The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis
Multiple sclerosis is a neurodegenerative disease associated with demyelination and neuroinflammation in the central nervous system. There is an urgent need to develop remyelinating therapies to better treat multiple sclerosis and other demyelinating diseases. The kappa opioid receptor (KOR) has bee...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2021.782190/full |
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| author | Kelly F. Paton Kelly F. Paton Katharina Robichon Katharina Robichon Nikki Templeton Nikki Templeton Lisa Denny Lisa Denny Afnan Al Abadey Afnan Al Abadey Dan Luo Thomas E. Prisinzano Anne C. La Flamme Anne C. La Flamme Anne C. La Flamme Bronwyn M. Kivell Bronwyn M. Kivell |
| author_facet | Kelly F. Paton Kelly F. Paton Katharina Robichon Katharina Robichon Nikki Templeton Nikki Templeton Lisa Denny Lisa Denny Afnan Al Abadey Afnan Al Abadey Dan Luo Thomas E. Prisinzano Anne C. La Flamme Anne C. La Flamme Anne C. La Flamme Bronwyn M. Kivell Bronwyn M. Kivell |
| author_sort | Kelly F. Paton |
| collection | DOAJ |
| description | Multiple sclerosis is a neurodegenerative disease associated with demyelination and neuroinflammation in the central nervous system. There is an urgent need to develop remyelinating therapies to better treat multiple sclerosis and other demyelinating diseases. The kappa opioid receptor (KOR) has been identified as a potential target for the development of remyelinating therapies; however, prototypical KOR agonists, such as U50,488 have side effects, which limit clinical use. In the current study, we investigated a Salvinorin A analog, ethoxymethyl ether Salvinorin B (EOM SalB) in two preclinical models of demyelination in C57BL/6J mice. We showed that in cellular assays EOM SalB was G-protein biased, an effect often correlated with fewer KOR-mediated side effects. In the experimental autoimmune encephalomyelitis model, we found that EOM SalB (0.1–0.3 mg/kg) effectively decreased disease severity in a KOR-dependent manner and led to a greater number of animals in recovery compared to U50,488 treatment. Furthermore, EOM SalB treatment decreased immune cell infiltration and increased myelin levels in the central nervous system. In the cuprizone-induced demyelination model, we showed that EOM SalB (0.3 mg/kg) administration led to an increase in the number of mature oligodendrocytes, the number of myelinated axons and the myelin thickness in the corpus callosum. Overall, EOM SalB was effective in two preclinical models of multiple sclerosis and demyelination, adding further evidence to show KOR agonists are a promising target for remyelinating therapies. |
| first_indexed | 2024-12-22T21:35:02Z |
| format | Article |
| id | doaj.art-39b6ddc719c14ca4983202a608459a81 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-22T21:35:02Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-39b6ddc719c14ca4983202a608459a812022-12-21T18:11:47ZengFrontiers Media S.A.Frontiers in Neurology1664-22952021-12-011210.3389/fneur.2021.782190782190The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple SclerosisKelly F. Paton0Kelly F. Paton1Katharina Robichon2Katharina Robichon3Nikki Templeton4Nikki Templeton5Lisa Denny6Lisa Denny7Afnan Al Abadey8Afnan Al Abadey9Dan Luo10Thomas E. Prisinzano11Anne C. La Flamme12Anne C. La Flamme13Anne C. La Flamme14Bronwyn M. Kivell15Bronwyn M. Kivell16School of Biological Sciences, Victoria University of Wellington, Wellington, New ZealandCentre for Biodiscovery, Victoria University of Wellington, Wellington, New ZealandSchool of Biological Sciences, Victoria University of Wellington, Wellington, New ZealandCentre for Biodiscovery, Victoria University of Wellington, Wellington, New ZealandSchool of Biological Sciences, Victoria University of Wellington, Wellington, New ZealandCentre for Biodiscovery, Victoria University of Wellington, Wellington, New ZealandSchool of Biological Sciences, Victoria University of Wellington, Wellington, New ZealandCentre for Biodiscovery, Victoria University of Wellington, Wellington, New ZealandSchool of Biological Sciences, Victoria University of Wellington, Wellington, New ZealandCentre for Biodiscovery, Victoria University of Wellington, Wellington, New ZealandDepartment of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United StatesDepartment of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United StatesSchool of Biological Sciences, Victoria University of Wellington, Wellington, New ZealandCentre for Biodiscovery, Victoria University of Wellington, Wellington, New ZealandMalaghan Institute of Medical Research, Wellington, New ZealandSchool of Biological Sciences, Victoria University of Wellington, Wellington, New ZealandCentre for Biodiscovery, Victoria University of Wellington, Wellington, New ZealandMultiple sclerosis is a neurodegenerative disease associated with demyelination and neuroinflammation in the central nervous system. There is an urgent need to develop remyelinating therapies to better treat multiple sclerosis and other demyelinating diseases. The kappa opioid receptor (KOR) has been identified as a potential target for the development of remyelinating therapies; however, prototypical KOR agonists, such as U50,488 have side effects, which limit clinical use. In the current study, we investigated a Salvinorin A analog, ethoxymethyl ether Salvinorin B (EOM SalB) in two preclinical models of demyelination in C57BL/6J mice. We showed that in cellular assays EOM SalB was G-protein biased, an effect often correlated with fewer KOR-mediated side effects. In the experimental autoimmune encephalomyelitis model, we found that EOM SalB (0.1–0.3 mg/kg) effectively decreased disease severity in a KOR-dependent manner and led to a greater number of animals in recovery compared to U50,488 treatment. Furthermore, EOM SalB treatment decreased immune cell infiltration and increased myelin levels in the central nervous system. In the cuprizone-induced demyelination model, we showed that EOM SalB (0.3 mg/kg) administration led to an increase in the number of mature oligodendrocytes, the number of myelinated axons and the myelin thickness in the corpus callosum. Overall, EOM SalB was effective in two preclinical models of multiple sclerosis and demyelination, adding further evidence to show KOR agonists are a promising target for remyelinating therapies.https://www.frontiersin.org/articles/10.3389/fneur.2021.782190/fullmultiple sclerosiskappa opioid receptorexperimental autoimmune encephalomyelitissalvinorin A analogremyelinationcuprizone-induced demyelination |
| spellingShingle | Kelly F. Paton Kelly F. Paton Katharina Robichon Katharina Robichon Nikki Templeton Nikki Templeton Lisa Denny Lisa Denny Afnan Al Abadey Afnan Al Abadey Dan Luo Thomas E. Prisinzano Anne C. La Flamme Anne C. La Flamme Anne C. La Flamme Bronwyn M. Kivell Bronwyn M. Kivell The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis Frontiers in Neurology multiple sclerosis kappa opioid receptor experimental autoimmune encephalomyelitis salvinorin A analog remyelination cuprizone-induced demyelination |
| title | The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis |
| title_full | The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis |
| title_fullStr | The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis |
| title_full_unstemmed | The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis |
| title_short | The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis |
| title_sort | salvinorin analogue ethoxymethyl ether salvinorin b promotes remyelination in preclinical models of multiple sclerosis |
| topic | multiple sclerosis kappa opioid receptor experimental autoimmune encephalomyelitis salvinorin A analog remyelination cuprizone-induced demyelination |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2021.782190/full |
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