Abstract
Severe accidents caused by the “armed” spider Phoneutria nigriventer cause neurotoxic manifestations in victims. In experiments with rats, P. nigriventer venom (PNV) temporarily disrupts the properties of the BBB by affecting both the transcellular and the paracellular route. However, it is unclear how cells and/or proteins participate in the transient opening of the BBB. The present study demonstrates that PNV is a substrate for the multidrug resistance protein-1 (MRP1) in cultured astrocyte and endothelial cells (HUVEC) and increases mrp1 and cx43 and down-regulates glut1 mRNA transcripts in cultured astrocytes. The inhibition of nNOS by 7-nitroindazole suggests that NO derived from nNOS mediates some of these effects by either accentuating or opposing the effects of PNV. In vivo, MRP1, GLUT1 and Cx43 protein expression is increased differentially in the hippocampus and cerebellum, indicating region-related modulation of effects. PNV contains a plethora of Ca2+, K+ and Na+ channel-acting neurotoxins that interfere with glutamate handling. It is suggested that the findings of the present study are the result of a complex interaction of signaling pathways, one of which is the NO, which regulates BBB-associated proteins in response to PNV interference on ions physiology. The present study provides additional insight into PNV-induced BBB dysfunction and shows that a protective mechanism is activated against the venom. The data shows that PNV has qualities for potential use in drug permeability studies across the BBB.
Highlights
Accidents involving the ‘‘armed’’ spider Phoneutria nigriventer can cause neurotoxic manifestations, which in severe cases may include convulsion [1]
The results of the present study found that P. nigriventer armed-spider venom is a substrate for multidrug resistance protein-1 (MRP1) activity in endothelial and astrocyte cells
P. nigriventer venom (PNV) affected the expression of mrp1, glut1 and cx43 mRNAs transcripts in astrocytes
Summary
Accidents involving the ‘‘armed’’ spider Phoneutria nigriventer can cause neurotoxic manifestations, which in severe cases may include convulsion [1]. P. nigriventer venom (PNV) impairs the BBB by increasing endothelial transcellular vesicular transport mediated by microtubules [2] and by down-regulation of inter-endothelial junctional proteins [3,4]. PNV induces swelling of the perivascular end-feet [5], increases cytoskeletal GFAP and S-100 calcium metabolism-associated protein expression [6], and upregulates aquaporin-4 [7], a water channel-forming protein involved in edema formation and resolution. A positive factor is that severe envenomation by P. nigriventer occurs in less than 0.5% of accidents involving humans [1], and that in experimental cases the effects of PNV are resolved in a few hours. It is important to further investigate the effect of PNV-induced BBB opening, taking
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