Abstract
We have previously demonstrated that Phoneutria nigriventer venom (PNV) causes blood–brain barrier (BBB) breakdown, swelling of astrocytes end-feet and fluid permeation into brain interstitium in rats. Caveolae and water channels respond to BBB alterations by co-participation in shear stress response and edema formation/resolution. Herein, we showed post-natal developmental-related changes of two BBB-associated transporter proteins: the endothelial caveolin-1 (Cav-1), the major scaffolding protein from caveolae frame, and the astroglial aquaporin-4 (AQP4), the main water channel protein expressed in astrocytic peri-vascular end-feet processes, in the hippocampus of rats intraperitoneally-administered PNV. Western blotting protein levels; immunohistochemistry (IHC) protein distribution in CA1, CA2, and CA3 subfields; and gene expression by Real Time-Polymerase Chain Reaction (qPCR) were assessed in post-natal Day 14 (P14) and 8–10-week-old rats over critical periods of envenomation. The intensity and duration of the toxic manifestations indicate P14 neonate rats more vulnerable to PNV than adults. Histologically, the capillaries of P14 and 8–10-week-old rats treated with PNV showed perivascular edema, while controls did not. The intensity of the toxic manifestations in P14 decreases temporally (2 > 5 > 24 h), while inversely the expression of AQP4 and Cav-1 peaked at 24 h when clinically PNV-treated animals do not differ from saline controls. IHC of AQP4 revealed that hippocampal CA1 showed the least expression at 2 h when toxic manifestation was maximal. Subfield IHC quantification revealed that in P14 rats Cav-1 peaked at 24 h when toxic manifestations were absent, whereas in 8–10-week-old rats Cav-1 peaked at 2 h when toxic signs were highest, and progressively attenuated such increases until 24 h, remaining though significantly above baseline. Considering astrocyte-endothelial physical and functional interactions, we hypothesize that age-related modulations of AQP4 and Cav-1 might be linked both to changes in functional properties of astrocytes during post-natal development and in the BBB breakdown induced by the venom of P. nigriventer.
Highlights
Accidents involving the spider Phoneutria nigriventer are common in the Southeast of Brazil
The animals exhibited severe toxicity which was characterized by piloerection, hyper salivation, intense redness of the ears, paralyses of hind limbs, respiratory distress and stayed motionless at the cage corner; 5 h after P. nigriventer venom (PNV) exposure, the animals started showing some signs of amelioration of their toxic condition; and 24 h after envenomation, the animals behavior were not different from the exhibited by the saline-treated animals
Considering the preponderance of PNV effects in post-natal Day 14 (P14) compared with 8–10 week-old rats we suggest the existence of differences in regulatory mechanisms related to AQP4 and Cav-1/caveolae system
Summary
Accidents involving the spider Phoneutria nigriventer are common in the Southeast of Brazil. They are responsible for great part of the notified cases of araneism in the country; the majority of accidents being characterized by intense local pain and edema which rarely evolves to serious complications or death. The P. nigriventer venom (PNV) produces important excitatory effects [2,3] and its mechanism of action indicates the nervous system a key target. Thereupon, a great therapeutic interest motivates the abundant number of physiological and pharmacological studies involving PNV aiming at the development of new drugs [6,7]
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