Study of Phoneutria nigriventer spider venom mechanism in the blood brain barrier and in the neural tissue and analysis of two purified toxins action as vehicle in the Glioma treatment

• Grant number: 11/08005-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2011
• End date: May 01, 2015
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Maria Alice da Cruz Hofling
• Grantee: Catarina Raposo Dias Carneiro
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 12/19245-0 - Analysis of Intracellular Ca2+ fluctuation and of inflammation markers in astrocytes co-cultured with brain endothelial cells, after exposure to Phoneutria nigriventer spider venom, BE.EP.PD

Abstract

It has been shown that the NO-cGMP signaling pathway regulates ion channels opening, protein phosphorylation and expression of transcription factors. In the CNS, NO-cGMP pathway seems to be involved in several events such as synaptic plasticity, increased neuronal coupling and excitability, neuroinflamatory responses, regulation of vascular tone and blood vessels permeability (hence in the blood brain barrier - BBB). The Phoneutria nigriventer spider venom (PNV) contains peptides with neurotoxic and neuroexcitatory actions. These peptides have been shown to increase the vascular permeability both in the corpus cavernosum and BBB, cause penile erection, affect íon channels and neurotransmitter release, and in the CNS cause neuronal activation, induce reactive gliosis and neuroinflammation. The involvement of NO-cGMP pathway in the peripheral action (penile erection) of PNV has been already demonstrated. Despite NO mediation also has been demonstrated in the neurotoxicity caused by venom, the PNV mechanism of action in the CNS remains poorly understood. This work aims to clarify, through morphological, biochemical and molecular assays, the role of NO-GCs-cGMP-PKG pathway in PNV action at the BBB and neural tissue. Given the richness of ion channels-acting neurotoxins present in the venom, the present study could provide an excellent model for studying the involvement of the NO-cGMP signaling pathway in the neurointoxication/neuroinflammation. Moreover, the reported effects of the venom on the CNS, entitles PNV as a useful tool to investigate the access of the chemotherapeutic drug, methotrexate, in tumor tissue implanted from the C6 Glioma cell line (human lineage), after simultaneous injection with two purified PNV-toxins with activity in BHE (previously tested and with low toxicity in rats). The study will allow to determine whether PNV-toxins increases the penetration of the drug into the tumor. Models that demonstrate the increased availability of chemotherapeutics drugs to tumor tissue may improve the treatment of brain tumors.

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE SANTANA NUNES, ANA KAROLINA; RAPOSO, CATARINA; DE OLIVEIRA, WILMA HELENA; THOME, RODOLFO; VERINAUD, LIANA; TOVAR-MOLL, FERNANDA; PEIXOTO, CHRISTINA ALVES. Phosphodiesterase-5 inhibition promotes remyelination by MCP-1/CCR-2 and MMP-9 regulation in a cuprizone-induced demyelination model. Experimental Neurology, v. 275, n. 1, p. 143-153, JAN 2016. (11/08005-6)

RAPOSO, CATARINA; BJORKLUND, ULRIKA; KALAPOTHAKIS, EVANGUEDES; BIBER, BJORN; DA CRUZ-HOFLING, MARIA ALICE; HANSSON, ELISABETH. Neuropharmacological effects of Phoneutria nigriventer venom on astrocytes. NEUROCHEMISTRY INTERNATIONAL, v. 96, p. 13-23, JUN 2016. (12/19245-0, 11/08005-6)

DE SANTANA NUNES, ANA KAROLINA; RAPOSO, CATARINA; DE OLIVEIRA, WILMA HELENA; THOME, RODOLFO; VERINAUD, LIANA; TOVAR-MOLL, FERNANDA; PEIXOTO, CHRISTINA ALVES. Phosphodiesterase-5 inhibition promotes remyelination by MCP-1/CCR-2 and MMP-9 regulation in a cuprizone-induced demyelination model. Experimental Neurology, v. 275, p. 11-pg., 2016-01-01. (11/08005-6)

SANTANA NUNES, ANA KAROLINA; RAPOSO, CATARINA; SANTOS ROCHA, SURA WANESSA; DE SOUSA BARBOSA, KARLA PATRICIA; DE ALMEIDA LUNA, RAYANA LEAL; DA CRUZ-HOEFLING, MARIA ALICE; PEIXOTO, CHRISTINA ALVES. Involvement of AMPK, IK beta alpha-NF kappa B and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model. Brain Research, v. 1627, p. 119-133, NOV 19 2015. (11/08005-6)

RAPOSO, CATARINA; DE ALMEIDA LUNA, RAYANA LEAL; SANTANA NUNES, ANA KAROLINA; THOME, RODOLFO; PEIXOTO, CHRISTINA ALVES. Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes. Brain Research Bulletin, v. 104, p. 60-73, MAY 2014. (11/08005-6)