Tags

Type your tag names separated by a space and hit enter

Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis.
Neurobiol Dis 2013; 56:131-44ND

Abstract

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.

Authors+Show Affiliations

Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience, UCLA School of Medicine, Los Angeles, CA 90095, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23603111

Citation

Kumar, Shalini, et al. "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, vol. 56, 2013, pp. 131-44.
Kumar S, Patel R, Moore S, et al. Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiol Dis. 2013;56:131-44.
Kumar, S., Patel, R., Moore, S., Crawford, D. K., Suwanna, N., Mangiardi, M., & Tiwari-Woodruff, S. K. (2013). 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, 56, pp. 131-44. doi:10.1016/j.nbd.2013.04.005.
Kumar S, et al. Estrogen Receptor Β Ligand Therapy Activates PI3K/Akt/mTOR Signaling in Oligodendrocytes and Promotes Remyelination in a Mouse Model of Multiple Sclerosis. Neurobiol Dis. 2013;56:131-44. PubMed PMID: 23603111.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. AU - Kumar,Shalini, AU - Patel,Rhusheet, AU - Moore,Spencer, AU - Crawford,Daniel K, AU - Suwanna,Nirut, AU - Mangiardi,Mario, AU - Tiwari-Woodruff,Seema K, Y1 - 2013/04/17/ PY - 2013/01/02/received PY - 2013/03/28/revised PY - 2013/04/09/accepted PY - 2013/4/23/entrez PY - 2013/4/23/pubmed PY - 2014/1/11/medline SP - 131 EP - 44 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 56 N2 - 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. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/23603111/Estrogen_receptor_β_ligand_therapy_activates_PI3K/Akt/mTOR_signaling_in_oligodendrocytes_and_promotes_remyelination_in_a_mouse_model_of_multiple_sclerosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(13)00119-8 DB - PRIME DP - Unbound Medicine ER -