of nerve-mediated twitches was significantly reversed upon washing the tissue at 5 min intervals. Oxylepitoxin-1 (30–300 nM) displayed competitive antagonism at the skeletal muscle nicotinic receptor with a pA 2 value of 7.16 ± 0.28 (i.e. approximately 10-fold more potent than tubocurarine). The venom had a high level of PLA 2 activity (765 ± 73 μmol/min/mg) while oxylepitoxin-1 displayed no PLA 2 activity. Partial N-terminal sequencing of oxylepitoxin-1 shows high sequence identity (i.e. 93%) to postsynaptic toxins isolated from the venom of the closely related coastal taipan ( Oxyuranus scutellatus scutellatus ).
Sanjaya Kuruppu - One of the best experts on this subject based on the ideXlab platform.
-
Neurotoxicity in Sri Lankan Russell’s Viper (Daboia russelii) Envenoming is Primarily due to U1-viperitoxin-Dr1a, a Pre-Synaptic Neurotoxin
Neurotoxicity Research, 2017Co-Authors: Anjana Silva, Robert J.a. Goode, Iekhsan Othman, Sanjaya Kuruppu, Wayne. C. Hodgson, Geoffrey K IsbisterAbstract:Russell’s vipers are snakes of major medical importance in Asia. Russell’s viper ( Daboia russelii ) envenoming in Sri Lanka and South India leads to a unique, mild neuromuscular paralysis, not seen in other parts of the world where the snake is found. This study aimed to identify and pharmacologically characterise the major Neurotoxic components of Sri Lankan Russell’s viper venom. Venom was fractionated using size exclusion chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC). In vitro Neurotoxicities of the venoms, fractions and isolated toxins were measured using chick biventer and rat hemidiaphragm preparations. A phospholipase A_2 (PLA_2) toxin, U1-viperitoxin-Dr1a (13.6 kDa), which constitutes 19.2 % of the crude venom, was isolated and purified using HPLC. U1-viperitoxin-Dr1a produced concentration-dependent in vitro Neurotoxicity abolishing indirect twitches in the chick biventer nerve-muscle preparation, with a t _90 of 55 ± 7 min only at 1 μM. The toxin did not abolish responses to acetylcholine and carbachol indicating pre-synaptic Neurotoxicity. Venom, in the absence of U1-viperitoxin-Dr1a, did not induce in vitro Neurotoxicity. Indian polyvalent antivenom, at the recommended concentration, only partially prevented the Neurotoxic effects of U1-viperitoxin-Dr1a. Liquid chromatography mass spectrometry analysis confirmed that U1-viperitoxin-Dr1a was the basic S-type PLA_2 toxin previously identified from this venom (NCBI—GI: 298351762 ; SwissProt: P86368 ). The present study demonstrates that Neurotoxicity following Sri Lankan Russell’s viper envenoming is primarily due to the pre-synaptic neurotoxin U1-viperitoxin-Dr1a. Mild Neurotoxicity observed in severely envenomed Sri Lankan Russell’s viper bites is most likely due to the low potency of U1-viperitoxin-Dr1a, despite its high relative abundance in the venom.
