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A Vicious NGF-p75NTR Positive Feedback Loop Exacerbates the Toxic Effects of Oxidative Damage in the Human Retinal Epithelial Cell Line ARPE-19.
Tringali, Giuseppe; Pizzoferrato, Michela; Lisi, Lucia; Marinelli, Silvia; Buccarello, Lucia; Falsini, Benedetto; Cattaneo, Antonino; Navarra, Pierluigi.
Afiliação
  • Tringali G; Section of Pharmacology, Department of Healthcare Surveillance and Bioethics, Catholic University Medical School, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
  • Pizzoferrato M; Section of Pharmacology, Department of Healthcare Surveillance and Bioethics, Catholic University Medical School, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
  • Lisi L; Section of Pharmacology, Department of Healthcare Surveillance and Bioethics, Catholic University Medical School, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
  • Marinelli S; European Brain Research Institute-Fondazione Rita Levi Montalcini, 00161 Rome, Italy.
  • Buccarello L; European Brain Research Institute-Fondazione Rita Levi Montalcini, 00161 Rome, Italy.
  • Falsini B; UOC Ophtalmology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
  • Cattaneo A; Department of Ophthalmology, Bambino Gesù IRCCS Children's Hospital, 00133 Rome, Italy.
  • Navarra P; European Brain Research Institute-Fondazione Rita Levi Montalcini, 00161 Rome, Italy.
Int J Mol Sci ; 24(22)2023 Nov 12.
Article em En | MEDLINE | ID: mdl-38003427
In spite of its variety of biological activities, the clinical exploitation of human NGF (hNGF) is currently limited to ocular pathologies. It is therefore interesting to test the effects of hNGF in preclinical models that may predict their efficacy and safety in the clinical setting of ocular disorders and compare the effects of hNGF with those of its analogs. We used a human retinal pigment cell line, ARPE-19 cells, to investigate the effects of hNGF and its analogs, mouse NGF (mNGF) and painless NGF (pNGF), on cell viability under basal conditions and after exposure to oxidative stimuli, i.e., hydrogen peroxide (H2O2) and ultraviolet (UV)-A rays. The effects of hNGF and pNGF were also tested on the gene expression and protein synthesis of the two NGF receptor subtypes, p75 neurotrophic receptors (p75NTR) and tyrosine kinase A (TrkA) receptors. We drew the following conclusions: (i) the exposure of ARPE-19 cells to H2O2 or UV-A causes a dose-dependent decrease in the number of viable cells; (ii) under baseline conditions, hNGF, but not pNGF, causes a concentration-dependent decrease in cell viability in the range of doses 1-100 ng/mL; (iii) hNGF, but not pNGF, significantly potentiates the toxic effects of H2O2 or of UV-A on ARPE-19 cells in the range of doses 1-100 ng/mL, while mNGF at the same doses presents an intermediate behavior; (iv) 100 ng/mL of hNGF triggers an increase in p75NTR expression in H2O2-treated ARPE-19 cells, while pNGF at the same dose does not; (v) pNGF, but not hNGF (both given at 100 ng/mL), increases the total cell fluorescence intensity for TrkA receptors in H2O2-treated ARPE-19 cells. The present findings suggest a vicious positive feedback loop through which NGF-mediated upregulation of p75NTR contributes to worsening the toxic effects of oxidative damage in the human retinal epithelial cell line ARPE-19. Looking at the possible clinical relevance of these findings, one can postulate that pNGF might show a better benefit/risk ratio than hNGF in the treatment of ocular disorders.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptor trkA / Peróxido de Hidrogênio Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptor trkA / Peróxido de Hidrogênio Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article