VEGF/VEGFR-2 system exerts neuroprotection against Phoneutria nigriventer spider envenomation through PI3K-AKT-dependent pathway

Autor(es)

Rodrigues Mesquita-Britto, Maria Helena ^{[1, 2]} ; Padilha Mendonca, Monique Culturato ^{[1, 2]} ; Soares, Edilene Siqueira ^[2] ; de Oliveira, Giovanna ^[2] ; Solon, Carina Silva ^[3] ; Velloso, Licio Augusto ^[3] ; da Cruz-Hofling, Maria Alice ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] State Univ Campinas UNICAMP, Fac Med Sci, Dept Pharmacol, Campinas, SP - Brazil

^[2] State Univ Campinas UNICAMP, Inst Biol, Dept Biochem & Tissue Biol, Campinas, SP - Brazil

^[3] State Univ Campinas UNICAMP, Fac Med Sci, Dept Clin Med, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Toxicon; v. 185, p. 76-90, OCT 15 2020.
• Citações Web of Science: 0

Resumo

This study was undertaken to elucidate why VEGF/VEGFR-2 is elevated in the hippocampus of rats injected with Phoneutria nigriventer spider venom (PNV). PNV delays Na+ channels inactivation; blocks Ca2+ and K+ channels, increases glutamate release, causes blood-brain breakdown (BBBb), brain edema and severe excitotoxicity. Analytical FT-IR spectroscopy showed profound alteration in molecular biochemical state, with evidences for VEGFR-2 (KDR/Flk-1) signaling mediation. By blocking VEGF/VEGFR-2 binding via pre-treatment with itraconazole we demonstrated that animals' condition was deteriorated soon at 1-2 h post-PNV exposure concurrently with decreased expression of VEGF, BBB-associated proteins, ZO-1, beta-catenin, laminin, P-gp (P-glycopmtein), Neu-N (neuron's viability marker) and MAPKphosphorylated-p38, while phosphorylated-ERK and Src pathways were increased. At 5 h and coinciding with incipient signs of animals' recuperation, the proteins associated with protection (HIF-1 alpha, VEGF, VEGFR-1, VEGFR-2, Neu-N, occludin, beta-catenin, laminin, P-gp efflux protein, phosphorylated-p38) increased thus indicating p38 pathway activation together with paracellular route strengthening. However, the BBB transcellular trafficking and caspase-3 increased (pro-apoptotic pathway activation). At 24 h, the transcellular route reestablished physiological state but the pro-survival pathway PI3K/(p-Akt) dropped in animals underwent VEGF/VEGFR-2 binding inhibition, whereas it was significantly activated at matched interval in PNV group without prior itraconazole; these results demonstrate impaired VEGF' survival effects at 24 h. The inhibition of VEGF/VEGFR-2 binding identified 5 h as turning point at which multi-level dynamic interplay was elicited to reverse hippocampal damage. Collectively, the data confirmed VEGFR-2 signaling via serine-threonine kinase Akt as neuropmtective pathway against PNV-induced damage. Further studies are needed to elucidate mechanisms underlying PNV effects. (AU)

• Processo FAPESP: 05/53625-1 - Ação dos mastoparanos e da fosfolipase A2 isolados do veneno de Polybia paulista (Hymenoptera, Epiponini) nos mecanismos de apoptose e necrose de células musculares e mitocôndrias isoladas de camundongos Balb/c
• Beneficiário: Maria Alice da Cruz Hofling
• Modalidade de apoio: Auxílio à Pesquisa - Regular