Phoneutria nigriventer Venom: Action in the Central Nervous System

Abstract

Accidents involving venomous animals are a significant public health problem, since bites can be lethal or induce clinical complications. Spider bites from the genus Phoneutria (Ctenidae, Araneomorphae), found in South America, are the second most frequent cause of accidents with spiders in Brazil. The P. nigriventer venom (PNV) is composed of potent basic peptides, some of them neurotoxic, although neurological dysfunction caused by natural neurotoxins is still a mistreated condition. The PNV and its toxins have been extensively studied in the last three decades, with most interest focusing on the neurotoxic effects on the peripheral nervous system. In the last decade, effects of PNV on the central nervous system (CNS), mainly on the blood-brain barrier (BBB) and astrocytes, have been characterized and can contribute to improving treatment in cases of accidental bites. It has been demonstrated experimentally that PNV impairs the BBB through paracellular and transcellular pathways; in astrocytes, PNV induces the swelling of perivascular end-feet, increases the expression of glial fibrillary acidic protein (GFAP) and the calcium metabolism-associated protein S-100, upregulates aquaporin-4 (AQP4), and induces a transient increase in the major gap junction (GJ) protein connexin 43 (Cx-43), being GFAP, S-100, AQP4, and Cx-43 important astrocyte markers that play a key role in astrocytic physiology. In central neurons, PNV causes activation in multiple brain areas, and upregulates the expression of vascular endothelial growth factor (VEGF) and its receptors Fms-like tyrosine kinase 1 (Flt-1) and fetal liver kinase 1 (Flk-1). Therefore, the recent data concerning the PNV mechanism in the CNS can contribute to improving the treatment in cases of phoneutrism. In addition, PNV has the potential to be explored as a tool for studies on drug permeability across the BBB. Apart from the BBB playing a seminal role in maintaining brain homeostasis, it also precludes the access of most drugs into the brain. The study of substances that allow manipulation of the BBB is relevant for the development of successful therapeutic strategies for overcoming restricted drug delivery into the brain. This potential is more relevant considering that PNV displays a low cytotoxicity in vitro and in vivo. The focus of this chapter is to review the state of art of the neurotoxicity of Phoneutria nigriventer spider venom, mainly focusing on the effect upon components of the neurovascular unit, endothelium, astrocytes and neurons, and in the blood-brain barrier.