A Polytherapy Intervention in an Experimental Traumatic Optic Neuropathy Mouse Model
David T Tse1, Hua Wang1, Wensi Tao2
1Department of Ophthalmology, Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, U.S.A.
Purpose:
To test a novel early polytherapy treatment strategy targeting mitochondrial bioenergetics, glutamate excitotoxicity, and sterile inflammatory response molecular pathways associated with retinal ganglion cell survival following optic nerve trauma.
Methods:
Twenty C57BL/6J mice were subjected to sonication-induced traumatic optic neuropathy injury. The control group (n = 10) received intravitreal, retrobulbar, and subcutaneous phosphate buffered saline injections on days 0 and 3 (no repeat retrobulbar vehicle). On day 0, the treatment group (n = 10) received injections of intravitreal interleukin-1 receptor antagonist with ketamine, retrobulbar ropivacaine, and subcutaneous etanercept. Treatment group animals had 1% (wt/vol) N-acetylcysteine ad libitum supplemented in drinking water from day 1. On day 3, intravitreal pan-ephrin receptor antagonist peptide and subcutaneous elamipretide and etanercept injections were given. Pattern electroretinogram assessments continued at weeks 0, 1, 2, 4, 6, 8, 10, and 12. Optical coherence tomography retinal layer thickness was measured on naive, control, and treatment groups at week 12. The whole mount retinas were harvested for retinal ganglion cell quantitation.
Results:
At 12 weeks, the averaged retinal ganglion cell density count in the control group was lower (413.37 ± 41.77 cells/mm 2 ) compared with treatment (553.97 ± 18.00 cells/mm 2 ; p < 0.001) and naive (595.94 ± 30.67cells/mm 2 ; p < 0.001) groups. Ganglion cell complex layer thicknesses showed control group (49.29 ± 5.48 μm) thinner than the treated (61.00 ± 2.57 μm; p = 0.004) and naive (67.00 ± 6.12 μm; p = 0.004) groups. No significant difference was seen at 12 weeks between the treated and naive groups. Pattern electroretinogram recordings in the control group revealed a statistically significant decrease in amplitudes for all time points. Apart from week 8, the amplitudes in the treatment group did not significantly differ from the baseline at any time point.
Conclusions:
Early combinatorial therapeutic intervention to address disparate molecular pathways following optic nerve trauma effectively halts retinal neurons' progressive structural and functional degeneration.
Insights
A novel polytherapy treatment targeting mitochondrial, excitotoxicity, and inflammatory pathways successfully protected retinal ganglion cells after optic nerve trauma. This approach preserved cell density and function, offering hope for vision recovery.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Optic nerve trauma leads to progressive retinal ganglion cell (RGC) loss.
- Current treatments lack efficacy in halting RGC degeneration post-injury.
- Understanding the molecular pathways involved is crucial for developing effective interventions.
Purpose of the Study:
- To evaluate a novel polytherapy strategy for RGC survival after optic nerve trauma.
- The strategy targets mitochondrial bioenergetics, glutamate excitotoxicity, and sterile inflammation.
- Investigate the impact on structural and functional RGC integrity.
Main Methods:
- Mice with sonication-induced traumatic optic neuropathy received a combination therapy including anti-inflammatory agents, NMDA receptor antagonists, and mitochondrial enhancers.
- Treatment involved intravitreal, retrobulbar, and subcutaneous injections, plus oral N-acetylcysteine.
- Functional (pattern electroretinogram) and structural (OCT, RGC counts) assessments were performed over 12 weeks.
Main Results:
- The treatment group showed significantly higher RGC density and retinal layer thickness compared to the control group at 12 weeks.
- Functional assessments revealed preserved electroretinogram amplitudes in the treatment group, unlike the control group.
- Treated eyes showed no significant difference in RGC density or thickness compared to naive eyes.
Conclusions:
- Early combinatorial therapy effectively halts progressive structural and functional degeneration of retinal neurons following optic nerve trauma.
- The polytherapy approach addresses multiple molecular pathways critical for RGC survival.
- This strategy holds promise for preserving vision after optic nerve injury.
