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New Perspectives in Drug Discovery Using Neuroactive Molecules From the Venom of Arthropods

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Márcia Renata Mortari and Alexandra Olimpio Siqueira Cunha

Submitted: March 28th, 2012 Published: July 1st, 2013

DOI: 10.5772/52382

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1. Introduction

Arthropods are one of the most ancient groups of animals in earth and their venoms have been responsible for their chemical defense in a very efficient way. Resulting from an intense and elaborated evolutionary process, venoms produced by arthropods have a very complex repertoire of biologically active molecules. When inoculated in mammals these molecules induce a wide range of systemic effects, including actions in the CNS. In mammalian CNS, venom compounds may either inhibit or stimulate with affinity and specificity structures such as: ion channels, neurotransmitter receptors and transporters [1-3]. Not surprisingly, these actions have attracted the attention of many investigators in search of tools to help the understanding of neural mechanisms as well as those in search of novel probes in CNS drug design for the last 20 years [3,4]. In addition to the growing interest in finding new neuroactive compounds, the improvement of proteomic and transcriptome techniques has stimulated great progress in the bioprospecting, enabling and accelerating the testing of new toxins in several animal models. Animal research aiming at the efficacy of peptides and acylpoliamines, isolated from arthropod venoms, have revealed the great potential of these compounds to treat various diseases, such as epilepsy, Parkinson's, Alzheimer's, chronic pain and anxiety disorders

According to World Health Organization (WHO), neurological and mental disorders are one of the greatest threats to public health not only for its direct and immediate effects, but also for the progressive nature of these diseases, often leading to disability and death [5]. The symptoms of most of these diseases are often well treated with a several pharmaceuticals, such as antidepressants, anxiolytics, anticonvulsants and analgesics. However, it is well known that neuroactive drugs may induce a complex range of adverse effects that limit the usage in some patients or may even function as a factor of impairment in people’s quality of life. According to [6], none of antiepileptic drugs discovered in the last 20 years, was efficient to cure or even suppress seizures in epileptic patients. Therefore, there is a continued need for the discovery of novel drugs to treat most neurological and mental disorders [7].

This chapter will target the discussion of recent contributions of research on the compounds of arthropod venom, for the discovery of novel tools to study the functioning of the structures of mammalian CNS, as well as the supply of novel alternatives to the treatment of neurological disorders. Among the major compounds, it will be highlighted those with the analgesic, anxiolytic, antiepileptic and neuroprotective effects, with emphasis on the most promising on preclinical or clinic evaluation.


2. Main targets of the neuroactive compounds isolated from arthropod venoms

Venom isolated from bee, scorpion and spider have been used to the treatment of various diseases in Chinese and Korean traditional medicine, such as epilepsy, stroke, facial paralysis, arthritis, rheumatism, back pain, cancerous, tumors, and skin diseases [8-10]. Moreover, venoms of arthropod animals have been used to study various physiopathological processes, and also offer opportunity to design and develop new therapeutic drugs [3,11,12] .

Arthropod venoms are rich in biologically active substances with different physiological actions, specially the neurotoxins. So far, identified neurotoxins generally comprise the classes of peptides or acylpolyamines, acting with affinity and specificity over excitatory or inhibitory neurotransmissions (for revision see [12]. The actions of these compounds include the interaction with Na+, K+ and Ca2+ ion channels, agonism or antagonism of metabotropic and ionotropic receptors for neurotransmitters as the excitatory neurotransmitter glutamate. At the presynaptic level, several studies have shown the interaction of arthropod neurotoxins with protein transporters of neurotransmitters, resulting in the facilitation or inhibition of their uptake.


3. Antinociceptive effects

Of extreme importance for the organism, pain is an indicator of corporal integrity and has been considered since January 2000, by the Joint Commission on Accreditation on Healthcare Organizations (JCAHO) as the fifth vital sign that should be assessed and recorded together with other signals immediately after birth. According to the International Association for the Study of Pain (IASP), pain is defined as an unpleasant sensation and emotional experience associated with actual or potential tissue damage. However, approximately one third of world population suffers from pathological persistent or recurrent pain, which is a common complaint in patients with different diseases, and exerts great impact on their social life [13]. In these cases, treatment is a challenge for researchers and health professionals who constantly seek new therapeutic strategies, since most of these are inadequate or cause serious side effects [14].

Analgesics and systemic conservative therapies are widely used for pain control. However, in many cases, especially in patients with neuropathic pain, more aggressive treatments are needed, which promote a significant clinical improvement but only in 30-50% of patients [15,16].

Although an injection of arthropod venoms is commonly reported to cause tonic pain and hyperalgesia, there is also evidence suggesting that these venoms might have antinociceptive effects on inflammation. Thus, nowadays, toxins isolated from arthropods are considered powerful tools, since they have congruent targets of the impulse transmission of pain, and may provide an attractive alternative to opioid treatments.

3.1. Polypeptide toxins from Scorpion

The most studied Arthropod venom is extracted from the Asian scorpion Mesobuthus martensi Karsch (BmK). It is composed of several toxins, and so far, ten have been described, which produce powerful antinociceptive effects. This is the case of the two β-excitatory anti-insect toxins BmK IT-AP (or Bm33-I) and BmK AngP1, two β- depressant anti-insect toxins BmK dITAP3 and BmK IT2, as well as six toxins yet without consensus classification, BmK AS, BmK AS1, BmK AGAP, BmK Ang M1, BmK AGP-SYPU1 and BmK AGP-SYPU2. These compounds probably belong to a family of peptides NaScTx that are composed of 60-76 amino acid residues with four disulfide bonds, the cysteine positions among these toxins are highly conserved [17,18]. Considering their structures, they might be able to bind to sodium channels impairing depolarization of the action potential in nerve and muscle, resulting in neurotoxicity [18], although it remains to be fully investigated.

The NaScTx family can be classified in at least two major families, α and β, according to the mode of action on Na+ channels [19]. The binding of α-toxins delays Nav channel inactivation, while that of β-toxins shifts the membrane potential dependence of channel activation to more negative potentials. α and β-toxins also exhibit pharmacological preferences for mammals or insects sodium channels. Therefore, considering their pharmacological activities, α and β NAScTx can be also divided into three groups:

  1. “classic” highly specific for mammals;

  2. “α-like toxins” active both on mammals and insects, which are far less specific and less active than the “classical” ones;

  3. α-toxins only specific for insects and without any toxicity on mammals, even at high concentrations. Moreover, the insect selective β-toxins have been divided into two groups: the excitatory insect toxins and the depressant insect toxins.

Regarding the β-excitatory anti-insect toxins, BmK IT-AP (Insect Toxin-Analgesic Peptide), which was isolated in 1999, produces a potent antinociceptive effect in mouse-twisting model, after i.v. injection [20]. The same toxin has also been sequenced by another group and named Bm K 33-I [21]. Later, Guan and colleagues [22] identified a novel toxin with analgesic effects, BmK AngP1, which shows an evident analgesic effect with simultaneous excitatory insect toxicity, but is devoid of any toxicity on mice even at high dosages. The analgesic effect was assessed with a mouse-twisting model. The analgesic effect on mice of the AngP1 is at least 4-5 times weaker than that of IT-AP, but the toxicity to insects is twice as strong as that of IT-AP [20,22]

In relation of depressant toxins isolated from BmK venom, BmK IT2 has been more studied from the venom of BmK (Fig 1). Intraplantar injection of BmK IT2 inhibited thermal hyperalgesia in carrageenan-treated rats and significantly prolonged paw withdrawal latency in normal rats [23]. This toxin also displays an inhibitory effect on the C component of the rat nociceptive flexion reflex by subcutaneous injection in vivo [24]. Peripheral or spinal delivery of BmK IT2 suppressed formalin-induced nociceptive behaviors and c-Fos expression in spinal cord [25,26]. Both BmK IT2 and Bm K dIT-AP3 (depressant Insect Toxin-Analgesic Peptide 3) are toxic for insects, but not for mammals [27], and shows 86.7% of sequence similarity [23]. BmK dIT-AP3 also induces analgesia in the mouse-twisting model [18]. Using whole-cell patch clamp, it has been shown that BmK dIT-AP3 inhibits Nav currents of rat dorsal root ganglion (DRG) neurons, blocking more selectively the tetrodotoxin-resistant (TTX-R) component of the Na+ currents. These results suggest that the inhibition of the rat nociceptive flexion reflex by BmK dITAP3 may be attributed to modulation of the DRG’s voltage-gated Na+ channels [24].

Wang and colleagues [28] isolated a new antinociceptive peptide, named BmK AGP-SYPU1. Recombinant BmK AGP-SYPU1 showed similar analgesic effects on mice compared to natural when assayed using a mouse-twisting model [28]. More recently, BmK AGP-SYPU2 was purified and tested, also in mouse-twisting model. Sequence determination showed that the mature BmK AGP-SYPU2 peptide is composed of 66 amino acid residues, and BmK AGP-SYPU2 is identical to BmK alpha2 and BmK alphaTX11.

