Brexanolone therapeutics in post-partum depression involves inhibition of systemic inflammatory pathways.
EBioMedicine
; 89: 104473, 2023 Mar.
Article
em En
| MEDLINE
| ID: mdl-36801618
ABSTRACT
BACKGROUND:
Brexanolone has rapid, long-lasting, and remarkable efficacy in the treatment of post-partum depression (PPD). We test the hypothesis that brexanolone inhibits proinflammatory modulators and macrophage activation in PPD patients, which may promote clinical recovery.METHODS:
PPD patients (N = 18) provided blood samples before and after brexanolone infusion according to the FDA-approved protocol. Patients were unresponsive to prior treatment before brexanolone therapy. Serum was collected to determine neurosteroid levels and whole blood cell lysates were examined for inflammatory markers and in vitro responses to the inflammatory activators lipopolysaccharide (LPS) and imiquimod (IMQ).FINDINGS:
Brexanolone infusion altered multiple neuroactive steroid levels (N = 15-18), reduced levels of inflammatory mediators (N = 11) and inhibited their response to inflammatory immune activators (N = 9-11). Specifically, brexanolone infusion reduced whole blood cell tumor necrosis factor-α (TNF-α, p = 0.003), and interleukin-6 (IL-6, p = 0.04) and these effects were correlated with HAM-D score improvement (TNF-α, p = 0.049; IL-6, p = 0.02). Furthermore, brexanolone infusion prevented LPS and IMQ-induced elevation of TNF-α (LPS p = 0.02; IMQ p = 0.01), IL-1ß (LPS p = 0.006; IMQ p = 0.02) and IL-6 (LPS p = 0.009; IMQ p = 0.01), indicating inhibition of toll-like receptor (TLR)4 and TLR7 responses. Finally, inhibition of TNF-α, IL-1ß and IL-6 responses to both LPS and IMQ were correlated with HAM-D score improvements (p < 0.05).INTERPRETATION:
Brexanolone actions involve inhibition of inflammatory mediator production and inhibition of inflammatory responses to TLR4 and TLR7 activators. The data suggest that inflammation plays a role in post-partum depression and that inhibition of inflammatory pathways contributes to the therapeutic efficacy of brexanolone.FUNDING:
The Foundation of Hope, Raleigh, NC and UNC School of Medicine, Chapel Hill.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator de Necrose Tumoral alfa
/
Depressão Pós-Parto
Tipo de estudo:
Guideline
Limite:
Female
/
Humans
Idioma:
En
Revista:
EBioMedicine
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos