Inhibition of VEGF-Flk-1 binding induced profound biochemical alteration in the hippocampus of a rat model of BBB breakdown by spider venom. A preliminary assessment using FT-IR spectroscopy

Abstract

Phoneutria nigriventer spider venom (PNV) contains ion channels-acting neuropeptides that in rat induces transitory blood-brain barrier breakdown (BBBb) in hippocampus in parallel with VEGF upregulation. We investigated whether VEGF has a neuroprotective role by inhibiting its binding to receptor Flk-1 by itraconazole (ITZ). FT-IR spectroscopy examined the biochemical status of hippocampus and evaluated BBBb in rats administered PNV or ITZ/PNV at periods with greatest toxicity (1-2h), recovery (5h) and visual absence of symptoms (24h), and compared to saline and ITZ controls. The antifungal treatment before venom intoxication aggravated the venom effects and increased BBB damage. FT-IR spectra of venom, hippocampi of controls, PNV and ITZ-PNV showed a 1400 cm band linked to symmetric stretch of carboxylate and 1467 cm band (CH bending: mainly lipids) that were considered biomarker and reference bands, respectively. Inhibition of VEGF/Flk-1 binding produced marked changes in lipid/protein stability at 1-2h. The largest differences were observed in spectra regions assigned to lipids, both symmetric (2852 cm) and asymmetric (2924 and 2968 cm). Quantitative analyses showed greatest increases in the 1400 cm/1467 cm ratio also at 1h. Such changes at period of rats' severe intoxication referred to wavenumber region from 3106 cm to 687 cm assigning for C-H and N-H stretching of protein, Amide I, C=N cytosine, N-H adenine, Amide II, CH bending: mainly lipids, C-O stretch: glycogen, polysaccharides, glycolipids, z-type DNA, C-C, C-O and CH out-of-plane bending vibrations. We conclude that VEGF has a neuroprotective role and can be a therapeutic target in PNV envenomation. FT-IR spectroscopy showed to be instrumental for monitoring biochemical changes in this model of P. nigriventer venom-induced BBB disruption.

Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling

“…In addition to the well-established effects of VEGF, recent research has demonstrated pivotal roles for VEGF/VEGFR2 in a broad range of neurotrophic and neuroprotective effects in the CNS that may relate to neurogenesis and angiogenesis [ 11 , 12 , 13 ]. The neurotrophic and neuroprotective effects of VEGF are predominantly mediated by VEGFR2, also called fetal Flk-1 [ 14 , 57 , 58 , 59 ], or kinase insert-domain containing receptor (KDR) [ 60 ]. VEGF/VEGFR2 (Flk-1) signaling may have neuroprotective effects in many neurological diseases, such as hemorrhagic or ischemic stroke [ 16 , 17 , 18 ], traumatic brain injury [ 61 ], amyotrophic lateral sclerosis [ 20 ], Huntington’s disease [ 62 ], Alzheimer’s disease [ 12 , 21 ], and Parkinson’s disease [ 12 , 22 ].…”