BmK AS had a strong analgesic effect on both visceral and somatic pain [29,30]. It relieves formalin-induced two-phase spontaneous flinching response and carrageenan-induced mechanical hyperalgesia, probably by modulating the voltage-gated Na+ channels of sensory neurons [31,32]. Moreover, BmK AS showed activity nearly equivalent to that of morphine. Later, a new peptide that possesses 86.3% of similarity with BmK AS was identified. Both polypeptides have 66 amino acids cross-linked by four disulfide bridges [29]. In addition, these two peptides show a poor similarity with other known types of scorpion toxins. BmK AS and AS1 are not toxic against mammals and only have a weak toxicity to insects. BmK AS, then BmK AS1, have been found to significantly stimulate the binding of [3H]-ryanodine to partially purified ryanodine receptors [33]. More recently, electrophysiological studies have shown that they are able to inhibit Na+ currents in NG108-15 cells [34] and to depress TTX-sensitive and TTX-resistant Na+ currents in rat small DRG neurons. Interestingly, in rat models, BmK AS1 also displays antinociceptive effects according to [33]. These authors concluded that the effects could be mediated by the modulation of voltage-gated Na+ channels and they also suggested that BmK AS and BmK AS1 could form a new family of scorpion insect toxins.

BmK AGAP (antitumor-analgesic peptide), isolated in 2003, had strong inhibitory effect on both viscera and soma pain [35]. To evaluate the extent to which residues of the toxin core contribute to its analgesic activity, nine mutants of BmK AGAP were produced and tested. However, further studies are necessarily to elucidate the mechanism of action as well as to exploit its analgesic activity [36]. In relation to BmK Ang M1 [37], it also was reported to exhibit potential analgesic effect. Moreover, electrophysiological studies showed that BmK AngM1 at the concentration of 1 µM inhibited voltage-dependent Na+ current (INa) and voltage-dependent delayed rectifier K+ current (IK), but had no effects on transient K+ current [37].

It is important to note that the excitatory and depressant anti-insect toxins belong to different groups, which have distinct modes of interaction with receptors. Thus, one can infer that the analgesic effect of these peptides may have a molecular mode and mechanism different from that of insect toxicity. Still, the mechanisms by which these scorpion toxins can modulate pain pathways remain to be clarified. According to [8], four different possibilities might be described:

  1. peptides act directly Na+ channels involved in the pathway of pain,

  2. peptides modulate indirectly the pain sensation,

  3. peptides also modulate other targets involved in pain pathway

  4. pain alleviation is only apparent and results from misinterpretations that might have occurred from animal models used.

3.2. Polypeptide toxins from Spider

Another group of arthropods that have very promising antinociceptive compounds are spiders [41]. In 1996, Roerig & Howse reported the effect of ω-agatoxina IVA (Fig 1) isolated from funnel spider Agelenopsis aperta venom, against thermal stimulation in the tail flick test, when co-administrated with morphine intrathecal. Intrathecal injection of ω-agatoxin IVA (0.2 nmol/kg) also decreased the licking time in both the early and late response phases in a dose-dependent manner in the Formalin test [42]. The use of this peptide as an analgesic could be of particular benefit in patients tolerant or opioid-dependent, since this compound exhibits selectivity for the P/Q Ca2+ channels [43]. Other spider venom very promissory is the venom of the Brazilian armed spider Phoneutria nigriventer, the purified fraction 3 (PhTx3) contains 6 toxin isoforms (Tx3-1 to -6) [44,45] that target Ca2+ channels with different affinity patterns. Moreover, one toxin, Tx3-6 (Phα1β), demonstrated that it preferentially blocks the N-type calcium current [46] and produce a potent antinociceptive effect with higher therapeutic index [44]. Dalmolin and colleagues [45] showed that Tx3-3 (purified the same fraction) caused a short-lasting antinociceptive effect in the nociceptive pain test and a long-lasting antinociceptive effect in neuropathic pain models, without producing detectable side effects. However, Tx3-3 did not change the inflammatory pain. Tx3-3 blockade of P/Q- and R-type Ca2+ channels and inhibit the glutamate release in rat brain cortical synaptosomes [47]. Other neurotoxin isolated from spider Phoneutria nigriventer is Phα1β, which is a potent toxin blocking neuronal voltage-sensitive Ca2+ channels. This peptide induced longer antiallodynic effect than µ-conotoxin MVIIA and morphine in mice [48].

In addition to toxins calcium modulators, compounds isolated from spider that interact with other ionic channels have shown great potential. A new class of peptide toxins named is the Huwentoxin I (HWTX-I, Fig 1) that is the most abundant toxic component in the crude venom of the Chinese bird spider Ornithoctonus huwena. Whole-cell patch clamp records revealed that HWTX-I selectively inhibits N-type Ca2+ channels in NG108-15 cells, and it also can block transmitter release from nerve endings by preventing depolarization induced by calcium influx [38] Antinociception effect of the HWTX-I in formalin test was greater and lasted two-fold longer time compared to morphine [39]. Furthermore, Tao and collaborators [40] demonstrated that intrathecal administration of HWTX-I is effective in antinociception in the rat model of rheumatoid arthritis more effective than ibuprofen.

Several studies have reported that intrathecal administration of non-selective blockers of Ca2+ channels shows antinociceptive effects in animals tested with thermal stimuli: hot plate and tail flick. According to [49], N and P/Q Ca2+ channels are probably involved in nociceptive behavior induced by formalin injection in rats, while the L-type channels has no effect. N- and P/Q-type Ca2+ channels are expressed specifically in the nervous system, and they have a major importance in controlling the excitation of spinal neurons from sensory afferents of inflamed tissues, relieving inflammatory pain.

A new class of peptide toxins named π-theraphotoxin-Pc1a (π-TRTX-Pc1a; also known as psalmotoxin-1 (PcTx1) was isolated from the venom of the spider neotropical Psalmopoeus cambridgei (Fig.1). π-TRTX-Pc1a is the most potent and selective blocker of ion channels sensitive to acid – ASICa [50]. These channels play important roles in pathological conditions such as cerebral ischemia or epilepsy, as well as being responsible for the sensation of pain that accompanies tissue acidosis and inflammation [51]. Since external acidification is a major factor in pain associated with inflammation (hematosis muscle and cardiac ischemia, or cancer), these neurotoxins can be used to control the pain sensation triggered by these channels [52]. π-TRTX-Pc1a was shown to be an effective analgesic, comparable to morphine, in rat models of acute and neuropathic pain when injected directly in Central Nervous System [53] and intranasal administration of this peptide resulted in neuroprotection of neurons in a mouse model of ischemic stroke even when administered hours after injury [54].

Other important target in the search for new analgesics isolated from spider venoms are NaV channels, since modulatory compounds of these channels are the dominant pharmacological species in spider venoms, although still poorly characterized. In this context, Intrathecal administration of β-TRTX-Gr1b (formerly GsAFI), a peptide obtained from venom of Grammostola spatulata, the Chilean pink tarantula spider, induced analgesia in a variety of rat pain models such as the tail flick latency test, hot plate threshold test, von Frey threshold test, and formalin pain test, without any confounding side-effects. Moreover, the β-TRTX-Gr1b peptide did not exhibit cross tolerance with morphine [55].

Further on spider venoms, Purotoxin-1 (PT1) was recently isolated the, from the venom of the Central Asian spider Geolycosa sp [56]. PT1 is a 35-residue peptide with four disulfide bonds, and it exerts a potent analgesic effect in rat models of acute and chronic inflammatory pain by injection of either carrageenan or Freund’s complete adjuvant, respectively. PT1 was also effective in reducing the number of nocifensive events triggered by the injection of capsaicin or formalin (only second phase) [56]. This molecule also inhibits P2X3 receptors in a powerful and selective manner. These ATP-activated receptors are largely expressed in mammalian sensory neurons play a key role in the pain perception. Thus, PT1 appears to be a promising lead compound for the development of analgesics that target these receptors [56].

3.3. Polypeptide toxins from Bees and Wasps

Bee venom has been traditionally used to relieve pain and treat chronic pain diseases (for revision see [57]). Moreover, acupoint stimulation into the subcutaneous region (acupuncture) rather than other injection sites may be important for the antinociceptive effects of this venom. There is increasing evidence suggesting that bee venom has antinociceptive effects on visceral nociceptive effects, mechanical and thermal hyperplasia, formalin-induced pain behavior and collagen-induced arthritic pain, as well as knee osteoarthritis (OA)-related pain [58-63]. BV contains at least 18 active components, including enzymes, peptides, and biogenic amines, which have a wide variety of pharmaceutical properties, and so multiple mechanisms associated to antinociceptive effects have been suggested, such as activation of the central and spinal opioid receptor and α2-adrenergic receptor, as well as activation of the descending serotonergic pathways (for revision see [64]).

Melittin is a small protein containing 26 amino acid residues and is the major bioactive component in BV (Fig.1). This polypeptide readily integrates into and disrupts both natural and synthetic phospholipid bilayers [65,66]. Melittin also enhances the activity of PLA2 [67] and has a variety of effects on living cells possibly through the disruption of the membrane [68]. The decrease in cyclooxygenase (COX)-2 and phospholipase PLA2 expression and the decrease in the levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-6, nitric oxide (NO) and oxygen reactive species (ROS) are suggested to be associated with the anti-arthritis effect of melittin [69]. This peptide has also been thought to play a role in production of anti-nociceptive and anti-inflammatory effects [64]. In addition, Merlo and colleagues [70] demonstrated the antinociceptive activity of the melittin in experimental models of nociceptive and inflammatory pain. Interestingly, melittin failed to increase the latency for the nociceptive response in the hot-plate model and in the first phase of the formalin test, revealing that melittin presents an activity that resembles more that of anti-inflammatory drugs and less that of centrally acting drugs [70]. Nevertheless, the molecular and cellular mechanisms underlying the anti-nociceptive effects of melittin are not entirely clear and remain to be further clarified by further experimental studies [57].

Addition of melittin, adolapin has been isolated from BV and it demonstrated a potent analgesic effect in mouse-twisting model and the Randall-Sellito's test [71]. The anti-inflammatory activity of adolapin was evaluated and it had a pronounced activity in the following tests: carrageenan, PG, adjuvant rat hind paw edema and adjuvant polyarthritis. The effects of adolapin are presumably due to its ability to inhibit the prostaglandin synthesis via inhibition of cyclooxygenase activity [71,72].

Venoms of wasps also have analgesic peptides. Mortari and colleagues [73] isolated a compound with antinociceptive activity from the venom of the Brazilian social wasp Polybia occidentalis. The isolated peptide is a neurokinin named Thr6-Bradykinin. This neurokinin is a small peptide consisting of nine amino acid residues, Arg-Pro-Pro-Gly-Phe-Thr-Pro-Phe-Arg-OH, which exhibits a high degree of homology with bradykinin (BK), except for the substitution of Thr for Ser in position 6 at BK. As a result, small changes in their secondary structures are observed [74]. This modification has been regarded as responsible for increasing B2 receptor affinity and potency of Thr6-BK in relation to BK in vitro and in vivo [74,75]. Thr6-BK antinociceptive effect was dose- and time- dependent, when injected directly into the CNS of rats in hot-plate and tail-flick tests, and it was three times more potent than morphine and 4 times more potent than BK in tail-flick test. Thr6-BK induced antinociception by activating presynaptic B2 receptors, which activate descending adrenergic pathways. Studies investigating the role of kinins in the CNS provide new information on the supraspinal system of the pain control, whose modulation may represent a new strategy to control pain-related pathologies [76].

Figure 1.

Tridimensional structure of antinociceptive peptides isolated from arthropod venoms. (A) BMK IT2; (B) HWTX 1; (C) ω-Agatoxin IVA; (D) π-Theraphotoxin-Pc1a; (E) Mellitin. Uniprot entry code: P68727, P56676, P30288, P60514 and P01501, respectively.

Besides peptides, some studies have evaluated the analgesic activity of acylpolyamines that can be used as new alternative drugs for the treatment of chronic pain, as well as tools for the study of the functional role of the AMPA/kainate receptors in the processing of nociceptive pain [77]. In this regard, intrathecal administration of different doses of these toxins blocked thermally induced allodynia [78] and hyperalgesia [79]. The effect of these neurotoxins may suggest a possible involvement of AMPA receptors in the spinal cord during the nociceptive excitatory stimulation [80,81].


4. Antiepileptic and neuroprotective effects

Neurodegenerative disorders comprise a wide range of conditions mostly characterized by a progressive loss of neuronal function and neuronal cell death. The incidence of these diseases in population differs greatly. In conditions such as Parkinson disease and Alzheimer, the number of cases significantly increases in elderly, whereas epileptic patients are mostly children and adolescents. Many processes may trigger neuronal cell death, such as trauma, stroke, tumors, infections, genetic factors and biochemical alterations. Among the latest, the alterations in Ca2+-mediated signaling is thought to play a key role in many neurodegenerative disorders and the increase in intracellular Ca2+ concentration might alter neuronal membrane potential [82]. Moreover, the hyperactivation of excitatory transmission mediated mostly by L-glutamate and its ionotropic receptors; kainate, AMPA and NMDA, is responsible for the excessive cationic influx that depolarizes neuronal cells and lead to sustained hyperexcitation observed in brain pathologies such as epilepsy [83]. This increase in glutamatergic activity often referred to as glutamate excitotoxicity [84], might also involve non-receptor neurochemical events such as failure in glutamate uptake system, which ends with an increase in the availability of this neurotransmitter in the synaptic cleft [85,86]. The importance of L-glutamate in neurological disorders relies on the fact that this neurotransmitter is release in the great majority of fast synapses in CNS [84,83]. In this context, many molecules mostly peptides and acylpolyamines, acting on ion channels, receptors and transporters were isolated from arthropod venoms, remarkably spiders, scorpions and wasps [3]. According to [82], polyamines are non-specific antagonist of ligand-gated ion channels, acting at glutamatergic and Ach receptors in an uncompetitive way, that is, the receptor must be activated in order to occur the blockade. This mode of action might diminish the side effects of newly designed medicines, since it blocks only the activated receptors, but does not prevent their opening.

The venom of the orb-web spider Nephilia clavata was one of the first venoms studied during the 80s, which resulted in the identification of small compounds named acylpolyamines, among whose we may find jorotoxin (JSTX), one of the first glutamate receptor uncompetitive antagonists [83,84]. Together with JSTX, another polyamines such as argiopin from the venom of the spider Argiope lobata [85] and philantotoxin (PhTx) from the venom of the solitary wasp Philanthus triangulum [86]. Following the structural characterization and studies in insect or crustaceans, the reports on the action of these polyamines in mammalian CNS started to take place, mostly during the 90s [87]. JSTX-1 and JSTX-3 are synthetic analogues of JSTX. The first inhibits kainate-induced seizures, whereas the latter block glutamate release and hippocampal epileptic discharges [88,89]. Later, JSTX-3 was shown to inhibit the formation of superoxide dismutase-1 (SOD-1) aggregates that lead mutant motor neurons (mSOD-1) to death during the familiar form of the neurodegenerative disease, amyotrophic lateral sclerosis [90]. The authors concluded that increased Ca2+ influx mainly through AMPA/kainate glutamate receptors make mutant neurons more vulnerable to damage and therefore, JSTX-3 is an interesting neuroprotective agent in this model.

The fraction of the venom of the spider Agelenopsis aperta containing argiotoxin, was first demonstrated to have anticonvulsant in NMDA-induced and audiogenic seizures [91]. The synthetic analogue of argiotoxin, Arg-636, is a selective antagonist of NMDA receptors binding to the Mg2+ binding site at the receptor with anticonvulsant and neuroprotective actions. In addition, from the venom of A. aperta, another NMDA receptor blocker, Agatoxin 489 was reported as anticonvulsant against kainate-induced seizures and its synthetic analogue Agel-505, was able to block cationic currents in oocytes transfected with NMDA receptor cDNA [92].

Aside from antagonizing glutamate receptors, arthropod neurotoxins may exert anticonvulsant and neuroprotective effects targeting other neurotransmitter systems. The venom of the Brazilian spider Phoneutria nigriventer has been extensively studied over the past 20 years. Neurotoxins isolated from the venom of P. nigriventer, such as PhTx-3 (Tx-3) were reported to inhibit Ca2+ dependent-glutamate release [47]. Tx3-3 and Tx3-4 also inhibit voltage-activated Ca2+ channels of P/Q type [93] and recently their neuroprotective activity was tested. According to [94], Tx3-3 and Tx3-4 protected hippocampal slices against damage and cell death induced by ischemic insult resulted from low oxygen and low glucose. Moreover, PhTx3, Tx3-3, and Tx3-4, inhibited cell loss in retinal slices submitted to the same ischemic protocol [95]. Another Brazilian species lives in Cerrado, the colonial spider Parawixia bistriata and has many neuroactive molecules with different modes of action [96]. Parawixin-1 was the first isolated neurotoxin from P. bistriata venom. In experiments using rat retinas, submitted to ischemic insult, the intravitreal injection of Parawixin inhibited cell loss [97], probably through a potent and specific enhancing action on glutamate transporters type EAAT2 [98]. Another neurotoxin isolated from the venom of P. bistriata, Parawixin II, formerly, FrPbAII, inhibited GABA and glycine uptakes in synaptosomes from rat cerebral cortices. In addition, the administration of Parawixin II into the vitreous humor of Wistar rats protected retinal neurons against ischemic insult resulted from an increase in the intra ocular pressure [96]. Data also show that Parawixin II blocked seizures induced by the injection of GABAergic antagonists, bicuculline [99], pentylenetetrazole (PTZ) and picrotoxin, as well as pilocarpine and kainic acid [100]. It is worth noting that the acute injection of Parawixin II does not alter rat behavior in the open field and repeated central injection does not impair acquisition and learning in the Morris water maze. Finally, Parawixin II induces ataxia in the rotarod in doses far higher than effective doses, indicating good therapeutic indexes [100].

Also from South America, the Chilean giant pink tarantula Grammostola spatulata paralyzes its preys by injecting a mixture of toxins that blocks ion channels [101]. w-Grammotoxin SIA was isolated from the venom of G. spatulata and the potent blocking effect over N-, P-, and Q-type but not L-type of voltage gated calcium channels was reported [102]. The antagonistic activity of w-grammotoxin over voltage dependent calcium channels is considered a therapeutic option to be used in neurodegenerative disorders such as ischemia.

The African tarantula Hysterocrates gigas known as the giant baboon spider, inhabits the rain forests of West Africa. The isolation of the venom of H. gigas, resulted in the identification of the peptide SNX-482 that blocks R-type voltage dependent calcium channels [103].

The arboreal tarantula Psalmopoeus cambridgei is an aggressive spider that lives in the tropical forests of Trindad. As mentioned before, PcTx-1 (π-theraphotoxin-Pc1a) present in P. cambridgei venom is the only gating modifier of ASICs [50]. In addition to pain inhibitor, it exerts an interesting neuroprotective and a possible antidepressant activity due to the involvement of ASICs in cell excitability. A drop in pH from neutral 7.4 to more acid extracellular environments, lead to opening of ASICs Na+ or Ca2+ permeable pore, membrane depolarization and increase in Ca2+ intracellular concentration [104].

In the light of these facts, Yang and coworkers [105] investigated the neuroprotective activity of PcTx in neurons from newborn piglets submitted to a model of asphyxia-induced cardiac arrest. Data show that the administration of PcTx before the hypoxia-ischemia insult partially prevents the death of neurons in putamen, the most vulnerable encephalic area in this model. The addition of MK-801, a NMDA antagonist, in combination with PcTx exerted better results in cell survival, but in low doses of MK-801. In addition to protection of neuronal cells, treatment with PcTx accelerated neurologic recovery. These results point PcTx as a very unique neurotoxin that should be used as tool in the investigation of processes underlying neuroprotection as well as the design of novel neuroprotective agents.

Bees and wasps are part of the group of the insects, whose stings release a cocktail of toxins, including enzymes, peptides and biogenic amines [106]. Toxins in bee venom have received attention for their properties as anti-inflammatory agents, and in many countries, physicians even prescribe bee stings as treatment of rheumatologic diseases. Recently, Doo and colleagues [107] showed that the bee venom when injected in rats with induced Parkinson disease prevent dopamine neurons cell death, possibly by the inhibition of Jun activation.

Regarding solitary wasps, the most studied wasp species is the European beewolf, Philanthus triangulum, the natural predators of honeybees. The adult individuals of this species are herbivores, whereas the larvae eat the paralyzed bees brought to the colony by foraging wasps. The isolation of venom contents begun in the early 80s and revealed that among other classes of molecules, P. triangulum venom contains potent acylpolyamines [86]. Philanthotoxins, like other acylpolyamines are mostly potent and selective antagonists of vertebrate and invertebrate glutamate receptors, particularly AMPA receptors [108]. The first isolated and most studied philathotoxin is PhTX-433 and its synthetic analogue, PhTx-343, which antagonize Ach and glutamate ionotropic receptors. The neuroprotective activity of PhTx-343 was tested in cerebellar granule cells culture challenged with NMDA and kainate toxicity and compared to that of Arg-636 [109]. Data showed that both polyamines protected cultures against damage, but Arg-636 was found to be less potent than PhTx-343 against kainate-induced damage. The structural change in PhTx-343 increased its potency, but in higher doses, toxic side effects, were observed.

Due to their lack of selectivity, the use of philanthotoxins as pharmaceuticals may have been limited, and so many modified synthetic analogues were designed for medical treatment purposes, so far [82]. However, the use of philanthotoxins and other polyamines as tools in research investigation has aided the understanding of several synaptic mechanisms. As it has been recently shown using Ca2+-permeable AMPA receptors expressed in HEK cells. According to [110] the block of these AMPA receptors by PhTx-74, a synthetic analogue of PhTX-433 will reflect structural and biophysical parameters of the channel, such as its subunit composition and mean conductance, respectively. In addition, the investigation of the antagonistic activity of PhTx-343 over ACh receptors showed that the interaction of the toxin with nicotinic receptors is largely voltage dependent, slow and uncompetitive, a similar mode by which they block glutamate ionotropic channels [111].

Going further on wasp venoms, the anticonvulsant and/or neuroprotective effects of molecules in the venom of two Brazilian social species of the genus Polybia, were investigated. According to Cunha and co-workers [112] and Mortari and co-workers [113], the non-enzymatic fraction of the venoms of Polybia ignobilis and Polybia occidentalis inhibit seizures evoked by the injection of several chemoconvulsants in Wistar rats. The neuroactive molecules present in the venom of P. ignobilis and P. occidentalis are now in phase of structure-function investigation.

Finally, neurotoxins from scorpion venoms have been subject of a wide range of works, mostly approaching the identification of voltage-dependent ion channel activators/blockers. The neuroprotective and/or anticonvulsant activity of these peptides, in turn have received a few lines of investigation [3] despite the ancient use of these animals whole or parts, in the popular medicine in oriental countries, like China [20]. One of the most studied species is the Asian scorpion Buthus martensi Karsch whose venom has several neuroactive peptides, among whose, we may find BmK AEP, which was the first anticonvulsant peptide isolated from scorpion venoms. According to [28], the injection of BmK AEP blocked seizures induced by the injection of coriaria lactone in doses causing no visible side effects [114]. Further isolation of venom of B. martensi led to the identification of other peptides, such as BmK AS and BmK Ts and other mostly with analgesic activity. According to Zhao and co-workers [115] BmK AS, a sodium channel modulator at site-4 receptor, inhibited PTZ induced behavioral and electroencephalographic seizures and decreased mean score of pilocarpine-induced seizures. Moreover, these authors showed that BmK AS does not impair locomotion or motor behavior.

The venom of the Mexican scorpion Centruroides limpidus limpidus, was fractionated and many activators of voltage-gated ion channel ligands were identified [116]. An exception is Cll9, which stands for Centruroides limpidus limpidus toxin nr 9. Cll9 is a 63-residue peptide that has a divergent mode of action; it inhibits sodium channels in superior cervical ganglion neurons and [117]. When injected in Wistar rats via i.c.v., Cll9 inhibited behavioral and electroencephalographic seizures evoked by the microinjection of penicillin into the basolateral amygdala. It is worth noticing that Cll9 has no effect on arthropods such as crickets or crayfish like many sodium channels modulators found in scorpion venoms.


5. Actions on mood disorders

According to the World Health Organization, depression, one of the most important mood disorders, affects up to 5-10% of people worldwide at any time of their lives. Patients with a diagnosed mood disorder are more likely to be women, in productive years, 20 to 40 year-old, and will need in most cases, psychotherapy and/or pharmacological intervention. The costs of these psychiatric and/or psychological disorders are immense, since they affect people regardless of education or socioeconomic status, accounting in the worse cases, for a huge number of suicides. In the United States up to 95% of all suicides, involve mentally ill people, accounting for 1.3% of all deaths [118]. A recent survey shows that generalized anxiety disorder, posttraumatic stress disorder, social anxiety disorder and panic disorder are highly predictive of suicidal idealization [118]. Many aspects of the pathophysiology of mood disorders, as well as the regulation of normal mood states remain unknown. However, with the improvement of techniques for research and diagnosis, such as positron emission tomography, magnetic resonance and multiple channels recording electroencephalogram, soon researchers will be capable to identify structures and neurochemical mechanism involved in the regulation of mental states, including mood. So far, we know that limbic structures, such as the amygdala, hippocampus, hypothalamus and pre-frontal cortex control the emotional aspects of brain function. There are plenty of connections among these structures, which might be involved in the onset of mood disorders [119].

Pharmacological treatment of mood disorders consists in daily intake of anti-depressants, anxiolytics or anti-psychotics, most of which cause a wide set of undesired side effects that impose restrictions to patients quality of life. In this regard novel drugs prescribed for mood disorder, such as serotonin uptake inhibitors might be better tolerated and safer than classical drugs, such as monoamine oxidase inhibitors. Among the observed undesired effects we can cite; dizziness, sedation, sexual dysfunction and suicidal though, a paradoxical effect of serotonin uptake inhibitors [119]. Aside from tolerability, medicines used as treatment of depression for example, take too long to produce effect in only a minority of patients; 35-45% of treated patients [120]. Therefore, there is a still great need for novel alternatives to be used both, in basic and clinical science.

The neurochemistry of mood disorders is complex and there is a list of candidates for targets of mood stabilizers, such as adrenaline, GABA, serotonin and glutamate receptors and transporters. There is not many works relating neurotoxins from arthropods and mood disorders, but the few works available showed that in some cases, these molecules might contribute for the development of novel drugs.

The venom of the Brazilian colonial spider Parawixia bistriata was fractionated and tested in many animal models of epilepsy, neurodegeneration and anxiety. According to [121], the microinjection of Parawixin 2 (formerly FrPbAII) in the dorsal hippocampus of male Wistar rats increased the time spent in the open arms of the elevated plus maze. Moreover, rats exposed to the light-dark choice apparatus spent more time in the light side of the box, similarly to what observed for diazepam or nipecotic acid, a GABA transporter-1 (GAT-1) inhibitor [121]. In another investigation of P. bistriata venom contents, Saidemberg and co-workers [122] isolated PwTx-I and tested the inhibitory activity of this neurotoxin and its enantiomers on mammalian monoamine oxidases (MAO)-A and -B. According to these authors, PwTx-I, acted as non-competitive inhibitors of MAO-A and MAO-B. MAO metabolizes monoamines dopamine, serotonin and adrenaline, terminating monoaminergic transmission. Inhibitors or MAO (MAOi) have been extensively used as mood stabilizers and currently they have received attention due to their protective activity against age-induced neurodegenerative disorders [123].

Considering alternative targets for mood stabilizers, interesting results were obtained with PcTx, isolated from the venom of the spider P. cambridgei, a selective blocker of ASICs. Data showed that both PcTx and amiloride attenuated the stress-induced hyperthermia, whereas only the administration of PcTx increased number of punished crosses measured in the four-plate test. These results indicate that both blockers could attenuate autonomic anxiety parameters, but only PcTx exerted effects on the behavioral anxiety parameters [124].

The aggressive Brazilian social wasp Agelaia vicina, builds huge nests where with over a million of individuals. The neurobiological activity of the venom of A. vicina, was investigated. Oliveira and colleagues [125] showed that the central injection of the non-enzymatic fraction of the venom induced catalepsy in Wistar compared to the neuroleptic drug haloperidol, a nonselective D2 dopamine antagonist. This effect was reversed by the injection of theophylline or ketamine. The fractionation of the venom led to the identification of two peptides, AvTx-7, mastoparan, and AvTx-8. The investigation of AvTx-8 mode of action in vivo, was performed in a model of panic induction through the activation of GABAergic pathways connecting mesencephalic substantia nigra pars reticulate to superior colliculus [126]. These experiments showed that intranigral microinjection of AvTx-8 inhibited the panic like response induced by the GABAergic blockade of superior colliculus. These effects were similar to those of baclofen, a GABAB agonist, but differed from the effects of muscimol, a GABAA agonist. Since post-synaptic GABAB is a metabotropic receptor complex with a potassium channel, AvTx-8 could act in many different sites that would end in channels opening and hyperpolarization of neuronal membrane.


