ABSTRACT
Post-stroke cognitive impairment (PSCI) severely affects the quality of a survivor's life, but its neurophysiological basis remains unknown. Neuroinflammation has been considered as an important contributor to PSCI, which could be induced or exacerbated by system inflammation. NACHT-LRR- and pyrin-domain-containing protein 3 (NLRP3) inflammasome is the most widely studied in the initiation of inflammation. Here, using a mouse model of photothrombotic stroke, we demonstrated that NLRP3 activation plays a critical role in PSCI. Intraperitoneal injection of the lipopolysaccharide-activated NLRP3 inflammasome, exacerbated the microglial activation and decreased the number of neurons, impaired the hippocampal neurogenesis, eventually aggravated PSCI. Intraperitoneal injection of MCC950 inhibited the NLRP3 activation, decreased the number of microglia, increased the number of neurons and promoted the hippocampal neurogenesis, eventually improved PSCI. Our results identified NLRP3 inflammasome as an important modifier of neuropathology in PSCI, which could be a could be a potential therapeutic target for PSCI treatment.
Subject(s)
Cognitive Dysfunction/immunology , Inflammasomes/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Neurogenesis/physiology , Stroke/immunology , Animals , Cognitive Dysfunction/metabolism , Disease Models, Animal , Furans/pharmacology , Indenes/pharmacology , Inflammasomes/drug effects , Inflammasomes/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neurogenesis/drug effects , Stroke/metabolism , Stroke/pathology , Sulfonamides/pharmacologyABSTRACT
BACKGROUND: Visfatin, a new adipocytokine, was reported to promote angiogenesis. Dimethylarginine dimethylaminohydrolase (DDAH), which could regulate vascular endothelial growth factor (VEGF) expression in endothelial cells, is thought as a novel modulator of angiogenesis. The aim of the study was to investigate the role of DDAH2 in visfatin-induced angiogenesis in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: Visfatin could concentration- and time-dependently enhance cell migration and tube formation reflecting angiogenic capability of HUVECs. Moreover, visfatin upregulated both mRNA and protein expressions of DDAH2 and VEGF. Angiogenic effects of visfatin were attenuated by DDAH2 small interfering RNA. Visfatin-induced protein kinase B (Akt) phosphorylation and phosphoinositide 3 kinase (PI3K) inhibitors could suppress visfatin-induced upregulation of DDAH2 and VEGF expressions. CONCLUSIONS: Taken together, our results demonstrate that PI3K/Akt-mediated upregulation of DDAH2 expression plays a critical role in visfatin-promoted angiogenesis via regulating VEGF-dependent pathway.
