June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Novel cytoprotective small compound M109S protects the retinal photoreceptor from mitochondria-dependent apoptosis
Author Affiliations & Notes
  • Shigemi Matsuyama
    Ophthalmology and Visual Science, Case Western Reserve University, Cleveland, Ohio, United States
    Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States
  • Joseph T Ortega
    Pharmacology, Case Western Reserve University, Cleveland, Ohio, United States
  • Beata Jastrzebska
    Pharmacology, Case Western Reserve University, Cleveland, Ohio, United States
  • Mieko Matsuyama
    Ophthalmology and Visual Science, Case Western Reserve University, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Shigemi Matsuyama None; Joseph Ortega None; Beata Jastrzebska None; Mieko Matsuyama None
  • Footnotes
    Support  DOD W81XWH-20-1-0735
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2423. doi:
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    • Get Citation

      Shigemi Matsuyama, Joseph T Ortega, Beata Jastrzebska, Mieko Matsuyama; Novel cytoprotective small compound M109S protects the retinal photoreceptor from mitochondria-dependent apoptosis. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2423.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We developed M109S (Molecular Weight 375) that rescues cells from Bax-mediated mitochondria-dependent apoptosis. M109S passed various toxicity tests, including neurotoxicity tests. M109S is orally bioactive and penetrates the blood-brain/retina barrier. We investigated the mechanism of action of M109S. We also examined whether M109S can protect the retinal photoreceptor from bright light-induced cell death.

Methods : The binding affinity of M109S and Bax (purified recombinant protein) by using Microscale thermophoresis (MST) assay. The following apoptotic stimuli were examined to evaluate M109S's effects: ABT737 (1 uM, 24h or 48h, MEFs), staurosporine (STS) (1 uM, 2h, mouse embryonic fibroblasts (MEFs)), etoposide (25 uM, 24 h, Neuro2a) and obatoclax (100 nM, 24h, ARPE19). Abc4-/-Rdh8-/- and Balb/CJ mice were used to examine whether M109S can protect photoreceptors from bright light-induced death. M109S (2.5, 5.0, or 10 mg/kg/day by oral gavage) was administered to these mice at day -1, 0 (the day of the bright light exposure, 1 hr before the exposure), 1, and 2 (total 4 times). For the bright light exposure, mice were treated with 10,000 lux for 30 min (Abc4-/-Rdh8-/-) or 12,000 lux for 2 hrs (Balb/CJ). On day 7, the eyes were collected for analysis. ROS-Glo-H2O2 Assay kit (Promega G8820) was used to measure ROS of MEFs treated (4 hrs) with various concentrations of M109S.

Results : The binding affinity of M109S to purified recombinant Bax protein was 153.75+55.8 nM (n=4). In MEFs, M109S inhibited active conformational change of Bax and mitochondrial accumulation of Bax. Apoptosis induced by ABT737, STS, etoposide, and obatoclax was significantly inhibited by M109S (effective concentration was 50-200 nM). M109S showed a dose-dependent effect to protect the retina from bright light-induced photoreceptor death. M109S inhibited ROS generation of cultured MEFs. N-acetyl cysteine (10uM) and M109S (100nM) showed similar activity to suppress ROS levels.

Conclusions : These results suggest that M109S has at least two mechanisms of action to rescue cells from mitochondria-dependent cell death; the inhibition of Bax and ROS. M109S has the potential to become a new research tool for cell death mechanisms and to develop therapeutics for various degenerative diseases involving mitochondria-dependent cell death, including retinal degenerative disorders.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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