6. Tools for the study of the functioning of the CNS: learning and memory

Neurotoxins isolated from arthropod are important tools to study of the normal function of the CNS, especially in the structure-function research of the ion channels and the interaction the blockers and modulators in the regulation of the learning and memory (for revision see [127]). In this context, the principal compound used in study of the mechanism of the learning and memory in models of experimental animals is the apamin. Apamin is a short peptide (18 aa) isolated from the venom of honeybee, Apis mellifera. It is generally accepted that apamin selectively blocks small conductance calcium-activated potassium channels (SK or Kca), although evidences point to an allosteric modulation of opening rather than the block of the pore [128]. Upon an increase in intracellular calcium, SK channels will open and allow an outward current of potassium ions that is responsible for the hyperpolarization phase of the action potentials. Most studies on structure-function of SK channels were conducted using apamin blockade. The homomeric or heteromeric expression of these channels occurs in higher brain areas such as the neocortex, hippocampus and sub-cortical areas such as thalamus and basal ganglia as well as in cerebellum and brainstem. Substantial data SK channels show the involvement of SK channels in processes of learning and memory, and apamin blockade of SK lead to an increase in cellular excitability, facilitates synaptic plasticity and memory processes run by the hippocampus. In addition, apamin induces alterations in dendritic morphology that might counteract aging and neurodegenerative processes that lead to cognitive and memory impairment [129]. In fact, SK channels co-localize with Ca2+-permeable NMDA receptors in the CA1 region of the hippocampus and the entry of calcium in the cell through these receptors might activate SK that will hyperpolarize membrane. The blockade of SK channels will modulate hippocampal excitability that is essential in memory processes such as long-term potentiation a commonly observed event of synaptic plasticity. Due to its actions, the use of apamin as a tool in research has been consolidated. In addition, the therapeutic use of apamin, in order to maintain hippocampal function and avoid the deleterious effects of aging in memory and cognitive processes have also been proposed [129].

Besides apamin, modulators peptides of the potassium channel isolated from scorpion also have been tested in models of the learning and memory. The good examples are: Charybdotoxin isolated from scorpion Leiurus quinquestriatus, Kaliotoxin isolated from Androctonus mauretanicus and Iberiotoxin from Buthus tasmulus. Charybdotoxin is a potent selective inhibitor of high (large or big) conductance Ca2+-activated potassium channels (KCa1.1, BK, or maxi-K), as well as a Kv1.3 channel [130]. Kaliotoxin is a specific inhibitor of Kv1.1 and Kv1.3 [131] and Iberiotoxin is a selective inhibitor of KCa1.1 channels (formerly BK) [132]. These peptides induced an improvement effect in passive avoidance test and olfactory discrimination task [133,134].


7. Final remarks

The stories of voltage-gated, ligand-gated ion channels and venom toxins are very closely tied. Indeed, the isolation and structural characterization of venom molecules provided a plethora of tools that have been used in the investigation of ion channels structure-function relationships. With the aid of arthropod toxins, remarkably, scorpionic toxins, the characterization of sodium channels was possible. Spider and wasps polyamines, in turn are considered unique ligands of glutamatergic and cholinergic ionotropic receptors. Regarding to peptides and small proteins, arthropod venoms possess an arsenal of these molecules that remain largely unknown and consequently, their pharmacological potential is left unexplored.

Due to the mode of action of neurotoxins, their affinity and selectivity for neuronal structures, many researchers consider them as probes to novel drugs design and development. However, despite of the thousands of patents made with neurotoxins in the past 30 years, very few molecules came to commercialization.



The authors thank Msc Juliana Castro e Silva for help in preparing the figure.


