Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa
Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form of IRD, is characterized by gradual dysfunction and degeneration of rod photoreceptors, followed by the loss of cone photorecept...
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eLife Sciences Publications Ltd
2025-04-01
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| Online Access: | https://elifesciences.org/articles/103888 |
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| author | Hyun Beom Song Laura Campello Anupam Mondal Holly Y Chen Milton A English Michael Glen Phillip Vanlandingham Rafal Farjo Anand Swaroop |
| author_facet | Hyun Beom Song Laura Campello Anupam Mondal Holly Y Chen Milton A English Michael Glen Phillip Vanlandingham Rafal Farjo Anand Swaroop |
| author_sort | Hyun Beom Song |
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| description | Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form of IRD, is characterized by gradual dysfunction and degeneration of rod photoreceptors, followed by the loss of cone photoreceptors. Recently, we identified reserpine as a lead molecule for maintaining rod survival in mouse and human retinal organoids as well as in the rd16 mouse, which phenocopy Leber congenital amaurosis caused by mutations in the cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, we show the therapeutic potential of reserpine in a rhodopsin P23H rat model of autosomal dominant RP. At postnatal day (P) 68, when males and females are analyzed together, the reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to the controls with little or no change in scotopic a-wave or cone-derived photopic b-wave. Interestingly, the reserpine-treated female rats display enhanced scotopic a- and b-waves and photopic b-wave responses at P68, along with a better contrast threshold and increased outer nuclear layer thickness. The female rats demonstrate better preservation of both rod and cone photoreceptors following reserpine treatment. Retinal transcriptome analysis reveals sex-specific responses to reserpine, with significant upregulation of phototransduction genes and proteostasis-related pathways, and notably, genes associated with stress response. This study builds upon our previously reported results reaffirming the potential of reserpine for gene-agnostic treatment of IRDs and emphasizes the importance of biological sex in retinal disease research and therapy development. |
| format | Article |
| id | doaj-art-cd735c832fea4fe990b0dc3c98504768 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-cd735c832fea4fe990b0dc3c985047682025-08-20T02:12:38ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011410.7554/eLife.103888Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosaHyun Beom Song0https://orcid.org/0000-0002-3500-2984Laura Campello1https://orcid.org/0000-0002-0869-1315Anupam Mondal2https://orcid.org/0000-0002-3572-6392Holly Y Chen3https://orcid.org/0000-0001-8320-6714Milton A English4Michael Glen5Phillip Vanlandingham6https://orcid.org/0000-0003-1884-6525Rafal Farjo7Anand Swaroop8https://orcid.org/0000-0002-1975-1141Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, United States; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of KoreaNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, United StatesNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, United StatesNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, United StatesNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, United StatesNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, United StatesEyeCRO, Oklahoma City, United StatesEyeCRO, Oklahoma City, United StatesNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, United StatesInherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form of IRD, is characterized by gradual dysfunction and degeneration of rod photoreceptors, followed by the loss of cone photoreceptors. Recently, we identified reserpine as a lead molecule for maintaining rod survival in mouse and human retinal organoids as well as in the rd16 mouse, which phenocopy Leber congenital amaurosis caused by mutations in the cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, we show the therapeutic potential of reserpine in a rhodopsin P23H rat model of autosomal dominant RP. At postnatal day (P) 68, when males and females are analyzed together, the reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to the controls with little or no change in scotopic a-wave or cone-derived photopic b-wave. Interestingly, the reserpine-treated female rats display enhanced scotopic a- and b-waves and photopic b-wave responses at P68, along with a better contrast threshold and increased outer nuclear layer thickness. The female rats demonstrate better preservation of both rod and cone photoreceptors following reserpine treatment. Retinal transcriptome analysis reveals sex-specific responses to reserpine, with significant upregulation of phototransduction genes and proteostasis-related pathways, and notably, genes associated with stress response. This study builds upon our previously reported results reaffirming the potential of reserpine for gene-agnostic treatment of IRDs and emphasizes the importance of biological sex in retinal disease research and therapy development.https://elifesciences.org/articles/103888small molecule drugretinal degenerationneuroprotectionrhodopsin mutationretinitis pigmentosa |
| spellingShingle | Hyun Beom Song Laura Campello Anupam Mondal Holly Y Chen Milton A English Michael Glen Phillip Vanlandingham Rafal Farjo Anand Swaroop Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa eLife small molecule drug retinal degeneration neuroprotection rhodopsin mutation retinitis pigmentosa |
| title | Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa |
| title_full | Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa |
| title_fullStr | Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa |
| title_full_unstemmed | Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa |
| title_short | Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa |
| title_sort | sex specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin p23h rat model of autosomal dominant retinitis pigmentosa |
| topic | small molecule drug retinal degeneration neuroprotection rhodopsin mutation retinitis pigmentosa |
| url | https://elifesciences.org/articles/103888 |
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