P2X7R/cryopyrin inflammasome axis inhibition reduces neuroinflammation after SAH.
Neurobiol Dis
; 58: 296-307, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-23816751
ABSTRACT
Neuroinflammation contributes to the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Cytotoxic events following SAH, such as extracellular accumulation of adenosine triphosphate (ATP), may activate the P2X purinoceptor 7 (P2X7R)/cryopyrin inflammasome axis, thus inducing the proinflammatory cytokine IL-1ß/IL-18 secretion. We therefore hypothesized that inhibition of P2X7R/cryopyrin inflammasome axis would ameliorate neuroinflammation after SAH. In the present study, SAH was induced by the endovascular perforation in rats. Small interfering RNAs (siRNAs) of P2X7R or cryopyrin were administered intracerebroventricularly 24h before SAH. Brilliant blue G (BBG), a non-competitive antagonist of P2X7R, was administered intraperitoneally 30min following SAH. Post-assessments including SAH severity score, neurobehavioral test, brain water content, Western blot and immunofluorescence, were performed. Administration of P2X7R and cryopyrin siRNA as well as pharmacologic blockade of P2X7R by BBG ameliorated neurological deficits and brain edema at 24h following SAH. Inhibition of P2X7R/cryopyrin inflammasome axis suppressed caspase-1 activation, which subsequently decreased maturation of IL-1ß/IL-18. To investigate the link between P2X7R and cryopyrin inflammasome in vivo, Benzoylbenzoyl-ATP (BzATP), a P2X7R agonist, was given to lipopolysaccharide (LPS) primed naive rats with scramble or cryopyrin siRNAs. In LPS-primed naive rats, BzATP induced caspase-1 activation and mature IL-1ß release were neutralized by cryopyrin siRNA. Thus, the P2X7R/cryopyrin inflammasome axis may contribute to neuroinflammation via activation of caspase-1 and thereafter mature IL-1ß/IL-18 production following SAH. Therapeutic interventions targeting P2X7R/cryopyrin pathway may be a novel approach to ameliorate EBI following SAH.
Palavras-chave
ANOVA; ASC; ATP; BBG; Benzoylbenzoyl-ATP; Brilliant blue G; BzATP; CNS; Cryopyrin; EBI; Early brain injury; Edema; IACUC; IL-1ß; Inflammation; Institutional Animal Care and Use Committee; LPS; MPO; NF-κB; NLR; P2X purinoceptor 7; P2X7R; SAH; SD; SpragueDawley; Subarachnoid hemorrhage; TLR4; Toll-like receptor 4; adenosine triphosphate; analysis of variance; apoptosis-associated speck-like protein containing a CAED; central nervous system; early brain injury; interleukin-1ß; lipopolysaccharide; myeloperoxidase; nuclear factor-kappa B; nucleotide-binding domain, leucine-rich repeat containing; siRNA; small interfering RNA; subarachnoid hemorrhage
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hemorragia Subaracnóidea
/
Transdução de Sinais
/
Receptores Citoplasmáticos e Nucleares
/
Encefalite
/
Receptores Purinérgicos P2X7
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Neurobiol Dis
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
China