  1. 1. Zhijian C. Chao D. Dahe J. Wenxin L. 2006 The effect of intron location on the splicing of BmKK2 in 293T cells. J Biochem Mol Toxicol 20 3 127 32
  2. 2. Estrada G. Villegas E. Corzo G. 2007 Spider venoms: a rich source of acylpolyamines and peptides as new leads for CNS drugs Nat Prod Rep 24 1 145 61
  3. 3. Mortari M. R. Cunha A. O. Ferreira L. B. dos Santos. W. F. 2007 Neurotoxins from invertebrates as anticonvulsants: from basic research to therapeutic application. Pharmacol Ther. 114 2 171 83
  4. 4. Rogoza L. N. Salakhutdinov N. F. Tolstikov G. A. 2005 Polymethyleneamine alkaloids of animal origin. I. Metabolites of marine and microbial organisms]. Bioorg Khim 31 6 563 77
  5. 5. WHO. 2007 Neurological Disorders: Public Health Challenges
  6. 6. Bialer M. White H. S. 2010 Key factors in the discovery and development of new antiepileptic drugs Nature reviews Drug discovery 9 1 68 82
  7. 7. Blier P. 2010 The well of novel antidepressants: running dry J Psychiatry Neurosci 35 4 219 20
  8. 8. Goudet C. Chi C. W. Tytgat J. 2002 An overview of toxins and genes from the venom of the Asian scorpion Buthus martensi Karsch Toxicon official journal of the International Society on Toxinology 40 9 1239 58
  9. 9. Cherniack E. P. 2011 Bugs as drugs, part two: worms, leeches, scorpions, snails, ticks, centipedes, and spiders. Alternative medicine review : a journal of clinical therapeutic 16 1 50 8
  10. 10. Ratcliffe N. A. Mello C. B. Garcia E. S. Butt T. M. Azambuja P. 2011 Insect natural products and processes: new treatments for human disease Insect Biochem Mol Biol 41 10 747 69
  11. 11. Monteiro M. C. Romao P. R. Soares A. M. 2009 Pharmacological perspectives of wasp venom. Protein and peptide letters 16 8 944 52
  12. 12. Beleboni R. D. Pizzo A. B. Fontana A. C. K. Carolino R. D. O. G. Coutinho-Netto J. dos Santos. W. F. 2004 Spider and wasp neurotoxins: pharmacological and biochemical aspects. Eur J Pharmacol 493 1-3 1 17
  13. 13. Ashburn M. A. Staats P. S. 1999 Management of chronic pain. Lancet 353 167 865 869
  14. 14. Stucky C. L. Gold M. S. Zhang X. 2001 Mechanisms of pain. Proc Natl Acad Sci U S A. 98 21 11845 6
  15. 15. Sindrup S. H. Jensen T. S. 1999 Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83 3 389 400
  16. 16. Villetti G. Bergamaschi M. Bassani F. Bolzoni P. T. Maiorino M. Pietra C. et al. 2003 Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 306 2 804 14
  17. 17. Ji Y. H. Mansuelle P. Terakawa S. Kopeyan C. Yanaihara N. Hsu K. et al. 1996 Two neurotoxins (BmK I and BmK II) from the venom of the scorpion Buthus martensi Karsch: purification, amino acid sequences and assessment of specific activity. Toxicon : official journal of the International Society on Toxinology 34 9 987 1001
  18. 18. Guan R. Wang C. G. Wang M. Wang D. C. 2001 A depressant insect toxin with a novel analgesic effect from scorpion Buthus martensii Karsch. Biochim Biophys Acta 1549 1 9 18
  19. 19. Rodriguez dela Vega R. C. Possani L. D. 2005 Overview of scorpion toxins specific for channels and related peptides: biodiversity, structure-function relationships and evolution. Toxicon : official journal of the International Society on Toxinology 46 8 831 44
  20. 20. Xiong Y. M. Lan Z. D. Wang M. Liu B. Liu X. Q. Fei H. et al. 1999 Molecular characterization of a new excitatory insect neurotoxin with an analgesic effect on mice from the scorpion Buthus martensi Karsch Toxicon 37 8 1165 80
  21. 21. Escoubas P. Stankiewicz M. Takaoka T. Pelhate M. Romi-Lebrun R. Wu F. Q. et al. 2000 Sequence and electrophysiological characterization of two insect-selective excitatory toxins from the venom of the Chinese scorpion Buthus martensi. FEBS Lett 483 2-3 175 80
  22. 22. Guan R. J. Wang M. Wang D. Wang D. C. 2001 A new insect neurotoxin AngP1 with analgesic effect from the scorpion Buthus martensii Karsch: purification and characterization The journal of peptide research official journal of the American Peptide Society 58 1 27 35
  23. 23. Wang C. Y. Tan Z. Y. Chen B. Zhao Z. Q. Ji Y. H. 2000 Antihyperalgesia effect of BmK IT2, a depressant insect-selective scorpion toxin in rat by peripheral administration. Brain research bulletin 53 3 335 8
  24. 24. Tan Z. Y. Xiao H. Mao X. Wang C. Y. Zhao Z. Q. Ji Y. H. 2001 The inhibitory effects of BmK IT2, a scorpion neurotoxin on rat nociceptive flexion reflex and a possible mechanism for modulating voltage-gated Na(+) channels. Neuropharmacology 40 3 352 7
  25. 25. Bai Z. T. Liu T. Pang X. Y. Chai Z. F. Ji Y. H. 2007 Suppression by intrathecal BmK IT2 on rat spontaneous pain behaviors and spinal c-Fos expression induced by formalin Brain Res Bull 73 4-6 248 253
  26. 26. Zhang X. Y. Bai Z. T. Chai Z. F. Zhang J. W. Liu Y. Ji Y. H. 2003 Suppressive effects of BmK IT2 on nociceptive behavior and c-Fos expression in spinal cord induced by formalin. J Neurosci Res 74 1 167 73
  27. 27. Li Y. J. Tan Z. Y. Ji Y. H. 2000 The binding of BmK IT2, a depressant insect-selective scorpion toxin on mammal and insect sodium channels. Neurosci Res 38 3 257 64
  28. 28. Wang Y. Wang L. Cui Y. Song Y. B. Liu Y. F. Zhang R. et al. 2011 Purification, characterization and functional expression of a new peptide with an analgesic effect from Chinese scorpion Buthus martensii Karsch (BmK AGP-SYPU1). Biomed Chromatogr 25 7 801 7
  29. 29. Ji-H Y. Li-J Y. Zhang-W J. Song-L B. Yamaki T. Mochizuki T. et al. 1999 Covalent structures of BmK AS and BmK AS-1, two novel bioactive polypeptides purified from Chinese scorpion Buthus martensi Karsch Toxicon 37 3 519 36
  30. 30. Lan-D Z. Dai L. Zhuo-L X. Feng-C J. Xu K. Chi-W C. 1999 Gene cloning and sequencing of BmK AS and BmK AS-1, two novel neurotoxins from the scorpion Buthus martensi Karsch Toxicon 37 5 815 23
  31. 31. Chen B. Ji Y. 2002 Antihyperalgesia effect of BmK AS, a scorpion toxin, in rat by intraplantar injection. Brain Res 952 2 2322 6
  32. 32. Chen J. Feng X. H. Shi J. Tan Z. Y. Bai Z. T. Liu T. et al. 2006 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. Peptides 27 9 182 92
  33. 33. Tan Z. Y. Mao X. Xiao H. Zhao Z. Q. Ji Y. H. 2001 Buthus martensi Karsch agonist of skeletal-muscle RyR-1, a scorpion active polypeptide: antinociceptive effect on rat peripheral nervous system and spinal cord, and inhibition of voltage-gated Na(+) currents in dorsal root ganglion neurons. Neurosci Lett 297 2 65 8
  34. 34. Wu Y. Ji Y. H. Shi Y. L. 2001 Sodium current in NG108-15 cell inhibited by scorpion toxin BmKAS-1 and restored by its specific monoclonal antibodies. J Nat Toxins 10 3 193 8
  35. 35. Liu Y. F. Ma R. L. Wang S. L. Duan Z. Y. Zhang J. H. Wu L. J. et al. 2003 Expression of an antitumor-analgesic peptide from the venom of Chinese scorpion Buthus martensii karsch in Escherichia coli. Protein Expr Purif 27 2 253 8
  36. 36. Cui Y. Guo G. L. Ma L. Hu N. Song Y. B. Liu Y. F. et al. 2010 Structure and function relationship of toxin from Chinese scorpion Buthus martensii Karsch (BmKAGAP): gaining insight into related sites of analgesic activity Peptides 31 6 995 1000
  37. 37. Cao Z. Y. Mi Z. M. Cheng G. F. Shen W. Q. Xiao X. Liu X. M. et al. 2004 Purification and characterization of a new peptide with analgesic effect from the scorpion Buthus martensi Karch J Pept Res 64 1 33 41
  38. 38. Peng K. Chen X. D. Liang S. P. 2001 The effect of Huwentoxin-I on Ca(2+) channels in differentiated NG108-15 cells, a patch-clamp study. Toxicon : official journal of the International Society on Toxinology 39 4 491 8
  39. 39. Chen J. Q. Zhang Y. Q. Dai J. Luo Z. M. Liang S. P. 2005 Antinociceptive effects of intrathecally administered huwentoxin-I, a selective N-type calcium channel blocker, in the formalin test in conscious rats. Toxicon : official journal of the International Society on Toxinology 45 1 15 20
  40. 40. Wen Tao. Z. Gu Yang. T. Ying R. Mao Cai. W. Lin L. Chi Miao. L. et al. 2011 The antinociceptive efficacy of HWTX-I epidurally administered in rheumatoid arthritis rats. Int J Sports Med 32 11 869 74
  41. 41. Saez N. J. Senff S. Jensen J. E. Er S. Y. Herzig V. Rash L. D. et al. 2010 Spider-venom peptides as therapeutics. Toxins 2 12 2851 71
  42. 42. Murakami M. Nakagawasai O. Suzuki T. Mobarakeh I. I. Sakurada Y. Murata A. et al. 2004 Antinociceptive effect of different types of calcium channel inhibitors and the distribution of various calcium channel alpha 1 subunits in the dorsal horn of spinal cord in mice. Brain Res 1024 1-2 122 9
  43. 43. Rajendra W. Armugam A. Jeyaseelan K. 2004 Toxins in anti-nociception and anti-inflammation Toxiconofficial journal of the International Society on Toxinology 44 1 1 17
  44. 44. Souza A. H. Ferreira J. Cordeiro Mdo. N. Vieira L. B. De Castro C. J. Trevisan G. et al. 2008 Analgesic effect in rodents of native and recombinant Ph alpha 1beta toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom. Pain 140 1 115 26
  45. 45. Dalmolin G. D. Silva C. R. Rigo F. K. Gomes G. M. Cordeiro Mdo. N. Richardson M. et al. 2011 Antinociceptive effect of Brazilian armed spider venom toxin Tx3-3 in animal models of neuropathic pain. Pain 152 10 2224 32
  46. 46. Vieira L. B. Kushmerick C. Hildebrand M. E. Garcia E. Stea A. Cordeiro M. N. et al. 2005 Inhibition of high voltage-activated calcium channels by spider toxin PnTx3-6. J Pharmacol Exp Ther 314 3 1370 7
