Inhibiting Microglia-Derived NLRP3 Alleviates Subependymal Edema and Cognitive Dysfunction in Posthemorrhagic Hydrocephalus after Intracerebral Hemorrhage via AMPK/Beclin-1 Pathway

For posthemorrhagic hydrocephalus (PHH) patients, whether occur subependymal edema indicates poor outcomes, partially manifested as cognitive impairment. In the brain, NLRP3 inflammasome mainly derived from microglia/macrophages is involved in proinflammatory and neurodeficits after hemorrhage, and...

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Published in:Oxidative medicine and cellular longevity 2022, Vol.2022, p.4177317-17
Main Authors: Zhang, Zhaoqi, Guo, Peiwen, Huang, Suna, Jia, Zhengcai, Chen, Tunan, Liu, Xin, Feng, Hua, Chen, Yujie
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases
Animal cognition
Animals
Antibodies
Apoptosis
Autophagy
Beclin-1
Cerebral Hemorrhage - drug therapy
Cognitive Dysfunction - complications
Cytokines
Edema
Hemorrhage
Humans
Hydrocephalus
Hydrocephalus - complications
Inflammasomes - metabolism
Inflammation
Laboratory animals
Microglia - metabolism
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Pathogenesis
Proteins
Rats
Traumatic brain injury
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Summary:For posthemorrhagic hydrocephalus (PHH) patients, whether occur subependymal edema indicates poor outcomes, partially manifested as cognitive impairment. In the brain, NLRP3 inflammasome mainly derived from microglia/macrophages is involved in proinflammatory and neurodeficits after hemorrhage, and autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggest that NLRP3 inflammasome and autophagy played an essential role after intracerebral hemorrhage (ICH). We aimed to dissect the mechanisms underlying subependymal edema formation and cognitive dysfunction. Here, based on the hydrocephalus secondary to ICH break into ventricular (ICH-IVH) in rats, this study investigated whether microglia/macrophage-derived NLRP3 induced subependymal edema formation and neuron apoptosis in subventricular zones (SVZ). In the acute phase of ICH-IVH, both the expression of NLRP3 inflammasome of microglia/macrophages and the autophagy of neurons were upregulated. The activated NLRP3 in microglia/macrophages promoted the release of IL-1beta to extracellular, which contributed to excessive autophagy, leading to neurons apoptosis both in vivo and in vitro through the AMPK/Beclin-1 pathway combined with transcriptomics. Administration of MCC950 (NLRP3 inflammasome specific inhibitor) after ICH-IVH significantly reduced edema formation and improved cognitive dysfunction. Thus, inhibiting NLRP3 activation in SVZ may be a promising therapeutic strategy for PHH patients that warrants further investigation.
ISSN:1942-0900
1942-0994
DOI:10.1155/2022/4177317