Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis
Abstract Evidence that myelin repair is crucial for functional recovery in multiple sclerosis (MS) led to the identification of bexarotene (BXT). This clinically promising remyelinating agent activates multiple nuclear hormone receptor subtypes implicated in myelin repair. However, BXT produces unac...
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BMC
2024-12-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01904-x |
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| author | Gracious D. S. Kasheke Basmah A. M. Hendy Gabriel G. Dorighello Nonthué A. Uccelli Jean-David M. Gothié Robyn J. Novorolsky Madison J. Oulton Jude Asainayagam Adam I. Makarov Kaitlyn S. Fraser Vidyasagar Vuligonda Martin E. Sanders Timothy E. Kennedy George S. Robertson |
| author_facet | Gracious D. S. Kasheke Basmah A. M. Hendy Gabriel G. Dorighello Nonthué A. Uccelli Jean-David M. Gothié Robyn J. Novorolsky Madison J. Oulton Jude Asainayagam Adam I. Makarov Kaitlyn S. Fraser Vidyasagar Vuligonda Martin E. Sanders Timothy E. Kennedy George S. Robertson |
| author_sort | Gracious D. S. Kasheke |
| collection | DOAJ |
| description | Abstract Evidence that myelin repair is crucial for functional recovery in multiple sclerosis (MS) led to the identification of bexarotene (BXT). This clinically promising remyelinating agent activates multiple nuclear hormone receptor subtypes implicated in myelin repair. However, BXT produces unacceptable hyperlipidemia. In contrast, IRX4204 selectively activates the retinoid X receptor (RXR). Given compelling links between RXR activation and increased myelin repair, we employed IRX4204 to investigate the impact of RXR agonism alone on functional recovery in mice subjected to experimental autoimmune encephalomyelitis (EAE). Since gait deficits are common in MS, we used machine learning to obtain highly sensitive and reliable measurements of sagittal hindleg joint movements for mice walking on a treadmill. IRX4204 not only blocked the progressive loss of knee and ankle movements but also reversed joint movement impairments in EAE mice. Our biochemical, transcriptional and histological measurements in spinal cord suggest these gait improvements reflect increased axon survival and remyelination and reduced inflammation. Using microglia, astrocytes and oligodendrocyte progenitor cells, we present additional data suggesting that IRX4204 may act on multiple glial subtypes to orchestrate myelin repair. These results inform the discovery of restorative neural therapeutics for MS by demonstrating that selective RXR agonism is sufficient for effective myelin repair. Moreover, our findings support the therapeutic potential of IRX4204 to promote functional recovery in MS. |
| format | Article |
| id | doaj-art-4613b5f10b8d427eaf9bd3550eb4ae54 |
| institution | OA Journals |
| issn | 2051-5960 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-4613b5f10b8d427eaf9bd3550eb4ae542025-08-20T01:57:14ZengBMCActa Neuropathologica Communications2051-59602024-12-0112111810.1186/s40478-024-01904-xSelective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitisGracious D. S. Kasheke0Basmah A. M. Hendy1Gabriel G. Dorighello2Nonthué A. Uccelli3Jean-David M. Gothié4Robyn J. Novorolsky5Madison J. Oulton6Jude Asainayagam7Adam I. Makarov8Kaitlyn S. Fraser9Vidyasagar Vuligonda10Martin E. Sanders11Timothy E. Kennedy12George S. Robertson13Department of Pharmacology, Faculty of Medicine, Dalhousie UniversityBrain Repair Centre, Life Sciences Research Institute, Dalhousie UniversityDepartment of Pharmacology, Faculty of Medicine, Dalhousie UniversityDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityDepartment of Pharmacology, Faculty of Medicine, Dalhousie UniversityDepartment of Pharmacology, Faculty of Medicine, Dalhousie UniversityDepartment of Pharmacology, Faculty of Medicine, Dalhousie UniversityDepartment of Pharmacology, Faculty of Medicine, Dalhousie UniversityBrain Repair Centre, Life Sciences Research Institute, Dalhousie UniversityIo Therapeutics, IncIo Therapeutics, IncDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityDepartment of Pharmacology, Faculty of Medicine, Dalhousie UniversityAbstract Evidence that myelin repair is crucial for functional recovery in multiple sclerosis (MS) led to the identification of bexarotene (BXT). This clinically promising remyelinating agent activates multiple nuclear hormone receptor subtypes implicated in myelin repair. However, BXT produces unacceptable hyperlipidemia. In contrast, IRX4204 selectively activates the retinoid X receptor (RXR). Given compelling links between RXR activation and increased myelin repair, we employed IRX4204 to investigate the impact of RXR agonism alone on functional recovery in mice subjected to experimental autoimmune encephalomyelitis (EAE). Since gait deficits are common in MS, we used machine learning to obtain highly sensitive and reliable measurements of sagittal hindleg joint movements for mice walking on a treadmill. IRX4204 not only blocked the progressive loss of knee and ankle movements but also reversed joint movement impairments in EAE mice. Our biochemical, transcriptional and histological measurements in spinal cord suggest these gait improvements reflect increased axon survival and remyelination and reduced inflammation. Using microglia, astrocytes and oligodendrocyte progenitor cells, we present additional data suggesting that IRX4204 may act on multiple glial subtypes to orchestrate myelin repair. These results inform the discovery of restorative neural therapeutics for MS by demonstrating that selective RXR agonism is sufficient for effective myelin repair. Moreover, our findings support the therapeutic potential of IRX4204 to promote functional recovery in MS.https://doi.org/10.1186/s40478-024-01904-xMultiple sclerosisNeural repairNeuroprotectionOligodendrocyte progenitor cellRehabilitation |
| spellingShingle | Gracious D. S. Kasheke Basmah A. M. Hendy Gabriel G. Dorighello Nonthué A. Uccelli Jean-David M. Gothié Robyn J. Novorolsky Madison J. Oulton Jude Asainayagam Adam I. Makarov Kaitlyn S. Fraser Vidyasagar Vuligonda Martin E. Sanders Timothy E. Kennedy George S. Robertson Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis Acta Neuropathologica Communications Multiple sclerosis Neural repair Neuroprotection Oligodendrocyte progenitor cell Rehabilitation |
| title | Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis |
| title_full | Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis |
| title_fullStr | Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis |
| title_full_unstemmed | Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis |
| title_short | Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis |
| title_sort | selective retinoid x receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis |
| topic | Multiple sclerosis Neural repair Neuroprotection Oligodendrocyte progenitor cell Rehabilitation |
| url | https://doi.org/10.1186/s40478-024-01904-x |
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