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SPIDERS
Brachypelma smithi
The nomenclature of spider toxins is, unlike that of scorpions, based on the same convention as that of cone-snails and snakes.
Boehimian red leg tarantula
Thus, alpha-toxins inhibit the acetylcholine receptor, mu-toxins directly abolish muscle action potentials through the inhibition of muscle sodium channels, and omega-toxins prevent voltage-activated entry of calcium into the nerve terminal and release of acetylcholine [100]. Two effects on neuromuscular transmission: postsynaptic inhibition and presynaptic excitation. These effects are explained by the actions of two classes of toxins purified by RPLC, the alpha- and mu-agatoxins. 3. The alpha-agatoxins are low molecular weight, acylpolyamines which cause rapid, reversible paralysis correlated with use-dependent postsynaptic block of EPSPs and ionophoretic glutamate potentials. The mu-agatoxins are cysteine-rich polypeptides which cause irreversible paralysis and repetitive action potentials originating in presynaptic axons or nerve terminals. 4. The joint actions of the alpha- and mu-agatoxins lead to significantly higher rates of paralysis than are obtained by either toxin class alone, and this may relate to enhancement by excitatory mu-agatoxins of use-dependent block caused by alpha-agatoxins. [101]
Citharischius crawshayi (King baboon), one of Africas largest and nastiest species.
Agelenopsis
Clinical effects of bite from Agelenopsis aperta (American funnel web-spider) are negligable, the venom, however, has yeilded several interesting compounds that have pharmocolocal properties that may prove to be quite useful. The structure of the neurotoxins from Agelenopsis aperta show strong sequential similarities, primarily in the locations of the cysteine residues, with neurotoxins from Phoneutria nigriventer and Hololena curta [102].
Studies indicate that the venom contains Aga-GI, a toxin capable of inhibiting an elusive neuronal calcium channel that is resistant to block by either omega-conotoxin GVIA or nifedipine. The presynaptic voltage-dependent Ca2+ channel is coupled to glutamate exocytosis in the mammalian central nervous system.. Thus Aga-GI is a novel tool with which to probe this. [103]. Aga-G2 is a low molecular weight fraction containing alpha-agatoxins has been isolated from venom. Intravenous or intracerebroventricular administration of AG2 produces dose-dependent suppression of behavioral convulsions induced in rats by kainic acid, picrotoxin, or bicuculline[104]. The low molecular weight compounds present in these venom fraction may provide novel tools for anticonvulsant research and therapy since alpha- agatoxins are selective and reversible noncompetitive antagonists at NMDA (N- methyl-D-aspartate ) receptors in mammalian brain [105-107].
Two specific mu-agatoxins have been identified, mu-agatoxin-I and mu-agatoxin-IV, both of which are irreversible voltage sensitive sodium channel blockers. These insect paralytic neurotoxins contain 36 amino acids and four internal disulfide bonds, toxins [108]. Although these toxins are specifically modify voltage- sensitive sodium channel activity, they posses common secondary and tertiary structural motifs with a plethora of other peptide toxins targeting a myriad of channel types [109, 110].
The omega-agatoxins consist of two subtypes of neuronal calcium channel toxins with different structural characteristics and calcium channel binding specificities. [111]. Omega-Aga-IA, omega-Aga-IB, and omega-Aga-IIA all block insect neuromuscular transmission presynaptically but are of different toxin types. Type I omega-toxins, such as IA and IB, share very similar amino acid sequences, and exhibit characteristic tryptophan-like UV absorbance spectra. Complete Edman sequencing of omega-Aga-IA reveals it to be a 66-amino acid polypeptide containing 9 cysteines and 5 tryptophan residues [111]. Omega-Aga-I may define a binding site on neuronal calcium channels which is common to both vertebrates and invertebrates [112]. Representative of Type II omega-toxins omega-Aga- II, III and IV all share limited amino acid sequence similarity with Type I toxins, in addition to exhibiting mixed tryptophan- and tyrosine-like absorbance. Omega-Aga-IIa shows shows a 60% homology with Phtx3 from Phoneutria nigriventer [113]. Nanomolar concentrations of omega-Aga-IIA inhibit the specific binding of the cone snail neurotoxin omega-conotoxin GVIA to chick synaptosomal membranes while omega-Aga-IA and -IB have no effect under identical conditions [111]. Omega-Aga-IIIA appears to bind L-, N-, P-, and O-type Ca2+ channels, and omega-Aga-IVA blocks dihydropyridine- and - omega-CTX-GVIA (from Conus geographus ) resistant Ca channels as does omega-CTX-GVIA from Conus magus [114]. Omega-Aga-IVA, IVB, and IVC are P-type calcium channel blockers containin 48 amino acids with four loops resulting from 4 disulfide bonds that specifically block P-type calcium channels in mammalian brain [115]. These neurotoxin are rich in basic residues that may have a role in binding to the anionic sites in the extracellular regions of the calcium channel thus blocking neuromuscular synapses at nanomolar concentrations, suppressesing transmitter release at insect and frog neuromuscular junctions and blocking calcium spikes in insect neuronal cell bodies. [112].
