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.
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