Acetaldehyde dehydrogenase 2 activation attenuates sepsis-induced brain injury through NLRP3 inflammasome regulation.
Brain Res Bull
; 194: 128-138, 2023 03.
Article
em En
| MEDLINE
| ID: mdl-36720319
ABSTRACT
OBJECTIVE:
Acetaldehyde dehydrogenase 2 (ALDH2) plays an important part in neuroprotection; however, its effect on sepsis-induced brain injury is nuclear. Our aim is to investigate the potential effect and mechanism of ALDH2 in this condition.METHODS:
We established an animal model using cecal ligation and perforation (CLP). Twenty-four rats were divided into sham group (n = 6), CLP group (n = 6), CLP + Alda-1 group (n = 6) and CLP + Cyanamide (CYA) group (n = 6). Vital signs were monitored, and arterial blood gas analysis, hippocampal histological staining and ALDH2 activity analysis were conducted. Western blot analysis and enzyme-linked immunosorbent assays were also carried out. Lipopolysaccharide (LPS)-treated HT22 cells were employed as an in vitro model of sepsis-induced brain injury, with and without pretreatment with Alda-1 or CYA, to further examine the potential mechanisms. Real-time quantitative polymerase chain reaction and western blot were used to determine the levels of pyrin domain-containing 3 (NLRP3) inflammasome.RESULTS:
We found hippocampal cell injury in the CLP group (p < 0.05), with decreased ALDH2 activity (p < 0.05) and suspected overexpression of NLRP3/caspase-1 axis (p < 0.05). In the group pretreated with Alda-1, there were increased ALDH2 activity (p < 0.05), decreased hippocampal cell damage (p < 0.05), and reduced protein levels of NLRP3, apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), cleaved caspase-1 and Gasdermin D (GSDMD) (p < 0.05). The levels of interleukin 18 (IL-18) and interleukin 1ß (IL-1ß) were also reduced (p < 0.05). In the group pretreated with CYA, ALDH2 activity was further declined, the cell injury grade increased, and the elevated levels of pyroptosis-related proteins aggravated (p < 0.05). LPS treatment decreased the cell viability and ALDH2 activity of the HT22 cells (p < 0.05), along with increased mRNA levels of the NLRP3 inflammasome, as well as IL-1ß and IL-18 (p < 0.05). Western blot further revealed elevated levels of NLRP3, ASC, cleaved caspase-1 and GSDMD (p < 0.05). In the LPS+Alda-1 group, there were increased cell viability (p < 0.05), elevated ALDH2 activity (p < 0.05), and reduced levels of NLRP3 inflammasome and pyroptosis-related proteins (p < 0.05). In the CYA+LPS group, cell viability and ALDH2 activity were further declined (p < 0.05), while levels of NLRP3 /caspase-1 axis were increased (p < 0.05).CONCLUSIONS:
The activation of ALDH2 can attenuate sepsis-induced brain injury, hypothetically through regulation of the NLRP3/caspase-1 signaling pathway. Therefore, ALDH2 could potentially be considered as a new therapeutic target for the treatment of sepsis-induced brain injury.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lesões Encefálicas
/
Sepse
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Brain Res Bull
Ano de publicação:
2023
Tipo de documento:
Article