Suppression of cGMP-Dependent Photoreceptor Cytotoxicity With Mycophenolate Is Neuroprotective in Murine Models of Retinitis Pigmentosa.

Abstract

Purpose:

To determine the effect of mycophenolate mofetil (MMF) on retinal degeneration on two mouse models of retinitis pigmentosa.

Methods:

Intraperitoneal injections of MMF were administered daily in rd10 and c57 mice starting at postoperative day 12 (P12) and rd1 mice starting at P8. The effect of MMF was assessed with optical coherence tomography, immunohistochemistry, electroretinography, and OptoMotry. Whole retinal cyclic guanosine monophosphate (cGMP) and mycophenolic acid levels were quantified with mass spectrometry. Photoreceptor cGMP cytotoxicity was evaluated with cell counts of cGMP immunostaining.

Results:

MMF treatment significantly delays the onset of retinal degeneration and cGMP-dependent photoreceptor cytotoxicity in rd10 and rd1 mice, albeit a more modest effect in the latter. In rd10 mice, treatment with MMF showed robust preservation of the photoreceptors up to P22 with associated suppression of cGMP immunostaining and microglial activation; The neuroprotective effect diminished after P22, but outer retinal thickness was still significantly thicker by P35 and OptoMotry response was significantly better up to P60. Whereas cGMP immunostaining of the photoreceptors were present in rd10 and rd1 mice, hyperphysiological whole retinal cGMP levels were observed only in rd1 mice.

Conclusions:

Early treatment with MMF confers potent neuroprotection in two animal models of RP by suppressing the cGMP-dependent common pathway for photoreceptor cell death. The neuroprotective effect of MMF on cGMP-dependent cytotoxicity occurs independently of the presence of hyperphysiological whole retinal cGMP levels. Thus our data suggest that MMF may be an important new class of neuroprotective agent that could be useful in the treatment of patients with RP.

• Authors: Paul Yang, Rachel Lockard, Hope Titus, Jordan Hiblar, Kyle Weller, Dahlia Wafai, Richard G Weleber, Robert M Duvoisin, Catherine W Morgans, Mark E Pennesi
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 61 Issue 10 Pg. 25 (08 03 2020) ISSN: 1552-5783 [Electronic] United States
• PMID: 32785677 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• Cyclic GMP
• Mycophenolic Acid

Topics

• Animals
• Cyclic GMP (metabolism)
• Disease Models, Animal
• Electroretinography
• Mass Spectrometry
• Mice
• Mice, Inbred C57BL
• Mycophenolic Acid (therapeutic use)
• Neuroprotective Agents (therapeutic use)
• Photoreceptor Cells, Vertebrate (drug effects)
• Retina (diagnostic imaging, enzymology, pathology)
• Retinitis Pigmentosa (diagnostic imaging, drug therapy, pathology, prevention & control)
• Tomography, Optical Coherence