**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 learn‐ ing and memory in models of experimental animals is the apamin. Apamin is a short pep‐ tide (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 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].

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‐ crimination task [133,134].

## **7. Final remarks**

[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

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

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

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‐

parameters, but only PcTx exerted effects on the behavioral anxiety parameters [124].

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

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 learn‐ ing and memory in models of experimental animals is the apamin. Apamin is a short pep‐ tide (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

neurodegenerative disorders [123].

Applications

104

ing and hyperpolarization of neuronal membrane.

**memory**

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, very few molecules came to commercialization.

## **Acknowledgements**

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

## **Author details**

Márcia Renata Mortari1\* and Alexandra Olimpio Siqueira Cunha2

\*Address all correspondence to: mmortari@unb.br

1 Department of Physiological Sciences, Institute of Biological Sciences, University of Brasí‐ lia, Brazil

[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 therapeu‐*

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**Author details**

lia, Brazil

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**Chapter 5**

**Venom Bradykinin-Related Peptides (BRPs) and Its**

The kallikrein-kinin system is an extensively studied biological pathway and involves a multiprotein complex, which includes serine proteinases from tissue and plasma. These proteinases act on substrates as kininogens (high and low molecular weight), releasing the active kinins.

Several studies aiming to evaluate the biological activities of the kinins revealed that this peptide is implicated in diverse physiological processes as regulation of blood pressure, cardiac, and renal function. Due to its ability to increase the vascular permeability by acting on endothelial cells, BK is correlated to several pathological processes including inflammation.

The knowledge on the role of BK in various biological pathways as coagulation cascade, blood pression regulation, and central nervous system modulation and signaling has been signifi‐ cantly improved, leading to the identification of BK receptors and posterior development of

This research was mainly driven by scientific studies on animal venoms, which lead to the identification of the BK-related peptides (BRPs). The best, and maybe also the first, example of such contribution was the discovery of the bradykinin-potentiating peptides (BPPs), first described in *Bothrops jararaca* venom [3, 4]. The BPPs are proline-rich oligopeptides that inhibit the angiotensin-converting enzyme (ACE), and that are responsible for the hypotensive effect of the *Bothrops* genus snake venoms. The pharmacological effects of these peptides have been studied since 70's [3, 4], and allowed not only to the discovery of the neuropeptide BK [5], but also to the development of the first active site-directed inhibitor of ACE as drug for the

> © 2013 Lameu et al.; 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,

© 2013 Lameu et al.; 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.

distribution, and reproduction in any medium, provided the original work is properly cited.

These actions have been observed and described in both mammals and rodents [1].

**Multiple Biological Roles**

Claudiana Lameu, Márcia Neiva and

Additional information is available at the end of the chapter

The main kinin is the nonapeptide bradykinin (BK).

Mirian A. F. Hayashi

**1. Introduction**

http://dx.doi.org/10.5772/52872

drugs targeting its pathways [2].
