June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Longitudinal Imaging Reveals Patterns of Neurodegenerative Inflammation in Rotenone-Induced Retinal Neurotoxicity
Author Affiliations & Notes
  • Jonathan David Luisi
    Internal Medicine and Pharmacology and Toxicology, The University of Texas Medical Branch at Galveston, The University of Texas Medical Branch at Galveston, Galveston, TX, US, academic/health, Galveston, Texas, United States
    Opthalmology and Visual Science, The University of Texas Medical Branch at Galveston, The University of Texas Medical Branch at Galveston, Galveston, TX, US, academic/health, Galveston, Texas, United States
  • Wenbo Zhang
    Opthalmology and Visual Science, The University of Texas Medical Branch at Galveston, The University of Texas Medical Branch at Galveston, Galveston, TX, US, academic/health, Galveston, Texas, United States
  • Massoud Motamedi
    Opthalmology and Visual Science, The University of Texas Medical Branch at Galveston, The University of Texas Medical Branch at Galveston, Galveston, TX, US, academic/health, Galveston, Texas, United States
  • Bill T Ameredes
    Internal Medicine and Pharmacology and Toxicology, The University of Texas Medical Branch at Galveston, The University of Texas Medical Branch at Galveston, Galveston, TX, US, academic/health, Galveston, Texas, United States
  • Footnotes
    Commercial Relationships   Jonathan Luisi None; Wenbo Zhang None; Massoud Motamedi None; Bill Ameredes None
  • Footnotes
    Support  NIEHS T32ES007254
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 691 – F0145. doi:
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    • Get Citation

      Jonathan David Luisi, Wenbo Zhang, Massoud Motamedi, Bill T Ameredes; Longitudinal Imaging Reveals Patterns of Neurodegenerative Inflammation in Rotenone-Induced Retinal Neurotoxicity. Invest. Ophthalmol. Vis. Sci. 2022;63(7):691 – F0145.

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

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Abstract

Purpose : Rotenone is a mitochondrial toxicant known to induce neurodegeneration, however, the neuroinflammatory progression has not yet been clearly characterized. As resident immune cells of the central nervous system, microglia are known to enhance the neurotoxicity of rotenone. We postulated that non-invasive imaging of the retina can reveal neurotoxic effects intravitreal injection of rotenone and correlate the phases of the neuroinflammatory progression.

Methods : We monitored the spatial and temporal changes in retina inflammation and neurotoxicity following direct exposure to rotenone by intravitreal injection, by combining imaging techniques including optical coherence tomography (OCT) and confocal scanning-laser funduscopic (cSLO). To visualize microglia activation, we used Cx3Cr1eGFP transgenic mice in which macrophages express green fluorescent protein. Accordingly, we utilized a non-invasive imaging protocol to assess neurotoxicity longitudinally, without an invasive biopsy (Fig1). The OCT images were processed to characterize and quantify rotenone-induced changes in retinal morphology.

Results : We found that a 0.3µL of a 10mM concentration of rotenone caused retinal thinning and neurodegeneration, during the late phase of inflammation. Retinal thinning at day 7 correlated to the first appearance of hyper-florescent puncta in the photoreceptor layer. Furthermore, the puncta proliferated at day 14, indicating lipid peroxidation. The Cx3Cr1 microglia, at day 7 post treatment (Fig 2), were aligned with the nerve fiber tracts (arrow). Before 7 days, microglia activation in the inner portion of retina was not detected. Based on the OCT findings, neurodegeneration was 7-14 days post-injury, and photoreceptor loss was not evident until day 14.

Conclusions : These studies showed a predominantly M1 verses M2 microglia phenotype at 7 days, suggesting transition into chronic inflammation rather than a resolving phase. These studies also indicated that a low dose of rotenone can facilitate development of a neurodegenerative pathology over time, and that the late phase M1 microglia activation may be the driving force of the delayed response and subsequent neurodegeneration. Furthermore, we believe that the non-invasive imaging used in the current study provides a novel approach for characterizing the inflammatory progression of neurotoxicity.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Fig 1 Fundus Imaging

Fig 1 Fundus Imaging

 

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