Chiracanthium (sac spiders)
Bites from this genus are primarily cytotoxic, producing erythematous urticarial plaques that form almost immediately , with punctate macules appearing later, and the bite site eventually becoming indurated with the potential for lethal reactions) [123-125]. No defined proteins have been reported for this genus.
Dolomedes (Fishing spiders)
Dolomedes okefinokensii bites rarely cause anything but the mildest of edema and possibly mild necrosis. The venom, however, has yielded a protein that may have use as an analgesic, this polyamine reversibly blocks L- and R- type voltage-sensitive calcium channels [126].
Hololena (Funnel web spiders)
Hololena curta is a non-threatening specie that happens to contain some interesting toxins termed curtatoxins. These 38 amino acid proteins act as reversible blockers of glutamate-sensitive calcium channels, thus inhibiting presynaptic activity [127, 128]. These toxins have been shown to inhibit dihydropyridine, omega-conotoxin insensitive Ca2+ channels in rat synaptosomes [129]. In addition, the curtatoxins have cysteine residues with locational homology with PhTx neurotoxins from Phoneutria nigriventer as well as neurotoxins from Agelenopsis aperta [102].
Latrodectus (Red-back and Widows)
female L. hasselti
The venom of this genus is contains some of the most potent biologic toxins that produce their effects through destabilization of cell membranes and degranulation of nerve terminals resulting in the release of neurotransmitters [130]. Typical envenomations, of varying degrees with mactans (Black widow) and hasselti (Red-backed spider) being the two most toxic members of the genus, produce painful abdominal cramping and rigidity accompanied by severe hypotension. As is true will all poisonings, the very young or elderly are at the greatest risk as are those with preexisting cardiovascular disease. Species often implicate in envenomations are L. mactans, L. hasselti, L. hesperus, L. indistinctus, L. menavodi, L. tredecimguttatus, and L. variolus all of which to provoke somewhat similar clinical pictures.[131].
A variant from Argentina showing the variation in colouration
L. geometricus (Brown widow) produces clinical effects similar to that of the black widow but the typical symptoms and signs being milder and tending to be restricted to the bite site and surrounding tissues. [132]. However, fatalities are on record, with the offending spiders having been captured and positively identified as female brown widows (Latrodectus geometricus). Symptomatology was described as â*remarkable with regard to severity (one fatality due to cardiovascular failure, one gangrene of the foot) as well as clinical manifestations (immediate local pain, kidney dysfunction, arterial hypertension)â** [133].
L. hasselti (Red backed spider) is a very toxic specie with clinical effects are virtually identical to that of the Black widow [134, 135]. No toxins have been specifically reported for this specie, but due to the extreme simillarity of symptoms it is logical to conclude that specific venom proteins found in mactans (black widow) or close analougs of these proteins are present in the venom of hasselti.
L. inactopus typically causes restlessness, profuse perspiration, severe abdominal pain and rigidity, and muscular twitching. These symptoms are all in keeping with typcial latrodectism, however there have been additional symptoms reported for this specie that appear to be unique to this specie. In 2 reported cases there was gastrointestinal involvement, with ileus and gastric dilatation [136].
Clinical effects of L. indistinctus envenomation are similar to that of the closely related L. geometricus. Neither species are considered truly dangerous to victims other than the extremely young or old. Local symptoms are pain with systemic effects consistent with bites from other members of this genus: excruciating abdominal cramping and rigidity, respiratory difficulty, and restlessness. Although symptoms are pronounced and dramatic, recovery is usually uneventful [123]. Indistinctus is noteable not only for causing symptoms similar to that of mactans but also that pulmonary edema is not uncommon in the bite pathology [137].
