Abstract
Apart from its angiogenic and vascular permeation activity, the vascular endothelial growth factor (VEGF) has been also reported as a potent neuronal protector. Newborn rats with low VEGF levels develop neuron degeneration, while high levels induce protective mechanisms in several neuropathological conditions. Phoneutria nigriventer spider venom (PNV) disrupts the blood-brain barrier (BBB) and causes neuroinflammation in central neurons along with excitotoxic signals in rats and humans. All these changes are transient. Herein, we examined the expression of VEGF and its receptors, Flt-1 and Flk-1 in the hippocampal neurons following envenomation by PNV. Adult and neonatal rats were evaluated at time limits of 2, 5 and 24 h. Additionally, BBB integrity was assessed by measuring the expression of occludin, β-catenin and laminin and neuron viability was evaluated by NeuN expression. VEGF, Flt-1 and Flk-1 levels increased in PNV-administered rats, concurrently with respective mRNAs. Flt-1 and Flk-1 immunolabeling was nuclear in neurons of hippocampal regions, instead of the VEGF membrane-bound typical location. These changes occurred simultaneously with the transient decreases in BBB-associated proteins and NeuN positivity. Adult rats showed more prominent expressional increases of the VEGF/Flt-1/Flk-1 system and earlier recovery of BBB-related proteins than neonates. We conclude that the reactive expressional changes seen here suggest that VEGF and receptors could have a role in the excitotoxic mechanism of PNV and that such role would be less efficient in neonate rats.
Highlights
Spider venoms are rich sources of low molecular mass compounds with a wide range of pharmacological effects on ion channels, neurotransmitter receptors and transporters and on synaptic transmission [1]
The data showed that the changes in the expression of vascular endothelial growth factor (VEGF), Fms-like tyrosine kinase 1 (Flt-1), Flk-1 and their respective mRNAs in the hippocampus of rats administered with the venom of P. nigriventer spider were time- and age-dependent
VEGF, Flt-1, Flk-1 and neuronal nuclear antigen (NeuN) were expressed by pyramidal and granule neurons
Summary
Spider venoms are rich sources of low molecular mass compounds with a wide range of pharmacological effects on ion channels, neurotransmitter receptors and transporters and on synaptic transmission [1]. Studies have shown that PNV presence in the blood flow induces blood-brain barrier (BBB) breakdown in the hippocampus of rats [5] by enhanced transendothelial microtubule-mediated vesicular transport [6], or by displacement and/or decrease of proteins that control the paracellular pathway [7]. These effects are accompanied by transient neurotoxic manifestations. Despite clinical reports and experimental studies showing that P. nigriventer spiderenvenoming causes neurotoxic manifestations and induces permeation of the BBB, little is known about molecular mechanisms triggered in the brain shortly after envenomation
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