  47. 47. Prado MA Guatimosim C. Gomez M. V. Diniz C. R. Cordeiro M. N. Romano-Silva MA 1996 A novel tool for the investigation of glutamate release from rat cerebrocortical synaptosomes: the toxin Tx from the venom of the spider Phoneutria nigriventer. Biochem J 314 Pt1 145 50
  48. 48. De Souza A. H. Lima M. C. Drewes C. C. da Silva. J. F. Torres K. C. Pereira E. M. et al. 2011 Antiallodynic effect and side effects of Phalpha1beta, a neurotoxin from the spider Phoneutria nigriventer: comparison with omega-conotoxin MVIIA and morphine. Toxicon : official journal of the International Society on Toxinology 58 8 626 33
  49. 49. Malmberg A. B. Yaksh T. L. 1994 Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J Neurosci 14 8 4882 90
  50. 50. Saez N. J. Mobli M. Bieri M. Chassagnon I. R. Malde A. K. Gamsjaeger R. et al. 2011 A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a. Mol Pharmacol 80 5 796 808Epub 2011/08/10.
  51. 51. Mc Cleskey E. W. Gold M. S. 1999 Ion channels of nociception. Annu Rev Physiol 61 835 56
  52. 52. Waldmann R. Champigny G. Lingueglia E. De Weille J. R. Heurteaux C. Lazdunski M. 1999 H(+)-gated cation channels. Ann N Y Acad Sci 868 67 76
  53. 53. Mazzuca M. Heurteaux C. Alloui A. Diochot S. Baron A. Voilley N. et al. 2007 A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat Neurosci 10 8 943 5
  54. 54. Pignataro G. Simon R. P. Xiong Z. G. 2007 Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia Braina journal of neurology 130 Pt 1 151 158
  55. 55. Lampe R. A. 1999 Analgesic peptides from venom of grammostola spatulata and use thereof.
  56. 56. Grishin E. V. Savchenko G. A. Vassilevski A. A. Korolkova Y. V. Boychuk Y. A. Viatchenko-Karpinski V. Y. et al. 2010 Novel peptide from spider venom inhibits 2X3receptors and inflammatory pain. Ann Neurol 67 5 680 3
  57. 57. Chen J. Lariviere W. R. 2010 The nociceptive and anti-nociceptive effects of bee venom injection and therapy: a double-edged sword Prog Neurobiol 92 2 151 83
  58. 58. Kwon Y. B. Kang M. S. Kim H. W. Ham T. W. Yim Y. K. Jeong S. H. et al. 2001 Antinociceptive effects of bee venom acupuncture (apipuncture) in rodent animal models: a comparative study of acupoint versus non-acupoint stimulation. Acupunct Electrother Res 26 1-2 59 68
  59. 59. Kwon Y. B. Kim J. H. Yoon J. H. Lee JD Han H. J. Mar W. C. et al. 2001 The analgesic efficacy of bee venom acupuncture for knee osteoarthritis: a comparative study with needle acupuncture. Am J Chin Med 29 2 187 99
  60. 60. Lee-H J. Kwon-B Y. Han-J H. Mar-C W. Lee-J H. Yang-S I. et al. 2001 Bee Venom Pretreatment Has Both an Antinociceptive and Anti-Inflammatory Effect on Carrageenan-Induced Inflammation. J Vet Med Sci 63 3 251 9
  61. 61. Lee J. D. Park H. J. Chae Y. Lim S. 2005 An Overview of Bee Venom Acupuncture in the Treatment of Arthritis. Evidence-based complementary and alternative medicine : eCAM 2 1 79 84
  62. 62. Kwon Y. B. Kang M. S. Han H. J. Beitz A. J. Lee J. H. 2001 Visceral antinociception produced by bee venom stimulation of the Zhongwan acupuncture point in mice: role of alpha(2) adrenoceptors. Neurosci Lett 308 2 133 7
  63. 63. Baek Y. H. Huh J. E. Lee J. D. Choi do Y. Park D. S. 2006 Antinociceptive effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory pain in the rat model of collagen-induced arthritis: Mediation by alpha2-Adrenoceptors. Brain Res 073-074 305 10
  64. 64. Son D. J. Kang J. Kim T. J. Song H. S. Sung K. J. do Yun Y. et al. 2007 Melittin, a major bioactive component of bee venom toxin, inhibits PDGF receptor beta-tyrosine phosphorylation and downstream intracellular signal transduction in rat aortic vascular smooth muscle cells. Journal of toxicology and environmental health Part A 70 15-16 1350 5
  65. 65. Lauterwein J. Bosch C. Brown L. R. Wuthrich K. 1979 Physicochemical studies of the protein-lipid interactions in melittin-containing micelles. Biochim Biophys Acta 556 2 244 64
  66. 66. Lavialle F. Levin I. W. Mollay C. 1980 Interaction of melittin with dimyristoyl phosphatidylcholine liposomes: evidence for boundary lipid by Raman spectroscopy. Biochim Biophys Acta 600 1 62 71
  67. 67. Shier WT. 1979 Activation of high levels of endogenous phospholipase A2 in cultured cells. Proc Natl Acad Sci U S A 76 1 195 9
  68. 68. Lad P. J. Shier W. T. 1979 Activation of microsomal guanylate cyclase by a cytotoxic polypeptide: melittin. Biochem Biophys Res Commun 89 1 315 21
  69. 69. Park H. J. Lee H. J. Choi M. S. Son D. J. Song H. S. Song M. J. et al. 2008 JNK pathway is involved in the inhibition of inflammatory target gene expression and NF-kappaB activation by melittin. J Inflamm (Lond). 5 7
  70. 70. Merlo L. A. Bastos L. F. Godin A. M. Rocha L. T. Nascimento E. B. Jr Paiva A. L. et al. 2011 Effects induced by Apis mellifera venom and its components in experimental models of nociceptive and inflammatory pain. Toxicon : official journal of the International Society on Toxinology 57 5 764 71
  71. 71. Shkenderov S. Koburova K. 1982 Adolapin- A newly isolated analgetic and anti-inflammatory polypeptide from bee venom. Toxicon 20 1 317 21
  72. 72. Koburova K. L. S. G. Michailova S. V. 1985 Shkenderov Further investigation on the antiinflammatory properties of adolapin--bee venom polypeptide. Acta Physiol Pharmacol Bulg 11 2 50 5
  73. 73. Mortari M. R. Cunha A. O. Carolino R. O. Coutinho-Netto J. Tomaz J. C. Lopes N. P. et al. 2007 Inhibition of acute nociceptive responses in rats after i.c.v. injection of Thr6-bradykinin, isolated from the venom of the social wasp, Polybia occidentalis Br J Pharmacol 151 6 860 9
  74. 74. Pellegrini M. Mammi S. Peggion E. Mierke D. F. 1997 Threonine6-bradykinin: structural characterization in the presence of micelles by nuclear magnetic resonance and distance geometry J Med Chem 40 1 92 8
  75. 75. Pellegrini M. Mierke D. F. 1997 Threonine6-bradykinin: molecular dynamics simulations in a biphasic membrane mimetic. J Med Chem 40 1 99 104
  76. 76. Nagy I. Paule C. White J. Urban L. 2007 Taking the sting out of pain Br J Pharmacol 151 6 721 2
  77. 77. Kawai N. MA Shimazaki K. Sahara Y. Robinson H. P. Nakajima T. 1991 Spider toxin and the glutamate receptors. Comp Biochem Physiol C 98 1 87 95
  78. 78. Sorkin L. S. Y. T. Doom C. M. 1999 Mechanical allodynia in rats is blocked by a Ca2+ permeable AMPA receptor antagonist. Neuroreport 10 17 3523 6
  79. 79. Stanfa L. C. Hampton D. W. Dickenson A. H. 2000 Role of Ca2+-permeable non-NMDA glutamate receptors in spinal nociceptive transmission. Neuroreport 11 14 3199 202Epub 2000/10/24.
  80. 80. Jones M. G. Lodge D. 1991 Comparison of some arthropod toxins and toxin fragments as antagonists of excitatory amino acid-induced excitation of rat spinal neurones. Eur J Pharmacol 204 2 203 9
  81. 81. Sorkin L. S. Yaksh T. L. Doom C. M. 2001 Pain models display differential sensitivity to Ca2+-permeable non-NMDA glutamate receptor antagonists. Anesthesiology 95 4 965 73
  82. 82. Andersen T. F. Vogensen S. B. Jensen L. S. Knapp K. M. Stromgaard K. 2005 Design and synthesis of labeled analogs of PhTX-56, a potent and selective AMPA receptor antagonist. Bioorg Med Chem 13 17 5104 12
  83. 83. Dingledine R. Borges K. Bowie D. Traynelis S. F. 1999 The glutamate receptor ion channels. Pharmacol Rev 51 1 7 61
  84. 84. Rajendra W. Armugam A. Jeyaseelan K. 2004 Neuroprotection and peptide toxins. Brain Res Brain Res Rev 45 2 125 41
  85. 85. Grishin E. V. Volkova T. M. Arseniev A. S. 1989 Isolation and structure analysis of components from venom of the spider Argiope lobata. Toxicon 27 5 541 9
  86. 86. Clark R. B. Donaldson P. L. Gration K. A. Lambert J. J. Piek T. Ramsey R. et al. 1982 Block of locust muscle glutamate receptors by delta-philanthotoxin occurs after receptor activations. Brain Res 241 1 105 14
  87. 87. Usherwood P. N. Blagbrough I. S. 1991 Spider toxins affecting glutamate receptors: polyamines in therapeutic neurochemistry. Pharmacol Ther 52 2 245 68Epub 1991/11/01.
  88. 88. Herold E. E. Yaksh T. L. 1992 Anesthesia and muscle relaxation with intrathecal injections of AR636 and AG489, two acylpolyamine spider toxins, in rat. Anesthesiology 77 3 507 12
  89. 89. Kanai H. Ishida N. Nakajima T. Kato N. 1992 An analogue of Joro spider toxin selectively suppresses hippocampal epileptic discharges induced by quisqualate. Brain Res 581 1 161 4
  90. 90. Roy J. Minotti S. Dong L. Figlewicz D. A. Durham H. D. 1998 Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurons by postsynaptic calcium-dependent mechanisms. J Neurosci 18 23 9673 84
  91. 91. Seymour P. A. M. E. 1989 In vivo antagonist activity of the polyamine spider venom component, Argiotoxin-636. Soc Neurosci Abs 15 463 24
  92. 92. K W 1993 Effects of Agelenopsis aperta toxins on the N-methyl-D-aspartate receptor: polyamine-like and high-affinity antagonist actions. J Pharmacol Exp Ther 266 1 231 6
  93. 93. Miranda D. M. Romano-Silva M. A. Kalapothakis E. Diniz C. R. Cordeiro M. N. Moraes-Santos T. et al. 2001 Spider neurotoxins block the beta scorpion toxin-induced calcium uptake in rat brain cortical synaptosomes. Brain Res Bull 54 5 533 6
  94. 94. Pinheiro A. C. da Silva A. J. Prado Cordeiro MA Mdo N. Richardson M. Batista M. C. et al. 2009 Phoneutria spider toxins block ischemia-induced glutamate release, neuronal death, and loss of neurotransmission in hippocampus Hippocampus 19 11 1123 9
