**5. Actions on mood disorders**

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. Ac‐ cording 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 subu‐ nit 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 tox‐ in with nicotinic receptors is largely voltage dependent, slow and uncompetitive, a similar

An Integrated View of the Molecular Recognition and Toxinology - From Analytical Procedures to Biomedical

Going further on wasp venoms, the anticonvulsant and/or neuroprotective effects of mole‐ cules 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-enzy‐ matic fraction of the venoms of *Polybia ignobilis* and *Polybia occidentalis* inhibit seizures evoked by the injection of several chemoconvulsants in Wistar rats. The neuroactive mole‐ cules present in the venom of *P. ignobilis* and *P. occidentalis* are now in phase of structure-

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 scorpio*n 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 in‐ duced by the injection of coriaria lactone in doses causing no visible side effects [114]. Fur‐ ther 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 behav‐ ioral and electroencephalographic seizures and decreased mean score of pilocarpine-in‐ duced seizures. Moreover, these authors showed that BmK AS does not impair locomotion

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 gan‐ glion 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 basolat‐ eral 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.

mode by which they block glutamate ionotropic channels [111].

function investigation.

Applications

102

or motor behavior.

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 yearold, 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 peo‐ ple 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 anxi‐ ety 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. Howev‐ er, with the improvement of techniques for research and diagnosis, such as positron emis‐ sion tomography, magnetic resonance and multiple channels recording electroencephalogram, soon researchers will be capable to identify structures and neuro‐ chemical mechanism involved in the regulation of mental states, including mood. So far, we know that limbic structures, such as the amygdala, hippocampus, hypothalamus and prefrontal cortex control the emotional aspects of brain function. There are plenty of connec‐ tions 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 classi‐ cal 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 de‐ pression 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 tar‐ gets of mood stabilizers, such as adrenaline, GABA, serotonin and glutamate receptors and transporters. There is not many works relating neurotoxins from arthropods and mood dis‐ orders, but the few works available showed that in some cases, these molecules might con‐ tribute 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 ex‐ posed to the light-dark choice apparatus spent more time in the light side of the box, similar‐ ly 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 enantiom‐ ers 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 transmis‐ sion. Inhibitors or MAO (MAOi) have been extensively used as mood stabilizers and cur‐ rently they have received attention due to their protective activity against age-induced neurodegenerative disorders [123].

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 us‐ ing 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 thala‐ mus 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 den‐ dritic morphology that might counteract aging and neurodegenerative processes that lead to cognitive and memory impairment [129]. In fact, SK channels co-localize with Ca2+-permea‐ ble 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 block‐ ade of SK channels will modulate hippocampal excitability that is essential in memory proc‐ esses 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 delete‐ rious effects of aging in memory and cognitive processes have also been proposed [129].

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

http://dx.doi.org/10.5772/ 52382

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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: Charybdo‐ toxin isolated from scorpion *Leiurus quinquestriatus*, Kaliotoxin isolated from *Androctonus mauretanicus* and Iberiotoxin from *Buthus tasmulus*. Charybdotoxin is a potent selective in‐ hibitor 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 dis‐

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 ple‐ thora 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 character‐ ization of sodium channels was possible. Spider and wasps polyamines, in turn are consid‐ ered 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 struc‐ tures, 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,

crimination task [133,134].

very few molecules came to commercialization.

**7. Final remarks**

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 mil‐ lion 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 theophyl‐ line 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 re‐ sponse induced by the GABAergic blockade of superior colliculus. These effects were simi‐ lar 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 po‐ tassium channel, AvTx-8 could act in many different sites that would end in channels open‐ ing and hyperpolarization of neuronal membrane.
