Study of structure/activity relationship for neurotoxic/neuroprotective actions of NSTX-3 and JSTX-3 acylpolyamino toxins in rodent CNS

• Grant number: 06/05649-1
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2007
• End date: February 28, 2009
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Mario Sergio Palma
• Grantee: Fernanda Pessoa de Sales
• Host Institution: Instituto de Biociências (IB). Universidade Estadual Paulista (UNESP). Campus de Rio Claro. Rio Claro , SP, Brazil

Abstract

Arthropods toxins present interesting chemical structures and mechanisms of actions. Since the compounds produced by these venomous animals are highly selective and generally present high affinity for neuronal receptors of mammals, they are considered model compounds for the development of novel neuropharmaceuticals drugs. It is known from literature that the polyamine toxins without the backbone “tail” constituted of basic amino acids, cause reversible action, while that those presenting the backbone “tail” present irreversible action. As this question involves one of the main factors that can direct the choice of the type of molecular structure of the leader-drug, we decided to perform a comparative study among two chemical structures, whose the only structural distinction among them is the presence of the arginine residue in the tail position. In this direction, the acylpolyamine toxins of Nephilinae spiders, JSTX-3 (without arginine tail) and NSTX-3 (with arginine tail) will be managed for icv application in Wistar rats, and will have their biological action in the monitored through the central nervous system (CNS), by means of the analysis of the expression of fos protein. This protein is a transcription factor activation-dependent used as a sensitive tool to mark the CNS neurons susceptible to different pharmacological, electric and/or physiological stimulations. From immunohistochemical assays, the brain areas that direct or indirectly suffer the action from the toxin during the analysis will express fos protein indicating a possible action of the neurotoxin these neurons. In general, these polyamines act preferentially in the different subtypes of glutamate receptors. Thus, the fos expressing neurons will be submitted to a of double staining, with secondary specific antibodies for different subtypes of receptors (fos/NMR1, fos/rGlu2/3, fos/rGlu1, fos/rGlu4, fos/tyrosine hydroxilase, fos/5HT2A). The main objective oh this investigation is to identify the sites of double labeling, in order to get an idea about the mechanisms of brain sensitization.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SALES, Fernanda Pessoa de. Estudo da relação estrutura/atividade para as ações neurotóxica/neuroprotetora das acilpoliaminotoxinas NSTX-3 e JSTX-3 em sistema nervoso central de ratos. 2009. Master's Dissertation - Universidade Estadual Paulista (Unesp). Instituto de Biociências. Rio Claro Rio Claro.