-
inhibition of presynaptic neurotoxins in taipan venom by suramin
Neurotoxicity Research, 2014Co-Authors: Sanjaya Kuruppu, Janeyuth Chaisakul, Ian A Smith, Wayne Clarence HodgsonAbstract:Taipans are amongst the most venomous snakes in the world, and Neurotoxicity is a major life-threatening symptom of envenoming by these snakes. Three species of taipans exist, and the venom from each species contains a presynaptic neurotoxin which accounts for much of the Neurotoxicity observed following human envenoming. The high cost of antivenom used to treat Neurotoxicity has resulted in the need to develop alternative but effective therapies. Therefore, in this study, we examined the ability of the P2Y receptor antagonist suramin to prevent the in vitro Neurotoxic effects of the three presynaptic neurotoxins in taipan venoms: taipoxin, paradoxin and cannitoxin. Toxins were purchased from commercial sources or purified in house, using multiple steps of gel filtration chromatography. All three toxins (11 nM) inhibited nerve-mediated twitches in the chick biventer cervicis nerve–muscle preparation within 300 min. The presence of suramin (0.3 mM) completely blocked the taipoxin and cannitoxin-mediated inhibition of nerve-mediated twitches within the course of the experiment (P < 0.0001). However, paradoxin induced a 32 % decrease in twitch height even in the presence of suramin within 360 min. This was significantly different compared to toxin alone (P < 0.0001). We also examined the effect of suramin on the Neurotoxic effects of textilotoxin and the products of phospholipase A2 action. Each toxin alone or in the presence of suramin failed to inhibit the responses to exogenous agonists ACh, CCh or KCl. Our results warrant clinical studies aimed determining the efficacy of suramin in preventing the onset of Neurotoxicity following taipan envenoming.
-
Inhibition of Presynaptic Neurotoxins in Taipan Venom by Suramin
Neurotoxicity Research, 2014Co-Authors: Sanjaya Kuruppu, Janeyuth Chaisakul, A. Ian Smith, Wayne Clarence HodgsonAbstract:Taipans are amongst the most venomous snakes in the world, and Neurotoxicity is a major life-threatening symptom of envenoming by these snakes. Three species of taipans exist, and the venom from each species contains a presynaptic neurotoxin which accounts for much of the Neurotoxicity observed following human envenoming. The high cost of antivenom used to treat Neurotoxicity has resulted in the need to develop alternative but effective therapies. Therefore, in this study, we examined the ability of the P2Y receptor antagonist suramin to prevent the in vitro Neurotoxic effects of the three presynaptic neurotoxins in taipan venoms: taipoxin, paradoxin and cannitoxin. Toxins were purchased from commercial sources or purified in house, using multiple steps of gel filtration chromatography. All three toxins (11 nM) inhibited nerve-mediated twitches in the chick biventer cervicis nerve–muscle preparation within 300 min. The presence of suramin (0.3 mM) completely blocked the taipoxin and cannitoxin-mediated inhibition of nerve-mediated twitches within the course of the experiment ( P
-
oxylepitoxin 1 a reversible neurotoxin from the venom of the inland taipan oxyuranus microlepidotus
Peptides, 2006Co-Authors: Carol Clarke, Ian A Smith, Shane Reeve, Sanjaya Kuruppu, Wayne Clarence HodgsonAbstract:Abstract This study describes the characterization of oxylepitoxin-1 (MW 6789), the first postsynaptic neurotoxin isolated from the venom of the Inland taipan ( Oxyuranus microlepidotus ), which is the most venomous snake in the world. Oxylepitoxin-1, purified using successive steps of size-exclusion and reverse phase-high performance liquid chromatography, produced concentration-dependent (0.3–1.0 μM) inhibition of nerve-mediated (0.1 Hz, 0.2 ms, supramaximal V) twitches of the chick biventer cervicis nerve-muscle preparation. Taipan antivenom (5 units/ml) prevented the Neurotoxic activity of whole venom (10 μg/ml), but had no significant effect on oxylepitoxin-1 (1 μM). The toxin-induced inhibition of nerve-mediated twitches was significantly reversed upon washing the tissue at 5 min intervals. Oxylepitoxin-1 (30–300 nM) displayed competitive antagonism at the skeletal muscle nicotinic receptor with a pA 2 value of 7.16 ± 0.28 (i.e. approximately 10-fold more potent than tubocurarine). The venom had a high level of PLA 2 activity (765 ± 73 μmol/min/mg) while oxylepitoxin-1 displayed no PLA 2 activity. Partial N-terminal sequencing of oxylepitoxin-1 shows high sequence identity (i.e. 93%) to postsynaptic toxins isolated from the venom of the closely related coastal taipan ( Oxyuranus scutellatus scutellatus ).
-
isolation and pharmacological characterization of cannitoxin a presynaptic neurotoxin from the venom of the papuan taipan oxyuranus scutellatus canni
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Sanjaya Kuruppu, Ian A Smith, Shane Reeve, Yajnavalka Banerjee, Manjunatha R Kini, Wayne Clarence HodgsonAbstract:The Papuan taipan ( Oxyuranus scutellatus canni ) is widely distributed throughout much of Papua New Guinea. Although Neurotoxicity is a major symptom of envenomation, no neurotoxins have been isolated from this venom. Using a series of size exclusion chromatography steps, we report the isolation of cannitoxin, a presynaptic neurotoxin (44,848 Da) that represents approximately 16% of the whole venom. The toxin displayed high phospholipase A2 (PLA2) activity (330 ± 5 μmol/min/mg) and caused concentration-dependent (11–66 nM) inhibition of indirect (0.2 ms; 0.1 Hz; supramaximal V) twitches of the chick biventer cervicis nerve-muscle preparation without effecting nicotinic receptor agonists. Prior addition of CSL Taipan antivenom (5 U/ml) or inhibition of phospholipase A2 activity by incubation with 4-bromophenacyl bromide prevented the inhibition of twitches. Cannitoxin is composed of three different subunits, α, β, and γ, with the possibility of two β isomers. However, only the α subunit displayed in vitro Neurotoxic activity of its own. Thus, cannitoxin is similar in structure and pharmacology to taipoxin, which has been isolated from the closely related Australian species O. scutellatus scutellatus (coastal taipan).
Valerie Choumet - One of the best experts on this subject based on the ideXlab platform.
-
reappraisal of vipera aspis venom Neurotoxicity
PLOS ONE, 2007Co-Authors: Elisabeth Ferquel, Luc De Haro, Isabelle Guillemin, Sabine Jourdain, Alexandre Teynie, Jacques Dalayer, Valerie ChoumetAbstract:BACKGROUND: The variation of venom composition with geography is an important aspect of intraspecific variability in the Vipera genus, although causes of this variability remain unclear. The diversity of snake venom is important both for our understanding of venomous snake evolution and for the preparation of relevant antivenoms to treat envenomations. A geographic intraspecific variation in snake venom composition was recently reported for Vipera aspis aspis venom in France. Since 1992, cases of human envenomation after Vipera aspis aspis bites in south-east France involving unexpected neurological signs were regularly reported. The presence of genes encoding PLA(2) neurotoxins in the Vaa snake genome led us to investigate any neurological symptom associated with snake bites in other regions of France and in neighboring countries. In parallel, we used several approaches to characterize the venom PLA(2) composition of the snakes captured in the same areas. METHODOLOGY/PRINCIPAL FINDINGS: We conducted an epidemiological survey of snake bites in various regions of France. In parallel, we carried out the analysis of the genes and the transcripts encoding venom PLA(2)s. We used SELDI technology to study the diversity of PLA(2) in various venom samples. Neurological signs (mainly cranial nerve disturbances) were reported after snake bites in three regions of France: Languedoc-Roussillon, Midi-Pyrenees and Provence-Alpes-Cote d'Azur. Genomes of Vipera aspis snakes from south-east France were shown to contain ammodytoxin isoforms never described in the genome of Vipera aspis from other French regions. Surprisingly, transcripts encoding venom Neurotoxic PLA(2)s were found in snakes of Massif Central region. Accordingly, SELDI analysis of PLA(2) venom composition confirmed the existence of population of Neurotoxic Vipera aspis snakes in the west part of the Massif Central mountains. CONCLUSIONS/SIGNIFICANCE: The association of epidemiological studies to genetic, biochemical and immunochemical analyses of snake venoms allowed a good evaluation of the potential Neurotoxicity of snake bites. A correlation was found between the expression of neurological symptoms in humans and the intensity of the cross-reaction of venoms with anti-ammodytoxin antibodies, which is correlated with the level of neurotoxin (vaspin and/or ammodytoxin) expression in the venom. The origin of the two recently identified Neurotoxic snake populations is discussed according to venom PLA(2) genome and transcriptome data.
-
Reappraisal of Vipera aspis venom Neurotoxicity.
PLoS ONE, 2007Co-Authors: Elisabeth Ferquel, Luc De Haro, Isabelle Guillemin, Sabine Jourdain, Alexandre Teynie, Virginie Jan, Jacques D'alayer, Valerie ChoumetAbstract:BACKGROUND: The variation of venom composition with geography is an important aspect of intraspecific variability in the Vipera genus, although causes of this variability remain unclear. The diversity of snake venom is important both for our understanding of venomous snake evolution and for the preparation of relevant antivenoms to treat envenomations. A geographic intraspecific variation in snake venom composition was recently reported for Vipera aspis aspis venom in France. Since 1992, cases of human envenomation after Vipera aspis aspis bites in south-east France involving unexpected neurological signs were regularly reported. The presence of genes encoding PLA(2) neurotoxins in the Vaa snake genome led us to investigate any neurological symptom associated with snake bites in other regions of France and in neighboring countries. In parallel, we used several approaches to characterize the venom PLA(2) composition of the snakes captured in the same areas. METHODOLOGY/PRINCIPAL FINDINGS: We conducted an epidemiological survey of snake bites in various regions of France. In parallel, we carried out the analysis of the genes and the transcripts encoding venom PLA(2)s. We used SELDI technology to study the diversity of PLA(2) in various venom samples. Neurological signs (mainly cranial nerve disturbances) were reported after snake bites in three regions of France: Languedoc-Roussillon, Midi-Pyrénées and Provence-Alpes-Côte d'Azur. Genomes of Vipera aspis snakes from south-east France were shown to contain ammodytoxin isoforms never described in the genome of Vipera aspis from other French regions. Surprisingly, transcripts encoding venom Neurotoxic PLA(2)s were found in snakes of Massif Central region. Accordingly, SELDI analysis of PLA(2) venom composition confirmed the existence of population of Neurotoxic Vipera aspis snakes in the west part of the Massif Central mountains. CONCLUSIONS/SIGNIFICANCE: The association of epidemiological studies to genetic, biochemical and immunochemical analyses of snake venoms allowed a good evaluation of the potential Neurotoxicity of snake bites. A correlation was found between the expression of neurological symptoms in humans and the intensity of the cross-reaction of venoms with anti-ammodytoxin antibodies, which is correlated with the level of neurotoxin (vaspin and/or ammodytoxin) expression in the venom. The origin of the two recently identified Neurotoxic snake populations is discussed according to venom PLA(2) genome and transcriptome data.
Elisabeth Ferquel - One of the best experts on this subject based on the ideXlab platform.
-
reappraisal of vipera aspis venom Neurotoxicity
PLOS ONE, 2007Co-Authors: Elisabeth Ferquel, Luc De Haro, Isabelle Guillemin, Sabine Jourdain, Alexandre Teynie, Jacques Dalayer, Valerie ChoumetAbstract:BACKGROUND: The variation of venom composition with geography is an important aspect of intraspecific variability in the Vipera genus, although causes of this variability remain unclear. The diversity of snake venom is important both for our understanding of venomous snake evolution and for the preparation of relevant antivenoms to treat envenomations. A geographic intraspecific variation in snake venom composition was recently reported for Vipera aspis aspis venom in France. Since 1992, cases of human envenomation after Vipera aspis aspis bites in south-east France involving unexpected neurological signs were regularly reported. The presence of genes encoding PLA(2) neurotoxins in the Vaa snake genome led us to investigate any neurological symptom associated with snake bites in other regions of France and in neighboring countries. In parallel, we used several approaches to characterize the venom PLA(2) composition of the snakes captured in the same areas. METHODOLOGY/PRINCIPAL FINDINGS: We conducted an epidemiological survey of snake bites in various regions of France. In parallel, we carried out the analysis of the genes and the transcripts encoding venom PLA(2)s. We used SELDI technology to study the diversity of PLA(2) in various venom samples. Neurological signs (mainly cranial nerve disturbances) were reported after snake bites in three regions of France: Languedoc-Roussillon, Midi-Pyrenees and Provence-Alpes-Cote d'Azur. Genomes of Vipera aspis snakes from south-east France were shown to contain ammodytoxin isoforms never described in the genome of Vipera aspis from other French regions. Surprisingly, transcripts encoding venom Neurotoxic PLA(2)s were found in snakes of Massif Central region. Accordingly, SELDI analysis of PLA(2) venom composition confirmed the existence of population of Neurotoxic Vipera aspis snakes in the west part of the Massif Central mountains. CONCLUSIONS/SIGNIFICANCE: The association of epidemiological studies to genetic, biochemical and immunochemical analyses of snake venoms allowed a good evaluation of the potential Neurotoxicity of snake bites. A correlation was found between the expression of neurological symptoms in humans and the intensity of the cross-reaction of venoms with anti-ammodytoxin antibodies, which is correlated with the level of neurotoxin (vaspin and/or ammodytoxin) expression in the venom. The origin of the two recently identified Neurotoxic snake populations is discussed according to venom PLA(2) genome and transcriptome data.
-
Reappraisal of Vipera aspis venom Neurotoxicity.
PLoS ONE, 2007Co-Authors: Elisabeth Ferquel, Luc De Haro, Isabelle Guillemin, Sabine Jourdain, Alexandre Teynie, Virginie Jan, Jacques D'alayer, Valerie ChoumetAbstract:BACKGROUND: The variation of venom composition with geography is an important aspect of intraspecific variability in the Vipera genus, although causes of this variability remain unclear. The diversity of snake venom is important both for our understanding of venomous snake evolution and for the preparation of relevant antivenoms to treat envenomations. A geographic intraspecific variation in snake venom composition was recently reported for Vipera aspis aspis venom in France. Since 1992, cases of human envenomation after Vipera aspis aspis bites in south-east France involving unexpected neurological signs were regularly reported. The presence of genes encoding PLA(2) neurotoxins in the Vaa snake genome led us to investigate any neurological symptom associated with snake bites in other regions of France and in neighboring countries. In parallel, we used several approaches to characterize the venom PLA(2) composition of the snakes captured in the same areas. METHODOLOGY/PRINCIPAL FINDINGS: We conducted an epidemiological survey of snake bites in various regions of France. In parallel, we carried out the analysis of the genes and the transcripts encoding venom PLA(2)s. We used SELDI technology to study the diversity of PLA(2) in various venom samples. Neurological signs (mainly cranial nerve disturbances) were reported after snake bites in three regions of France: Languedoc-Roussillon, Midi-Pyrénées and Provence-Alpes-Côte d'Azur. Genomes of Vipera aspis snakes from south-east France were shown to contain ammodytoxin isoforms never described in the genome of Vipera aspis from other French regions. Surprisingly, transcripts encoding venom Neurotoxic PLA(2)s were found in snakes of Massif Central region. Accordingly, SELDI analysis of PLA(2) venom composition confirmed the existence of population of Neurotoxic Vipera aspis snakes in the west part of the Massif Central mountains. CONCLUSIONS/SIGNIFICANCE: The association of epidemiological studies to genetic, biochemical and immunochemical analyses of snake venoms allowed a good evaluation of the potential Neurotoxicity of snake bites. A correlation was found between the expression of neurological symptoms in humans and the intensity of the cross-reaction of venoms with anti-ammodytoxin antibodies, which is correlated with the level of neurotoxin (vaspin and/or ammodytoxin) expression in the venom. The origin of the two recently identified Neurotoxic snake populations is discussed according to venom PLA(2) genome and transcriptome data.
Thomas F Murray - One of the best experts on this subject based on the ideXlab platform.
-
Brevetoxin derivatives act as partial agonists at neurotoxin site 5 on the voltage-gated Na+ channel
Brain Research, 2003Co-Authors: Keith T. Lepage, Daniel G. Baden, Thomas F MurrayAbstract:Abstract Brevetoxins (PbTx-1 to PbTx-10) are potent lipid-soluble polyether neurotoxins produced by the marine dinoflagellate Karina brevis, an organism associated with ‘red tide’ blooms in the Gulf of Mexico. Ingestion of shellfish contaminated with K. brevis produces Neurotoxic shellfish poisoning (NSP) in humans. NSP symptoms emanate from brevetoxin activation of neurotoxin site 5 on voltage-gated sodium channels (VGSC) [Toxicon 20 (1982) 457]. In primary cultures of rat cerebellar granule neurons (CGN), brevetoxins produce acute neuronal injury and death. The ability of a series of naturally occurring and synthetic brevetoxins to trigger Ca2+ influx in CGN was explored in the present study. Intracellular Ca2+ concentration was monitored in fluo-3-loaded CGN using a fluorescent laser imaging plate reader. The naturally occurring derivatives PbTx-1, PbTx-2 and PbTx-3 all produced a rapid and concentration-dependent increase in cytosolic [Ca2+]. The maximum response to PbTx-1 was approximately two-fold greater than that of either PbTx-2 or PbTx-3. Two synthetic derivatives of PbTx-3, α-naphthoyl-PbTx-3 and β-naphthoyl-PbTx-3, were also tested. Both α- and β-naphthoyl-PbTx-3 stimulated a rapid and concentration-dependent Ca2+ influx that was, however, less efficacious than that of PbTx-3. These data indicate that, analogous to neurotoxin site 2 ligands, activators of neurotoxin site 5 display a range of efficacies, with PbTx-1 being a full agonist and other derivatives acting as partial agonists.
-
antillatoxin is a marine cyanobacterial toxin that potently activates voltage gated sodium channels
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: W I Li, Frederick W Berman, Fumiaki Yokokawa, Takayuki Shioiri, Tatsufumi Okino, William H Gerwick, Thomas F MurrayAbstract:Antillatoxin (ATX) is a lipopeptide derived from the pantropical marine cyanobacterium Lyngbya majuscula. ATX is Neurotoxic in primary cultures of rat cerebellar granule cells, and this neuronal death is prevented by either N-methyl-d-aspartate (NMDA) receptor antagonists or tetrodotoxin. To further explore the potential interaction of ATX with voltage-gated sodium channels, we assessed the influence of tetrodotoxin on ATX-induced Ca2+ influx in cerebellar granule cells. The rapid increase in intracellular Ca2+ produced by ATX (100 nM) was antagonized in a concentration-dependent manner by tetrodotoxin. Additional, more direct, evidence for an interaction with voltage-gated sodium channels was derived from the ATX-induced allosteric enhancement of [3H]batrachotoxin binding to neurotoxin site 2 of the α subunit of the sodium channel. ATX, moreover, produced a strong synergistic stimulation of [3H]batrachotoxin binding in combination with brevetoxin, which is a ligand for neurotoxin site 5 on the voltage-gated sodium channel. Positive allosteric interactions were not observed between ATX and either α-scorpion toxin or the pyrethroid deltamethrin. That ATX interaction with voltage-gated sodium channels produces a gain of function was demonstrated by the concentration-dependent and tetrodotoxin-sensitive stimulation of 22Na+ influx in cerebellar granule cells exposed to ATX. Together these results demonstrate that the lipopeptide ATX is an activator of voltage-gated sodium channels. The Neurotoxic actions of ATX therefore resemble those of brevetoxins that produce neural insult through depolarization-evoked Na+ load, glutamate release, relief of Mg2+ block of NMDA receptors, and Ca2 + influx.