L. mactans (Black widow) is the best known and one of the two toxic members of this genus, with many others species incorrectly referred to as the black widow. Bites produce a great degree of cramping and pain with the definate capacity of paralysis or death from respiratory failure. Loxoscelism from this specie has minimal skin changes but produces massive hemolysis and neuromuscular-related symptoms such as lower extremity weakness [138, 139]. The highly neurotoxic venom affects the presynaptic motor endplate allowing massive noradrenaline (norepinephrine) and acetylcholine release into synapses resulting in excessive stimulation and fatigue of the motor end plate and muscle [140]. The major bioactive component of the venom of mactans is latrotoxin which is responsible for many of the neurological symptoms and causes a massive release of acetylcholine stimulated by the presense of Ca2+ ions [141]. This increased synaptic vesicle fusion this activation results morphological changes in electric organ synaptosomes such as swelling resuling in a 55% increase in section area in addition to decreasing the number of synaptic vesicles per unit area about three-fold, with rows of docked synaptic vesicles being almost entirely absent (as opposed to normal synaptosomes). [142].
It is interesting to compare alpha-latrotoxin with omega-conotoxin, alpha-Ltx being an activator of synaptosomal calcium uptake, and omega-conotoxin GVIA, an inhibitor of voltage-sensitive calcium channels of the N-type [143].
Latrodectus tredecimguttatus (Karakurt or Mediterranean black widow spider) has a clinical picture quite similar to that of L. mactans and nearly as serious with the most common signs and symptoms being: pain and abdominal stiffness, erythema, or pain at the site of the bite, thoracic pain, pain in extremities and contractures and psychomotor alterations (6 cases) with laboratory findings limited to leukocytosis, increase in creatinphosphokinase count, and proteinuria [144]. Research studies have demonstrated a similar effect upon the neurons as does L. mactans with swelling of sensory endings with progressive degeneration of annulospiral endings [145]. The protein likely responsible for this is latrodectin, an 88 amino acid neurotoxic peptide similar to alpha-latrotoxin from the black widow L. mactans [146]. This specie also contains alpha-latrotoxin, as many other species are likely to in varying quantities [147].
Loxosceles
L. reclusa
Loxosceles reclusa (Brown recluse) is a dangerous specie that causes significant and prolonged clinical effects. Typical bite pathology consists of deep and very slow healing necrotic wounds at bite site but the bite is capable of causing death from systemic effects such as intravascular coagulation and renal failure [148, 149]. Systemic loxoscelism differs from dermonectotic loxoscelism in that there are minimal skin changes but produces massive hemolysis [139, 150].
localised necrosis resulting from a L. reclusa bite
Mechanisms of action of the toxins from L. reclusa is not exactly known but certain facets of it have been characterised. One very interesting feature is the fact that the necrotic effects are totally reliant upon the victimâ*s neutrophiles, however no neutrophilic activation is observed. The inflammatory respones are due to venom components acting as endothelial cell agonists resulting in a dysregulated PMN response resulting in a state where adhesion and degranulation are completely dissociated from shape change and transmigration [151]. Other aspects of significance are complement inactivation [152]. Localised necrosis is also deeply due to the presense of toxic phospholipase D as well as spingomyelinase D [153]. The spingomyelinase D present in the venom has been shown expirementally to produce skin necrosis [154]. In addition, human platelet aggregation was induced by purfied forms of this toxin and this could be a major factor in the localised necrosis typically seen in bites [155]. Other blood effects, such as hemolysis, may be due to the binding of the venom from reclusa to human erythrocyte cell membranes with structural changes occuring on the venom attatched membranes [156].
L. laeta (South American fiddle back) bites produce clinical effects consisting of severe local necrosis with systemic effects in about 15% of the cases with death from renal failure [157]. Venom composition is on line with L. reclusa including the presense of spingomylelinase D causing membrane damage with resulting lysis [140]. Expirements have successfully demonstrated that in this specie, and likely reclusa also, lysis of erythrocytes is due to a direct action of the venom that is complement dependent without any antibody mediation [158].
Lycosa (Wolf spiders)
Despite its relatively large size, and morphological similarity with Loxosceles, the wolf spiders are essentially nonvenomous to humans. In typical cases there is seldom anymore than mild localised pain and very rarely and cutaneous necrosis or systemic effects from this cytotoxic venom [123, 159, 160]. One interesting neurotoxic protein that has been identified from this genus is LycIV from from L. erythrognatha but likely to also be present in godeffroyi. This neurotoxic polypeptide alters the repolarisation fo action potentials likely through the inhibition of sodium channel inactivation [161].
