Propofol Attenuates Inflammatory Damage <i>via</i> Inhibiting NLRP1-Casp1-Casp6 Signaling in Ischemic Brain Injury

Abstract

Stroke is a common cerebrovascular disease. Inflammation-induced neuronal death is one of the key factors in stroke pathology. Propofol has been shown to ameliorate neuroinflammatory injury, but the exact mechanism of its neuroprotective role remains to be fully elucidated. In the present study, we found that inflammation was activated in ischemic cortical neurons, and the expression of nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 1 (NLRP1), NLRP3 inflammasome and effectors in primary cortical neurons increased. However, we found that propofol could inhibit the increased expression of NLRP1 and NLRP3 inflammasome induced by oxygen-glucose deprivation (OGD). Furthermore, the effector molecule caspase-1 (casp1) was revealed to be the downstream target of NLRP1 and propofol repressed the activation of caspase-1 via inhibiting NLRP1 in cortical neurons. Moreover, propofol inhibits caspase-6 activation in neurons through the NLRP1-caspase-1 pathway. Once the expression of caspase6 increases, propofol reduced its neuroprotective effect in OGD-treated cortical neurons. In the stroke middle cerebral artery occlusion (MCAO) model, infusion of caspase-6 inhibitors enhanced the protective effect of propofol on infarct size and neurological function. In conclusion, our results suggest that propofol plays a neuroprotective role in stroke by inhibiting the inflammatory pathway of NLRP1-caspase-1-caspase-6. Overall, these data suggest that propofol plays a key role in the inflammatory-dependent pathway after stroke, providing an important evidence for propofol as an effective strategy for neuroprotection in stroke.

The Effects of Propofol on Hypoxia- and TNF-α-Mediated Brain-Derived Neurotrophic Factor/Tyrosine Kinase Receptor B Pathway Dysregulation in Primary Rat Hippocampal Neurons and Astrocytes

“…A large amount of in vitro studies revealed that propofol may improve BBB function [21], protect neuron apoptosis [18] and autophagy [17], and maintain microglia function [32]. In addition, animal studies demonstrated that propofol may improve brain function in rats with ischemia-reperfusion injury [33] and may ameliorate neuroin ammatory injury in rats [34,35].…”

“…Accordingly, we concluded that propofol may regulate hypoxia-and TNF-α-mediated BDNF/TrkB dysregulation, through both affecting BDNF expression and affecting TrkB phosphorylation only in hippocampal neurons. ERK/CREB and p35/Cdk5 were involved in the bene cial effect of propofol against hypoxia-and TNF-αmediated BDNF/TrkB dysregulation The mechanism involved in the neuro-protective effect of propofol against hypoxia-and in ammationmediated injuries has been widely studied both in the in vitro model and in the animal model, and may include but not be limited to phosphatidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathway [34], PIM-1/nitric oxide synthase (NOS)/NO pathway [36], rapamycin/ribosomal protein S6 kinase beta-1 pathway [37], janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway [38], HSF1/heat shock protein 27 (HSP27) and Nrf2/ HSP32 pathway [22], and Ca 2+ /calmodulin-dependent protein kinase II (CAMKII)/extracellular regulated protein kinases (ERK)/NF-κB pathway [21,23]. However, the molecular mechanism responsible for propofol-modulated BDNF/TrkB regulation still remains unknown.…”

Propofol Affects EGF’s Activity in Intestinal Cell by Down-Regulating EGFR-Mediated Intracellular Signaling

“…2) For example, it has been reported that propofol has anti-inflammatory effects. [10][11][12][13][14][15] Inflammatory reactions are accompanied by the generation of oxygen free radicals. Propofol reacts with oxygen free radicals to form stable phenoxy groups and scavenge oxygen free radicals, which in turn exhibits an anti-inflammatory role.…”

“…Propofol reacts with oxygen free radicals to form stable phenoxy groups and scavenge oxygen free radicals, which in turn exhibits an anti-inflammatory role. 11,12) In addition, some studies have shown that propofol has an antianxiety effect. Some experimental studies have shown that propofol exhibits better anxiolytic effects in animal models.…”

Artesunate Provides Neuroprotection against Cerebral Ischemia–Reperfusion Injury <i>via</i> the TLR-4/NF-κB Pathway in Rats

“…4) The early inflammatory response to brain injury has great importance in the pathogenesis of ischemia/reperfusion (I/R) injury and this has produced enthusiasm for developing anti-inflammatory cures to combat I/R-caused damage. [5][6][7] Artesunate (ART) is a water-soluble, semisynthetic compound derived from artemisinin. It has positive effects on dermatitis, arthritis, allergic asthma, and other conditions.…”