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.
N1 - Funding Information:
This work was generously supported by the NMSS grant RG 4538-A-2 and the NIH grant R21NS075198 to STW. We would like to thank Dr. Wendy Macklin and Dr. Terri Wood for helpful discussions and Ms. Anna Khalaj for manuscript editing. We would also like to thank the BRI core facility at UCLA for EM assistance and Sasol, North America for the generous gift of miglyol oil.
PY - 2013/8
Y1 - 2013/8
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.
AB - 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.
KW - Axon conduction
KW - Demyelination
KW - Estrogen receptor ligands
KW - Experimental autoimmune encephalomyelitis
KW - Multiple sclerosis
KW - Neuroprotective drug
KW - Oligodendrocytes
KW - Remyelination
KW - Second messenger signaling
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U2 - 10.1016/j.nbd.2013.04.005
DO - 10.1016/j.nbd.2013.04.005
M3 - Article
C2 - 23603111
AN - SCOPUS:84878119767
SN - 0969-9961
VL - 56
SP - 131
EP - 144
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -