Spermine oxidase inhibitor, MDL 72527, reduced neovascularization, vascular permeability, and acrolein-conjugated proteins in a mouse model of ischemic retinopathy

ABSTRACT

Disruptions in polyamine metabolism have been identified as contributing factors to various central nervous system disorders. Our laboratory has previously highlighted the crucial role of polyamine oxidation in retinal disease models, specifically noting elevated levels of spermine oxidase (SMOX) in inner retinal neurons. Our prior research demonstrated that inhibiting SMOX with MDL 72527 protected against vascular injury and microglial activation induced by hyperoxia in the retina. However, the effects of SMOX inhibition on retinal neovascularization and vascular permeability, along with the underlying molecular mechanisms of vascular protection, remain incompletely understood. In this study, we utilized the oxygen-induced retinopathy (OIR) model to explore the impact of SMOX inhibition on retinal neovascularization, vascular permeability, and the molecular mechanisms underlying MDL 72527-mediated vasoprotection in the OIR retina. Our findings indicate that inhibiting SMOX with MDL 72527 mitigated vaso-obliteration and neovascularization in the OIR retina. Additionally, it reduced OIR-induced vascular permeability and Claudin-5 expression, suppressed acrolein-conjugated protein levels, and downregulated P38/ERK1/2/STAT3 signaling. Furthermore, our results revealed that treatment with BSA-Acrolein conjugates significantly decreased the viability of human retinal endothelial cells (HRECs) and activated P38 signaling. These observations contribute valuable insights into the potential therapeutic benefits of SMOX inhibition by MDL 72527 in ischemic retinopathy.

KEYWORDS:

• Acrolein
• ischemic retinopathy
• MDL 72527
• spermine oxidase
• vascular damage
• vision

Acknowledgments

The study has been accomplished partially using the resources and facilities at the Charlie Norwood VA Medical Center, Augusta, GA, and a core grant from the National Eye Institute (NEI) to the Augusta University Vision Discovery Institute (P30EY031631). The contents of this study do not represent the views of the Department of Veterans Affairs or the United States Government. The funders have no role in the study design, data collection and analysis, and decision to publish the data. The authors thank support from the Electron microscopy and histology core, Augusta University for their help in tissue sectioning and Dr. Moaddey Alfarhan for his technical assistance in this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Conception and design: AA, FL, PRS, and SPN; Data production, analysis, and interpretation: AA, FL, SS, EJ, NN, PRS, and SPN; writing the manuscript: AA, FL, SS, and SPN. All authors reviewed the manuscript.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21688370.2024.2347070

Additional information

Funding

This work was funded by the University of Georgia College of Pharmacy intramural funds and the National Institutes of Health grant [R01EY028569 to SPN]. This research was also supported by the National Center for Advancing Translational Sciences (NCATS) grant [UL1TR002378 to PRS].