The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation.
Acta Pharmacol Sin
; 45(3): 490-501, 2024 Mar.
Article
en En
| MEDLINE
| ID: mdl-37935896
ABSTRACT
Oligodendrocytes (OLs) are glial cells that ensheath neuronal axons and form myelin in the central nervous system (CNS). OLs are differentiated from oligodendrocyte precursor cells (OPCs) during development and myelin repair, which is often insufficient in the latter case in demyelinating diseases such as multiple sclerosis (MS). Many factors have been reported to regulate OPC-to-OL differentiation, including a number of G protein-coupled receptors (GPCRs). In an effort to search pathways downstream of GPCRs that might be involved in OPC differentiation, we discover that U73122, a phosphoinositide specific phospholipase C (PI-PLC) inhibitor, dramatically promotes OPC-to-OL differentiation and myelin regeneration in experimental autoimmune encephalomyelitis model. Unexpectedly, U73343, a close analog of U73122 which lacks PI-PLC inhibitory activity also promotes OL differentiation, while another reported PI-PLC inhibitor edelfosine does not have such effect, suggesting that U73122 and U73343 enhance OPC differentiation independent of PLC. Although the structures of U73122 and U73343 closely resemble 17ß-estradiol, and both compounds do activate estrogen receptors Erα and Erß with low efficacy and potency, further study indicates that these compounds do not act through Erα and/or Erß to promote OPC differentiation. RNA-Seq and bioinformatic analysis indicate that U73122 and U73343 may regulate cholesterol biosynthesis. Further study shows both compounds increase 14-dehydrozymostenol, a steroid reported to promote OPC differentiation, in OPC culture. In conclusion, the aminosteroids U73122 and U73343 promote OPC-to-OL generation and myelin formation by regulating cholesterol biosynthesis pathway.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirrolidinonas
/
Receptor alfa de Estrógeno
/
Estrenos
/
Vaina de Mielina
Idioma:
En
Revista:
Acta Pharmacol Sin
Asunto de la revista:
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China