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Triggering of protection mechanism against Phoneutria nigriventer spider venom in the brain

Abstract

Severe accidents caused by the "armed" spider Phoneutria nigriventer causeneurotoxic manifestations in victims. In experiments with rats, P. nigriventer venom(PNV) temporarily disrupts the properties of the blood brain barrier (BBB) by affecting both the transcellularand the paracellular route. However, it is unclear how cells and/or proteins participatein the transient opening of the BBB. The present study demonstrates that PNV is asubstrate for the multidrug resistance protein-1 (MRP1) in cultured astrocyte andendothelial cells (HUVEC) and increases mrp1 and cx43 and down-regulates glut1mRNA transcripts in cultured astrocytes. The inhibition of nNOS by 7-nitroindazolesuggests that NO derived from nNOS mediates some of these effects by eitheraccentuating or opposing the effects of PNV. In vivo, MRP1, GLUT1 and Cx43 proteinexpression is increased differentially in the hippocampus and cerebellum, indicatingregion-related modulation of effects. PNV contains a plethora of Ca2+, K+ and Na+channel-acting neurotoxins that interfere with glutamate handling. It is suggested thatthe findings of the present study are the result of a complex interaction of signalingpathways, one of which is the NO, which regulates BBB-associated proteins inresponse to PNV interference on ions physiology. The present study providesadditional insight into PNV-induced BBB dysfunction and shows that a protectivemechanism is activated against the venom. The data shows that PNV has qualities forpotential use in drug permeability studies across the BBB. (AU)

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