RAD001 (everolimus) attenuates experimental autoimmune neuritis by inhibiting the mTOR pathway, elevating Akt activity and polarizing M2 macrophages.
Exp Neurol
; 280: 106-14, 2016 06.
Article
en En
| MEDLINE
| ID: mdl-27063582
ABSTRACT
Guillain-Barre' syndrome (GBS) is an acute, postinfectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. As a classical animal model of GBS, experimental autoimmune neuritis (EAN) has become well-accepted. Additionally, the potent immune modulation exerted by mammalian target of rapamycin (mTOR) inhibitors has been used to treat cancers and showed beneficial effects. Here we demonstrate that the mTOR inhibitor RAD001 (everolimus) protected rats from the symptoms of EAN, as shown by decreased paralysis, diminished inflammatory cell infiltration, reductions in demyelination of peripheral nerves and improved nerve conduction. Furthermore, RAD001 shifted macrophage polarization toward the protective M2 phenotype and modified the inflammatory milieu by downregulating the production of pro-inflammatory cytokines including IFN-γ and IL-17as well as upregulating the release of anti-inflammatory cytokines such as IL-4 and TGF-ß. Amounts of the mTOR downstream targets p-P70S6K and p-4E-BP1 in sciatic nerves decreased, whereas the level of its upstream protein p-Akt was elevated. This demonstrated that RAD001 inhibited the mTOR pathway and encouraged the expression of p-Akt, which led to M2 macrophage polarization, thus improved the outcome of EAN in rats. Consequently, RAD001 exhibits strong potential as a therapeutic strategy for ameliorating peripheral poly-neuropathy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Proteínas Proto-Oncogénicas c-akt
/
Serina-Treonina Quinasas TOR
/
Everolimus
/
Inmunosupresores
/
Neuritis Autoinmune Experimental
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Exp Neurol
Año:
2016
Tipo del documento:
Article
País de afiliación:
China