Nephila clavata (Joro spider)
JSTX is an interesting toxin that has been quite useful in studying receptors for excitatory amino acinds inthe mammalian central nervous system. Receptors for excitatory amino acids in the mammalian central nervous system are classified into three major subtypes, ones which prefer N-methyl-D-aspartate (NMDA), quisqualate (QA), or kainate (KA) as type agonists respectively. [162]. Jorotoxin has been shown to be a specific blocker of the postsynaptic glutamate receptors, in contrast with pertuissus toxin which blocks the presynaptic glutamate receptors. [163].
Phoneutria
Phoneutria nigriventer (Brazilian wandering spider) contains extremely toxic venom with the potential danger of this specie compounded by the fact that this large spider is extremely aggressive and often bites multiple times in quick succession. The immediate effects are intense local pain and edema followed by severe, painful and potentially life-threatening systemic effects such as arrythmic heartbeat, clotting inhibition, priapism, pulmonary edema, and vomiting [164, 165].
The toxins of Phoneutria shares strong structural similarity, particularily in the location of the cysteine residues, with neurotoxins from Agelenopsis aperta and Hololena curta [102].
The lethal neurotoxin PhTx1 is made up of a single polypeptide of 77 amino acid residues containing significant amount of cysteines with the primary structure showing no homology to other identified spider toxins [166]. However, studies involving cDNA libraries constructed from the venom glands and subsequent production of a clone coding for Tx1 revealed that the structure of the preprotoxin initially synthesized by the Tx1 gene shows similarity in structure and also in processing with the synthesis and processing of omega-agatoxin IA from Agelenopsis aperta [167]. PhTx2 - inhibits the closure of voltage-sensitive Na+ channels and causes a rapid increase in the intrasynaptosomal free Ca2+ concentration and a dose-dependent release of glutamate [168]. Neurotoxin PhTx2 variants -1, -5, and -6 produce spastic paralysis in lab mice with the variant PhTx2-9 causing only tail erection and scratching. [169]. Phtx2-1, -5, and -6 show strong homology and are all similar in size (53, 49, and 48 amino acids respectively) while PhTx2-9 is smaller, 32 amino acids, and shows limited similarity [169]. PhTx3 inhibits Ca(2+)-dependent glutamate release and the increase in cytosolic free Ca2+ in response to membrane depolarization, this site of action is coupled to the process of release of acetylcholine in brain and autonomic nervous system [170]. Injection of laboratory mice with 5 micrograms/mouse, Tx3-3 and Tx3- 4 caused rapid general flaccid paralysis followed by death in 10-30 min; Tx3-2 induced immediate clockwise gyration and flaccid paralysis after 6 hr; Tx3-1, Tx3-5 and Tx3-6 produced paralysis only in the posterior limbs and gradual decreases in movement and aggression during 24 hr. [102].
Selenocosmia
S. javanensis
Although clinical references concerning bites from this genus, in laboratory testing, using single doses, Selenocosmia stirlingi venom was shown to be highly toxic to rats, and therefore potentially toxic to humans [171]. While this specie has not had any specific venom proteins identified from it, S. huwena (Chinese bird spider) has had two very bioactive proteins identified: huwentoxin-1 and SHLP-1. Huwentoxin is a 33 amino acid neurotoxin that shows a good degree of sequence homology with the mu-agatoxins of Agelenopsis aperta [110]. SHLP-I is a 32 amino acid hemotoxin that has significant haemagglutination activity towards both mice and human red blood cells [172].
Sicarius sp (Transvaal 6-eyed crab spiders)
Species in this genus are not considered capable of delivering life-threatening bites, however the cytotoxic and hemotoxic nature of the venom makes them capable of causing localised necrosis [123].
Steatoda
Both nobilis and paykulliana are capable of bites producing intense local pain and edema [173, 174]. The venoms act presynaptically eliciting massive release of transmitters and also form channels in bilayer lipid membranes (BLM) that are selective for cations [175-177]
Tegenaria
male T. agrestis
This genus contains a member, Tegenaria agrestis (Hobo-spider), that is capable of producing marked dermal lesions and severe toxicosis in humans... [178]. Typical localised reactions are local pain, erythematous papula, and mild edema and systemic effects consisting of pain in the limbs, tremor and rigidities, sweating, limbs and arms paresthesia and abdominal pain [179]. No specific toxins have been identified.
female T. agrestis