Dexpramipexole ameliorates cognitive deficits in sepsis-associated encephalopathy through suppressing mitochondria-mediated pyroptosis and apoptosis.
Neuroreport
; 34(4): 220-231, 2023 03 01.
Article
em En
| MEDLINE
| ID: mdl-36719835
ABSTRACT
OBJECTIVES:
This study was aimed at evaluating the effects of dexpramipexole (DPX) - a mitochondrial protectant that sustains mitochondrial function and energy production - on cognitive function in a mouse model of sepsis-associated encephalopathy (SAE) induced by peripheral administration of lipopolysaccharide (LPS) and examining the potential mechanisms.METHODS:
C57BL/6 male mice were randomized into one of four treatment protocols Con+Sal, Con+DPX, LPS+Sal or LPS+DPX. The mice were intraperitoneally (i.p.) injected with LPS or equivalent volumes of normal saline once daily for 3 consecutive days. To evaluate the protective effects of DPX, we administered DPX or normal saline i.p. to the mice once daily for 6 consecutive days. Six mice in each group were decapitated on day 7, and each brain was rapidly removed and separated into two halves for biochemical and histochemical analysis. The remaining surviving mice in each group were subjected to behavioral tests from days 7 to 10.RESULTS:
Peripheral administration of LPS to mice led to learning and memory deficits in behavioral tests, which were associated with mitochondrial impairment and ATP depletion in the hippocampus. Repeated DPX treatment protected the mitochondria against LPS-induced morphological and functional impairment; inhibited the activation of the Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1-dependent pyroptosis pathway and cytochrome c (Cyt-c)-caspase-3-dependent apoptosis pathway; and attenuated LPS-induced neuroinflammation and cell death in the hippocampus in SAE mice.CONCLUSIONS:
Mitochondria-mediated pyroptosis and apoptosis are involved in the pathogenesis of cognitive deficits in a mouse model of SAE and DPX protects mitochondria and suppresses the mitochondria-medicated pyroptosis and apoptosis pathways, and ameliorates LPS-induced neuroinflammation and cognitive deficits. This study provides theoretical evidence supporting DPX for the treatment of SAE.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Encefalopatia Associada a Sepse
Tipo de estudo:
Guideline
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Neuroreport
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2023
Tipo de documento:
Article