Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis
The identification of a drug that stimulates endogenous myelination and spares axon degeneration during multiple sclerosis (MS) could potentially reduce the rate of disease progression. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we have previously shown that prophyla...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-08-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996113001198 |
| _version_ | 1818611088031219712 |
|---|---|
| author | Shalini Kumar Rhusheet Patel Spencer Moore Daniel K. Crawford Nirut Suwanna Mario Mangiardi Seema K. Tiwari-Woodruff |
| author_facet | Shalini Kumar Rhusheet Patel Spencer Moore Daniel K. Crawford Nirut Suwanna Mario Mangiardi Seema K. Tiwari-Woodruff |
| author_sort | Shalini Kumar |
| collection | DOAJ |
| description | The identification of a drug that stimulates endogenous myelination and spares axon degeneration during multiple sclerosis (MS) could potentially reduce the rate of disease progression. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we have previously shown that prophylactic administration of the estrogen receptor (ER) β ligand 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) decreases clinical disease, is neuroprotective, stimulates endogenous myelination, and improves axon conduction without altering peripheral cytokine production or reducing central nervous system (CNS) inflammation. Here, we assessed the effects of therapeutic DPN treatment during peak EAE disease, which represents a more clinically relevant treatment paradigm. In addition, we investigated the mechanism of action of DPN treatment-induced recovery during EAE. Given that prophylactic and therapeutic treatments with DPN during EAE improved remyelination-induced axon conduction, and that ER (α and β) and membrane (m)ERs are present on oligodendrocyte lineage cells, a direct effect of treatment on oligodendrocytes is likely. DPN treatment of EAE animals resulted in phosphorylated ERβ and activated the phosphatidylinositol 3-kinase (PI3K)/serine–threonine-specific protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, a pathway required for oligodendrocyte survival and axon myelination. These results, along with our previous studies of prophylactic DPN treatment, make DPN and similar ERβ ligands immediate and favorable therapeutic candidates for demyelinating disease. |
| first_indexed | 2024-12-16T15:24:46Z |
| format | Article |
| id | doaj.art-c213691ececc4fc8acbfaebd2dd492e8 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T15:24:46Z |
| publishDate | 2013-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-c213691ececc4fc8acbfaebd2dd492e82022-12-21T22:26:32ZengElsevierNeurobiology of Disease1095-953X2013-08-0156131144Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosisShalini Kumar0Rhusheet Patel1Spencer Moore2Daniel K. Crawford3Nirut Suwanna4Mario Mangiardi5Seema K. Tiwari-Woodruff6Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience, UCLA School of Medicine, Los Angeles, CA 90095, USAMultiple Sclerosis Program, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USAMultiple Sclerosis Program, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USAMultiple Sclerosis Program, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USAIntellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience, UCLA School of Medicine, Los Angeles, CA 90095, USAMultiple Sclerosis Program, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USAMultiple Sclerosis Program, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USA; Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA; Corresponding author at: Multiple Sclerosis Program at UCLA, Department of Neurology, UCLA School of Medicine, Neuroscience Research Building 1, 475C, 635 Charles E Young Drive, Los Angeles, CA 90095-1769, USA. Fax: +1 310 206 7282.The identification of a drug that stimulates endogenous myelination and spares axon degeneration during multiple sclerosis (MS) could potentially reduce the rate of disease progression. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we have previously shown that prophylactic administration of the estrogen receptor (ER) β ligand 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) decreases clinical disease, is neuroprotective, stimulates endogenous myelination, and improves axon conduction without altering peripheral cytokine production or reducing central nervous system (CNS) inflammation. Here, we assessed the effects of therapeutic DPN treatment during peak EAE disease, which represents a more clinically relevant treatment paradigm. In addition, we investigated the mechanism of action of DPN treatment-induced recovery during EAE. Given that prophylactic and therapeutic treatments with DPN during EAE improved remyelination-induced axon conduction, and that ER (α and β) and membrane (m)ERs are present on oligodendrocyte lineage cells, a direct effect of treatment on oligodendrocytes is likely. DPN treatment of EAE animals resulted in phosphorylated ERβ and activated the phosphatidylinositol 3-kinase (PI3K)/serine–threonine-specific protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, a pathway required for oligodendrocyte survival and axon myelination. These results, along with our previous studies of prophylactic DPN treatment, make DPN and similar ERβ ligands immediate and favorable therapeutic candidates for demyelinating disease.http://www.sciencedirect.com/science/article/pii/S0969996113001198Multiple sclerosisExperimental autoimmune encephalomyelitisNeuroprotective drugRemyelinationDemyelinationEstrogen receptor ligands |
| spellingShingle | Shalini Kumar Rhusheet Patel Spencer Moore Daniel K. Crawford Nirut Suwanna Mario Mangiardi Seema K. Tiwari-Woodruff Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis Neurobiology of Disease Multiple sclerosis Experimental autoimmune encephalomyelitis Neuroprotective drug Remyelination Demyelination Estrogen receptor ligands |
| title | Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis |
| title_full | Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis |
| title_fullStr | Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis |
| title_full_unstemmed | Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis |
| title_short | Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis |
| title_sort | estrogen receptor β ligand therapy activates pi3k akt mtor signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis |
| topic | Multiple sclerosis Experimental autoimmune encephalomyelitis Neuroprotective drug Remyelination Demyelination Estrogen receptor ligands |
| url | http://www.sciencedirect.com/science/article/pii/S0969996113001198 |
| work_keys_str_mv | AT shalinikumar estrogenreceptorbligandtherapyactivatespi3kaktmtorsignalinginoligodendrocytesandpromotesremyelinationinamousemodelofmultiplesclerosis AT rhusheetpatel estrogenreceptorbligandtherapyactivatespi3kaktmtorsignalinginoligodendrocytesandpromotesremyelinationinamousemodelofmultiplesclerosis AT spencermoore estrogenreceptorbligandtherapyactivatespi3kaktmtorsignalinginoligodendrocytesandpromotesremyelinationinamousemodelofmultiplesclerosis AT danielkcrawford estrogenreceptorbligandtherapyactivatespi3kaktmtorsignalinginoligodendrocytesandpromotesremyelinationinamousemodelofmultiplesclerosis AT nirutsuwanna estrogenreceptorbligandtherapyactivatespi3kaktmtorsignalinginoligodendrocytesandpromotesremyelinationinamousemodelofmultiplesclerosis AT mariomangiardi estrogenreceptorbligandtherapyactivatespi3kaktmtorsignalinginoligodendrocytesandpromotesremyelinationinamousemodelofmultiplesclerosis AT seemaktiwariwoodruff estrogenreceptorbligandtherapyactivatespi3kaktmtorsignalinginoligodendrocytesandpromotesremyelinationinamousemodelofmultiplesclerosis |