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Published on: October 24, 2013
Rod Photoreceptor Neuroprotection in Dark-Reared Pde6brd10 Mice
Bruce A Berkowitz1, Robert H Podolsky2, Karen Lins Childers2
1Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States.
Purpose:
The purpose of this study was to test the hypothesis that anti-oxidant and / or anti-inflammation drugs that suppress rod death in cyclic light-reared Pde6brd10 mice are also effective in dark-reared Pde6brd10 mice.
Methods:
In untreated dark-reared Pde6brd10 mice at post-natal (P) days 23 to 24, we measured the outer nuclear layer (ONL) thickness (histology) and dark-light thickness difference in external limiting membrane-retinal pigment epithelium (ELM-RPE) (optical coherence tomography [OCT]), retina layer oxidative stress (QUEnch-assiSTed [QUEST] magnetic resonance imaging [MRI]); and microglia/macrophage-driven inflammation (immunohistology). In dark-reared P50 Pde6brd10 mice, ONL thickness was measured (OCT) in groups given normal chow or chow admixed with methylene blue (MB) + Norgestrel (anti-oxidant, anti-inflammatory), or MB or Norgestrel separately.
Results:
P24 Pde6brd10 mice showed no significant dark-light ELM-RPE response in superior and inferior retina consistent with high cGMP levels. Norgestrel did not significantly suppress the oxidative stress of Pde6brd10 mice that is only found in superior central outer retina of males at P23. Overt rod degeneration with microglia/macrophage activation was observed but only in the far peripheral superior retina in male and female P23 Pde6brd10 mice. Significant rod protection was measured in female P50 Pde6brd10 mice given 5 mg/kg/day MB + Norgestrel diet; no significant benefit was seen with MB chow or Norgestrel chow alone, nor in similarly treated male mice.
Conclusions:
In early rod degeneration in dark-reared Pde6brd10 mice, little evidence is found in central retina for spatial associations among biomarkers of the PDE6B mutation, oxidative stress, and rod death; neuroprotection at P50 was limited to a combination of anti-oxidant/anti-inflammation treatment in a sex-specific manner.
Insights
Antioxidant and anti-inflammatory drugs protected rod cells in dark-reared Pde6brd10 mice, but only in females when combined. This combination treatment showed sex-specific neuroprotection in early retinal degeneration.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- The Pde6brd10 mouse model exhibits retinal degeneration.
- Understanding factors influencing rod cell death is crucial for developing treatments.
- Previous studies suggest antioxidant and anti-inflammatory drugs may protect rod cells.
Purpose of the Study:
- To investigate if antioxidant/anti-inflammatory drugs that prevent rod death in light-reared Pde6brd10 mice are effective in dark-reared Pde6brd10 mice.
- To test the hypothesis of drug efficacy in a different environmental condition.
Main Methods:
- Assessed outer nuclear layer (ONL) thickness and retinal layer oxidative stress using histology, optical coherence tomography (OCT), and magnetic resonance imaging (MRI).
- Evaluated microglia/macrophage-driven inflammation via immunohistology.
- Administered diets with methylene blue (MB) + Norgestrel, MB alone, or Norgestrel alone to dark-reared Pde6brd10 mice at postnatal day 50.
Main Results:
- No significant dark-light response was observed in P24 mice, indicating high cGMP levels.
- Norgestrel did not significantly reduce oxidative stress in Pde6brd10 mice.
- Significant rod protection was observed in female P50 mice treated with MB + Norgestrel, but not with individual components or in male mice.
Conclusions:
- Early rod degeneration in dark-reared Pde6brd10 mice shows limited spatial association between mutation biomarkers, oxidative stress, and rod death in central retina.
- Neuroprotection at P50 was achieved through a combination of antioxidant/anti-inflammatory treatment, demonstrating a sex-specific effect.
