Comparison of Neuroprotective Effects of Monomethylfumarate to the Sigma 1 Receptor Ligand (+)-Pentazocine in a Murine Model of Retinitis Pigmentosa

Investigative Ophthalmology & Visual Science
Haiyan XiaoS B Smith

Abstract

Activating the cell survival modulator sigma 1 receptor (Sig1R) delays cone photoreceptor cell loss in Pde6βrd10/J (rd10) mice, a model of retinitis pigmentosa. Beneficial effects are abrogated in rd10 mice lacking NRF2, implicating NRF2 as essential to Sig1R-mediated cone neuroprotection. Here we asked whether activation of NRF2 alone is sufficient to rescue cones in rd10 mice. Expression of antioxidant genes was evaluated in 661W cells and in mouse retinas after treatment with monomethylfumarate (MMF), a potent NRF2 activator. Rd10 mice were administered MMF (50 mg/kg) or the Sig1R ligand (+)-pentazocine (PTZ; 0.5 mg/kg) intraperitoneally (every other day, P14-42). Mice were evaluated for visual acuity (optokinetic tracking response), retinal function (electroretinography) and architecture (SD-OCT); histologic retinal sections were evaluated morphometrically. MMF treatment increased Nrf2, Nqo1, Cat, Sod1, and Hmox1 expression in vitro and in vivo. Visual acuity of (+)-PTZ-treated rd10 mice was similar to wild-type mice; however, MMF treatment did not alter acuity compared with nontreated rd10 mice. Cone electroretinography b-wave amplitudes were greater in PTZ-treated than nontreated or MMF-treated rd10 mice. SD-OCT assessmen...Continue Reading

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Citations

Nov 3, 2020·Investigative Ophthalmology & Visual Science·Jing WangSylvia B Smith
Feb 16, 2021·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Sebastiano IntagliataChristopher R McCurdy
Jun 22, 2021·Journal of Diabetes Research·Shani PillarAndrzej Grzybowski

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Methods Mentioned

BETA
carbonylation
PCR
light microscopy

Software Mentioned

Igor Pro
GraphPad Prism
OCT
OptoMotry
Zeiss Zen23pro
InVivoVue Diver

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