Activation of LRP1 Ameliorates Cerebral Ischemia/Reperfusion Injury and Cognitive Decline by Suppressing Neuroinflammation and Oxidative Stress through TXNIP/NLRP3 Signaling Pathway in Mice.
Oxid Med Cell Longev
; 2022: 8729398, 2022.
Article
en En
| MEDLINE
| ID: mdl-36035210
ABSTRACT
Cerebral ischemia/reperfusion (I/R) injury is a clinical event associated with high morbidity and mortality. Neuroinflammation plays a crucial role in the pathogenesis of I/R-induced brain injury and cognitive decline. Low-density lipoprotein receptor-related protein-1 (LRP1) can exert strong neuroprotection in experimental intracerebral hemorrhage. However, whether LRP1 can confer neuroprotective effects after cerebral I/R is yet to be elucidated. The present study is aimed at investigating the effects of LRP1 activation on cerebral I/R injury and deducing the underlying mechanism involving TXNIP/NLRP3 signaling pathway. Cerebral I/R injury was induced in mice by bilateral common carotid artery occlusion. LPR1 ligand, apoE-mimic peptide COG1410, was administered intraperitoneally. To elucidate the underlying mechanism, overexpression of TXNIP was achieved via the hippocampal injection of AAV-TXNIP before COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, Western blot, enzyme-linked immunosorbent assay, HE, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. Our results showed that the expressions of endogenous LRP1, TXNIP, NLRP3, procaspase-1, and cleaved caspase-1 were increased after cerebral I/R. COG1410 significantly ameliorated cerebral I/R-induced neurobehavioral deficits, brain edema, histopathological damage, and poor survival rate. Interestingly, COG1410 inhibited microglia proinflammatory polarization and promoted anti-inflammatory polarization, decreased oxidative stress, attenuated apoptosis, and inhibited the expression of the TXNIP/NLRP3 signaling pathway. However, the benefits of COG1410 were abolished by TXNIP overexpression. Thus, our study suggested that LRP1 activation with COG1410 attenuated cerebral I/R injury at least partially related to modulating microglial polarization through TXNIP/NLRP3 signaling pathway in mice. Thus, COG1410 treatment might serve as a promising therapeutic approach in the management of cerebral I/R patients.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_cardiovascular_diseases
/
6_cerebrovascular_disease
/
6_mental_health_behavioral_disorders
Asunto principal:
Daño por Reperfusión
/
Isquemia Encefálica
/
Estrés Oxidativo
/
Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad
/
Disfunción Cognitiva
Límite:
Animals
Idioma:
En
Revista:
Oxid Med Cell Longev
Asunto de la revista:
METABOLISMO
Año:
2022
Tipo del documento:
Article
País de afiliación:
China