1. Academic Validation
  2. The S1P1 receptor-selective agonist CYM-5442 protects retinal ganglion cells in endothelin-1 induced retinal ganglion cell loss

The S1P1 receptor-selective agonist CYM-5442 protects retinal ganglion cells in endothelin-1 induced retinal ganglion cell loss

  • Exp Eye Res. 2017 Nov;164:37-45. doi: 10.1016/j.exer.2017.08.005.
Román Blanco 1 Gema Martínez-Navarrete 2 Francisco J Valiente-Soriano 3 Marcelino Avilés-Trigueros 3 Consuelo Pérez-Rico 4 Ana Serrano-Puebla 5 Patricia Boya 5 Eduardo Fernández 2 Manuel Vidal-Sanz 3 Pedro de la Villa 6
Affiliations

Affiliations

  • 1 Department of Surgery, Medical and Social Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain. Electronic address: roman.blanco@uah.es.
  • 2 Institute of Bioengineering, Miguel Hernandez University, Elche, Alicante, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain.
  • 3 Department of Ophthalmology, University of Murcia and Murcia Institute of Biosanitary Research Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
  • 4 Department of Surgery, Medical and Social Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain; Department of Ophthalmology, Principe de Asturias University Hospital, Alcalá de Henares, Madrid, Spain.
  • 5 Department of Cellular and Molecular Biology, Biological Research Center, CSIC, Madrid, Spain.
  • 6 Department of Systems Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain.
Abstract

We investigated the feasibility and efficacy of using a specific sphingosine 1-phosphate (S1P1) receptor agonist, CYM-5442, to slow or block retinal ganglion cell (RGC) loss in endothelin-1 (ET-1) induced RGC loss. A single intravitreal injection of ET-1 (20pmol/ul), a potent vasoactive peptide that produces retinal vessels vasoconstriction, was used to induce and characterize RGC-specific cell death. CYM-5442 (1 mgr/kg) or vehicle was administered intraperitoneally for five consecutive days after ET-1-induced RGC loss. The functional extent of RGC loss injury was evaluated with pattern visual evoked potentials (VEP) and electroretinography. RGCs and retinal nerve fiber layer (RNFL) thickness were assessed in vivo using optical coherence tomography and ex vivo using Brn3a immunohistochemistry in flat-mounted retinas. ET-1 caused significant RGC loss and function loss one week after intravitreal injection. VEP showed preserved visual function after CYM-5442 administration compared to vehicle-treated Animals (11.95 ± 0.86 μV vs 3.47 ± 1.20 μV, n = 12) (p < 0.05). RNFL was significantly thicker in the CYM treated-animals compared to the vehicle (93.62 ± 3.22 μm vs 77.72 ± 0.35 μm, n = 12) (p < 0.05). Furthermore, Brn3a immunohistochemistry validated this observation, showing significantly higher RGCs numbers in CYM treated rats than in the vehicle group (76,540 ± 303 vs 52,426 ± 1,932 cells/retina, n = 9) (p = 0.05). CYM-5442 administration was associated with significant retinal cleaved Caspase-3 deactivation, indicating reduced apoptotic levels. The results of the present study further demonstrate the important role of S1P1 receptor agonists to lessen intravitreal ET-1 induced RGC loss.

Keywords

CYM-5442; Neuroprotection; Retinal ganglion cells; S1P1 receptor agonists.

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