  95. 95. Agostini R. M. Nascimento do Pinheiro A. C. Binda N. S. Romano Silva. Nascimento do Cordeiro. M. Richardson M. et al. 2011 Phoneutria spider toxins block ischemia-induced glutamate release and neuronal death of cell layers of the retina. Retina 31 7 1392 9
  96. 96. Beleboni R. O. Guizzo R. Fontana A. C. Pizzo A. B. Carolino R. O. Gobbo-Neto L. et al. 2006 Neurochemical characterization of a neuroprotective compound from Parawixia bistriata spider venom that inhibits synaptosomal uptake of GABA and glycine. Mol Pharmacol 69 6 1998 2006
  97. 97. Fontana A. C. Guizzo R. de Oliveira Beleboni. R. Meirelles E. S. A. R. Coimbra N. C. Amara S. G. et al. 2003 Purification of a neuroprotective component of Parawixia bistriata spider venom that enhances glutamate uptake Br J Pharmacol 139 7 1297 309
  98. 98. Fontana A. C. de Oliveira Beleboni. R. Wojewodzic M. W. Ferreira Dos. Santos W. Coutinho-Netto J. Grutle N. J. et al. 2007 Enhancing glutamate transport: mechanism of action of Parawixin1, a neuroprotective compound from Parawixia bistriata spider venom. Mol Pharmacol 72 5 1228 37
  99. 99. Cairrão M. A. R. R. A. Pizzo A. B. Fontana A. C. K. Beleboni R. O. Coutinho-Neto J. Miranda A. Santos W. F. 2002 Anticonvulsant and GABA uptake inhibition properties of P. bistriata and S. raptoria spider venom fractions. Pharm Biol 40 6 472 7
  100. 100. Gelfuso E. A. Cunha A. O. Mortari M. R. Liberato J. L. Paraventi K. H. Beleboni R. O. et al. 2007 Neuropharmacological profile of FrPbAII, purified from the venom of the social spider Parawixia bistriata (Araneae, Araneidae), in Wistar rats. Life Sci 80 6 566 72
  101. 101. Lampe R. A. Defeo P. A. MD Davison Young. J. Herman J. L. Spreen R. C. et al. 1993 Isolation and pharmacological characterization of omega-grammotoxin SIA, a novel peptide inhibitor of neuronal voltage-sensitive calcium channel responses. Mol Pharmacol 44 2 451 60
  102. 102. Piser T. M. Lampe R. A. Keith R. A. Thayer S. A. 1995 Complete and reversible block by ω-grammotoxin SIA of glutamatergic synaptic transmission between cultured rat hippocampal neurons. Neurosci Lett 201 2 135 8
  103. 103. Newcomb R. P. A. Szoke B. G. Tarczy-Hornoch K. Hopkins W. F. Cong R. L. Miljanich G. P. Dean R. Nadasdi L. Urge L. Bowersox S. S. 2005 inventor; Elan Pharmaceuticals Inc US, assignee. Class e voltage-gated calcium channel antagonist and methods patent 0920504
  104. 104. Chu X. P. Papasian C. J. Wang . J. Q. Xiong Z. G. 2011 Modulation of acid-sensing ion channels: molecular mechanisms and therapeutic potential. International journal of physiology, pathophysiology and pharmacology 3 4 288 309
  105. 105. Yang Z. J. Ni X. Carter E. L. Kibler K. Martin L. J. Koehler R. C. 2011 Neuroprotective effect of acid-sensing ion channel inhibitor psalmotoxin-1 after hypoxia-ischemia in newborn piglet striatum Neurobiol Dis 43 2 446 54
  106. 106. Libersat F. 2003 Wasp uses venom cocktail to manipulate the behavior of its cockroach prey. Journal of comparative physiology A, Neuroethology, sensory, neural, and behavioral physiology 189 7 497 508
  107. 107. Doo A. R. Kim S. T. Kim S. N. Moon W. Yin C. S. Chae Y. et al. 2010 Neuroprotective effects of bee venom pharmaceutical acupuncture in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Neurol Res 32 1 88 91
  108. 108. Stromgaard K. 2005 Natural products as tools for studies of ligand-gated ion channels. Chem Rec 5 4 229 39
  109. 109. Green A. C. Nakanishi K. Usherwood P. N. 1996 Polyamine amides are neuroprotective in cerebellar granule cell cultures challenged with excitatory amino acids. Brain Res 717 1-2 135 46
  110. 110. Jackson A. C. Milstein A. D. Soto D. Farrant M. Cull-Candy S. G. Nicoll R. A. 2011 Probing TARP modulation of AMPA receptor conductance with polyamine toxins J Neurosci 31 20 7511 20
  111. 111. Brier T. J. Mellor I. R. Tikhonov D. B. Neagoe I. Shao Z. Brierley MJ et al. 2003 Contrasting actions of philanthotoxin-343 and philanthotoxin-(12) on human muscle nicotinic acetylcholine receptors. Mol Pharmacol 64 4 954 64
  112. 112. Cunha A. O. Mortari M. R. Oliveira L. Carolino R. O. Coutinho-Netto J. dos Santos W. F. 2005 Anticonvulsant effects of the wasp Polybia ignobilis venom on chemically induced seizures and action on GABA and glutamate receptors. Comparative biochemistry and physiology Toxicology & pharmacology : CBP 141 1 50 7
  113. 113. Mortari M. R. Cunha A. O. de Oliveira L. Vieira E. B. Gelfuso E. A. Coutinho-Netto J. et al. 2005 Anticonvulsant and behavioural effects of the denatured venom of the social wasp Polybia occidentalis (Polistinae, Vespidae) Basic & clinical pharmacology & toxicology 97 5 289 95
  114. 114. Wang C. G. He X. L. Shao F. Liu W. Ling M. H. Wang D. C. et al. 2001 Molecular characterization of an anti-epilepsy peptide from the scorpion Buthus martensi Karsch. Eur J Biochem 2268 8 480 5
  115. 115. Zhao R. Weng-C C. Feng Q. Chen L. Zhang-Y X. Zhu-Y H. et al. 2011 Anticonvulsant activity of BmK AS, a sodium channel site 4-specific modulator Epilepsy & Behavior 20 2 267 76
  116. 116. Martin BM R. A. Gurrola G. B. Nobile M. Prestipino G. Possani L. D. Novel K. 1994 channel-blocking toxins from the venom of the scorpion Centruroides limpidus limpidusKarsch. Biochem J 15 304 51 6
  117. 117. Corona M. Coronas F. V. Merino E. Becerril B. Gutiérrez R. Rebolledo-Antunez S. et al. 2003 A novel class of peptide found in scorpion venom with neurodepressant effects in peripheral and central nervous system of the rat. Biochimica et Biophysica Acta BBA)- Proteins & Proteomics 1649 1 58 67
  118. 118. Cougle J. R. ME Keough Riccardi. C. J. Sachs-Ericsson N. 2009 Anxiety disorders and suicidality in the National Comorbidity Survey-Replication J Psychiatr Res 43 9 825 9
  119. 119. Hatcher S. Arroll B. 2012 Newer antidepressants for the treatment of depression in adults BMJ 344 d8300
  120. 120. Nemeroff C. B. Owens M. J. 2002 Treatment of mood disorders. Nat Neurosci. Suppl 5 1068 70
  121. 121. Liberato J. L. Cunha A. O. Mortari M. R. Gelfuso E. A. Beleboni Rde. O. Coutinho-Netto J. et al. 2006 Anticonvulsant and anxiolytic activity of FrPbAII, a novel GABA uptake inhibitor isolated from the venom of the social spider Parawixia bistriata (Araneidae: Araneae) Brain Res 1124 1 19 27
  122. 122. Saidemberg D. Ferreira M. Takahashi M. A. Gomes T. N. Cesar-Tognoli P. C. da L. M. Silva-Filho L. C. et al. 2009 Monoamine oxidase inhibitory activities of indolylalkaloid toxins from the venom of the colonial spider Parawixia bistriata: functional characterization of PwTX-I. Toxicon 54 6 717 24
  123. 123. Maruyama M. Na W. Monoamine Oxidase Inhibitors as Neuroprotective Agents in Age-Dependent Neurodegenerative Disorders. Curr Pharm Des 19 799 817
  124. 124. Dwyer J. M. Rizzo S. J. Neal S. J. Lin Q. Jow F. Arias R. L. et al. 2009 Acid sensing ion channel (ASIC) inhibitors exhibit anxiolytic-like activity in preclinical pharmacological models Psychopharmacology (Berl) 203 1 41 52
  125. 125. de Oliveira L. Cunha A. O. Mortari M. R. Coimbra N. C. Dos Santos. W. F. 2006 Cataleptic activity of the denatured venom of the social wasp Agelaia vicina (Hymenoptera, Vespidae) in Rattus norvegicus (Rodentia, Muridae) Prog Neuropsychopharmacol B ol Psychiatry 30 2 198 203
  126. 126. de Oliveira L. Cunha A. O. Mortari M. R. Pizzo A. B. Miranda A. Coimbra N. C. et al. 2005 Effects of microinjections of neurotoxin AvTx8, isolated from the social wasp Agelaia vicina (Hymenoptera, Vespidae) venom, on GABAergic nigrotectal pathways. Brain Res 1031 1 74 81
  127. 127. Gati C. D. Mortari M. R. Schwartz E. F. 2012 Towards therapeutic applications of arthropod venom k(+)-channel blockers in CNS neurologic diseases involving memory acquisition and storage. Journal of toxicology 756358
  128. 128. Dilly S. Lamy C. Marrion N. V. Liegeois . J. F. Seutin . V. 2011 Ion-channel modulators: more diversity than previously thought. Chembiochem : a European journal of chemical biology 12 12 1808 12
  129. 129. Romero-Curiel A. Lopez-Carpinteyro D. Gamboa C. De la Cruz F. Zamudio S. Flores G. 2011 Apamin induces plastic changes in hippocampal neurons in senile Sprague-Dawley rats. Synapse 65 10 1062 72
  130. 130. Gimenez-Gallego G. Navia MA Reuben J. P. Katz G. M. Kaczorowski G. J. Garcia M. L. 1988 Purification, sequence, and model structure of charybdotoxin, a potent selective inhibitor of calcium-activated potassium channels. Proc Natl Acad Sci U S A 85 10 3329 33
  131. 131. Crest M. Jacquet G. Gola M. Zerrouk H. Benslimane A. Rochat H. et al. 1992 Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom. J Biol Chem 267 3 1640 7
  132. 132. Galvez A. Gimenez-Gallego G. Reuben J. P. Roy-Contancin L. Feigenbaum P. Kaczorowski G. J. et al. 1990 Purification and characterization of a unique, potent, peptidyl probe for the high conductance calcium-activated potassium channel from venom of the scorpion Buthus tamulus. J Biol Chem 265 19 11083 90
  133. 133. Kourrich S. Mourre C. Soumireu-Mourat B. 2001 Kaliotoxin, a Kv1.1 and Kv1.3 channel blocker, improves associative learning in rats. Behav Brain Res 120 1 35 46
  134. 134. Edwards T. M. Rickard N. S. 2006 Pharmaco-behavioural evidence indicating a complex role for ryanodine receptor calcium release channels in memory processing for a passive avoidance task. Neurobiol Learn Mem 86 1 1 8

Written By

Márcia Renata Mortari and Alexandra Olimpio Siqueira Cunha

Submitted: March 28th, 2012 Published: July 1st, 2013