Idebenone attenuates cerebral inflammatory injury in ischemia and reperfusion via dampening NLRP3 inflammasome activity.

Idebenone is a well-appreciated mitochondrial protectant while the mechanisms underlying the neuroprotection in cerebral ischemia and reperfusion (I/R) remain elusive. It has been manifested NLRP3 inflammasom activation contributed to I/R induced damage. It raises questions how exactly NLRP3 inflammasom was activated in microglia and neuron and whether idebenone reverses the process in I/R. I/R rat model was utilized and BV2, primary microglia and PC12 cells were subjected to oxygen-glucose deprivation (OGD). Then, western-blotting, q-PCR, immunofluorescence staining, ELISA, flow cytometry and immunoprecipitation analysis were performed. We found ROS-NLRP3 singaling was activated in BV2 cells at OGD/R 24 h. Importantly, microglial NLRP3 activation was essential for NLRP3 activation in PC12 cells under microglial-neuronal co-culture circumstance, which has been confirmed to induced neuronal apoptosis. Further, we found mitochondrial dysfunction in OGD/R led to mt-DNA translocation as well as generation of mt-ROS, resulting cytosolic accumulation of oxidized mt-DNA. Ultimately, oxidized mt-DNA binding to NLRP3 contributed to further activation of NLRP3 and dramatically augmented inflammation in BV2 and PC12 cells. Furthermore, idebenone treatment inhibited the process, thus suppressing the NLRP3-mediated inflammatory injury after OGD/R. In vivo, NLRP3 was activated in microglia of I/R rats and inhibition of NLRP3 was observed in idebenone treatment group, which had less neurological deficit and less infarct volume. Our data revealed the anti-inflammatory effects of idebenone via suppressing activation of NLRP3 and ameliorating NLRP3-mediating damage in I/R, which may provide new insight in therapeutic strategy for ischemic stroke.

Peng J ，Wang H ，Gong Z ，Li X ，He L ，Shen Q ，Pan J ，Peng Y ... -  《-》

Bakuchiol ameliorates cerebral ischemia-reperfusion injury by modulating NLRP3 inflammasome and Nrf2 signaling.

Cerebral ischemia/reperfusion (I/R) injury is a common cerebrovascular disease with high mortality. Bakuchiol (BAK), extracted from the seeds of psoralea corylifolia, exhibits anti-inflammatory effects on lung, kidney and heart injuries. However, the effect of BAK on brain I/R injury remains elusive. In our study, a cerebral I/R model in mice was established by 1-h middle cerebral artery occlusion and 24-h reperfusion (1-h MCAO/24-h R). Prior to it, mice were gavaged with BAK (2.5 or 5 mg/kg) per day for 5 days. BAK pre-treatment improved neurological deficit, and reduced infarct volume, cerebral edema and neuronal injury in MCAO/R-injured mice. BAK decreased the number of Iba1-immunoreactive cells in the brain, indicating a reduction of microglial activation. BAK also reduced the expressions of NLRP3, ASC, cleaved-caspase-1, IL-1β and IL-18. BAK triggered Nrf2 nuclear accumulation and elevated HO-1 level. Further, the role of BAK was explored in BV-2 microglia with 3-h oxygen-glucose deprivation/24-h reperfusion (3-h OGD/24-h R). It was found that the functions of BAK in vitro were consistent with those in vivo, as manifested by reduced NLRP3 inflammasome and activated Nrf2 signaling. In addition, BV-2 cells were treated with Brusatol, an Nrf2 inhibitor. Results showed that Brusatol partially reversed the protective effect of BAK on OGD/R-injured BV-2 cells, further confirming that BAK might exhibit its anti-inflammatory property via activating Nrf2 signaling. In short, BAK is more meaningful in improving cerebral ischemic injury through suppressing NLRP3-mediated inflammatory response and activating the Nrf2 signaling pathway.

Xu Y ，Gao X ，Wang L ，Yang M ，Xie R ... -  《-》

Aloe-emodin alleviates cerebral ischemia-reperfusion injury by regulating microglial polarization and pyroptosis through inhibition of NLRP3 inflammasome activation.

Li X ，Yao M ，Li L ，Ma H ，Sun Y ，Lu X ，Jing W ，Nie S ... -  《-》

The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling.

Neuroinflammation remains the primary cause of morbidity and mortality in stroke-induced secondary brain injury. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is involved in diverse inflammatory diseases, including cerebral ischemia, and is thus considered an effective therapeutic target. In the present study, we investigated the neuroprotection of Sinomenine (SINO), a potent natural anti-apoptotic and anti-inflammatory molecule, against cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO) in vivo and in an oxygen glucose deprivation (OGD)-treated astrocytes/microglia model in vitro. SINO administration intraperitoneally alleviated the cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency after MCAO induction. SINO also attenuated astrocytic and microglial activation in the ischemic hemisphere. NLRP3 inflammasome activation after MCAO and OGD induction, with the up-regulation of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1 and pro-inflammatory cytokines, was significantly inhibited by SINO treatment both in vivo and in vitro. In addition, SINO reversed the OGD-induced inhibition of AMPK phosphorylation in vitro. Further, the suppressive effect of SINO on NLRP3 inflammasomes was blocked by an AMPK inhibitor, Compound C. Our findings demonstrate that SINO exerts a neuroprotective effect in ischemic stroke by inhibiting NLRP3 inflammasomes via the AMPK pathway, which also provides evidence of a novel treatment for clinical stroke therapy.

Qiu J ，Wang M ，Zhang J ，Cai Q ，Lu D ，Li Y ，Dong Y ，Zhao T ，Chen H ... -  《-》

Salvianolic Acids for Injection alleviates cerebral ischemia/reperfusion injury by switching M1/M2 phenotypes and inhibiting NLRP3 inflammasome/pyroptosis axis in microglia in vivo and in vitro.

Ma DC ，Zhang NN ，Zhang YN ，Chen HS ... -  《-》