June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
A reproducible and efficient rat model for glaucoma neuroprotection studies
Author Affiliations & Notes
  • Katie Dolan
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Chuanxi Xiang
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Nhi Vo
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Joanna Vrouvlianis
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Erika Lima
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Nalini V Rangaswamy
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Amy Chen
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Chad E Bigelow
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Ganesh Prasanna
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Katie Dolan Novartis, Code E (Employment); Chuanxi Xiang Novartis, Code E (Employment); Nhi Vo Novartis, Code E (Employment); Joanna Vrouvlianis Novartis, Code E (Employment); Erika Lima Novartis, Code E (Employment); Nalini Rangaswamy Novartis, Code E (Employment); Amy Chen Novartis, Code E (Employment); Chad Bigelow Novartis, Code E (Employment); Ganesh Prasanna Novartis, Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4741. doi:
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      Katie Dolan, Chuanxi Xiang, Nhi Vo, Joanna Vrouvlianis, Erika Lima, Nalini V Rangaswamy, Amy Chen, Chad E Bigelow, Ganesh Prasanna; A reproducible and efficient rat model for glaucoma neuroprotection studies. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4741.

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

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Abstract

Purpose : To develop a reproducible, efficient and relevant rat model of glaucoma using hyaluronic acid glycidyl methacrylate (HAGM) polymerization in the anterior segment. Glaucoma is a devastating optic neuropathy associated with elevated IOP, progressive optic nerve degeneration, retinal ganglion cell (RGC) death and blindness. A model recapitulating key aspects of glaucoma pathophysiology is critical for understanding pathogenic disease mechanisms.

Methods : We previously developed a mouse hypertensive model of glaucoma by rapid photopolymerization of HAGM in the anterior segment to induce chronic IOP elevation, reducing duration and variability compared to current models (PMID: 29949582). By adapting this approach, we developed an efficient rat glaucoma model. Here, 8µl of 1.8% HAGM was used to induce ocular hypertension for 7 days. IOP was measured with a rebound tonometer following 8 minutes of isoflurane anesthesia. Positive scotopic threshold response (pSTR) measurements were acquired on anesthetized rats after overnight dark adaptation and analyzed using custom scripts in MATLAB. Retinal flat mounts and optic nerve cross sections were quantified with custom algorithms in CellProfiler.

Results : The rat glaucoma model displayed significant, sustained IOP elevation ~2-fold over baseline following injection of 1.8% HAGM ultraviolet A (UVA) cross-linked (xl) (48.9±9.4 mmHg versus 23.0±4.9 mmHg, P<0.0001). After 7 days, 1.8% HAGM xl induced significant reduction of mean RGC density (39.2±4.0%, P<0.0001), total axons (32.9±4.3%, P<0.0001) and RGC function (pSTR, ~72%, -4.0 log (cd s) m−2) compared to HAGM monomer. Further, 1.8% HAGM xl induced significant thinning of the ganglion cell complex (GCC) relative to baseline (17.40±3.1%, P=0.0013). In contrast, 1.1% HAGM xl, HAGM monomer or PBS+UVA treatment controls did not induce significant IOP elevation, RGC or axon loss compared to naive controls, or GCC thinning compared to baseline. Gene expression analysis showed 1.8% HAGM xl reduced neuronal markers and elevated inflammation.

Conclusions : This rat model displays key aspects of glaucoma pathophysiology in human patients including GCC thinning, RGC/axon loss and gene expression changes in RGC, axon and inflammation markers. The model offers an efficient, reproducible and robust neurodegeneration window, making it a useful tool for investigating RGC degeneration and preclinical testing of glaucoma neuroprotective therapies.

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

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