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

Abstract

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.

Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage

“…At 24 h after IVH, the ventricular wall was examined by RNA-seq analysis to determine changes in mRNA expression 35 . T2-weighted images were obtained using 7.0 T small animal magnetic resonance imaging (MRI) 3 and 7 days after IVH, and the volume of the lateral ventricles was calculated using 3D Slicer software to dynamically monitor changes in ventricular volume 17 .…”

Autophagy regulates inflammation in intracerebral hemorrhage: Enemy or friend?

“…Several targets modulate inflammation through autophagy in the ICH ( Table 3 ). MCC950, an NLRP3 inflammasome-specific inhibitor, inhibits NLRP3 derived from microglia via the AMPK/Beclin-1 pathway to prevent excessive autophagy and reduce the release of IL-1β into the cell ( Zhang et al, 2022b ). Besides, alpha 7 nicotinic receptor (α-7nAChR) is a subtype of acetylcholine receptor primarily found in the CNS, and α-7nAChR is activated against inflammatory diseases by triggering cholinergic anti-inflammatory pathways.…”

Oxymatrine ameliorates white matter injury by modulating gut microbiota after intracerebral hemorrhage in mice

“…12,13 A growing body of research demonstrates that NLRP3 inflammasome plays an important role in the pathophysiology of ICH. [14][15][16] In our previous study, selectively inhibiting NLRP3 inflammasome was sufficient to modulate the gut microbial composition, ameliorate CST injury of the cervical enlargement, and alleviate neurological deficits after ICH. 17 Therefore, gut microbiota may be an important therapeutic target for the progression of ICH.…”

“…The nucleotide‐binding oligomerization domain‐, leucine‐rich repeat and pyrin domain‐containing 3 (NLRP3) inflammasome is a molecular complex of the innate immune system and considered as a key contributor to the development and progression of a variety of neuropsychiatric disorders 12,13 . A growing body of research demonstrates that NLRP3 inflammasome plays an important role in the pathophysiology of ICH 14–16 . In our previous study, selectively inhibiting NLRP3 inflammasome was sufficient to modulate the gut microbial composition, ameliorate CST injury of the cervical enlargement, and alleviate neurological deficits after ICH 17 .…”