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

Márcia Renata Mortari and Alexandra Olimpio Siqueira Cunha

Additional information is available at the end of the chapter

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

## **1. Introduction**

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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 in‐ tense 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 mamma‐ lian CNS, venom compounds may either inhibit or stimulate with affinity and specificity structures such as: ion channels, neurotransmitter receptors and transporters [1-3]. Not sur‐ prisingly, 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 pharmaceuti‐ cals, 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

© 2013 Mortari and Siqueira Cunha; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Mortari and Siqueira Cunha; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 effi‐ cient 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].

constantly seek new therapeutic strategies, since most of these are inadequate or cause seri‐

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

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

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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 antinocicep‐ tive effects on inflammation. Thus, nowadays, toxins isolated from arthropods are consid‐ ered powerful tools, since they have congruent targets of the impulse transmission of pain,

The most studied Arthropod venom is extracted from the Asian scorpion *Mesobuthus mar‐ tensi* 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 antiinsect 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 ami‐ no 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

The NaScTx family can be classified in at least two major families, α and β, according to the

tion, 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 activi‐

**ii.** "α-like toxins" active both on mammals and insects, which are far less specific and

**iii.** α-toxins only specific for insects and without any toxicity on mammals, even at

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 mod‐ el, 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 analge‐ sic effects, BmK AngP1, which shows an evident analgesic effect with simultaneous excitato‐

high concentrations. Moreover, the insect selective β-toxins have been divided into

channels [19]. The binding of α-toxins delays Nav channel inactiva‐

and may provide an attractive alternative to opioid treatments.

neurotoxicity [18], although it remains to be fully investigated.

ties, α and β NAScTx can be also divided into three groups:

**i.** "classic" highly specific for mammals;

less active than the "classical" ones;

**3.1. Polypeptide toxins from Scorpion**

mode of action on Na+

ous side effects [14].

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 struc‐ tures of mammalian CNS, as well as the supply of novel alternatives to the treatment of neu‐ rological 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.
