MCC950 attenuated early brain injury by suppressing NLRP3 inflammasome after experimental SAH in rats.

Nucleotide oligomerization domain(NOD)-like receptor protein-3(NLRP3) inflammasome is a multiprotein complex, which results in the inflammatory response in early brain injury(EBI) after subarachnoid hemorrhage(SAH). MCC950, a specific NLRP3 inhibitor, plays neuroprotective effects in several central nervous system diseases. However, the role of MCC950 in SAH remains elusive. This study aims to investigate whether MCC950 exerts neuroprotection after experimental SAH and further explore the potential mechanisms. The SAH model was induced by endovascular perforation process using adult male Sprague-Dawley rats. MCC950 was injected intraperitoneally 1 h after SAH with a dose of 10 mg/kg. The results showed that MCC950 significantly ameliorated severe brain edema and neurological dysfunction. Furthermore, MCC950 efficiently reduced NLRP3 inflammasome expression as well as the pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6. In addition, the protective effect of MCC950 was blunted by lipopolysaccharide. In conclusion, our findings suggest that MCC950 alleviated SAH-induced EBI by suppressing inflammation.

Luo Y ，Lu J ，Ruan W ，Guo X ，Chen S ... -  《-》

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome.

Shao A ，Wu H ，Hong Y ，Tu S ，Sun X ，Wu Q ，Zhao Q ，Zhang J ，Sheng J ... -  《-》

Dexmedetomidine attenuated early brain injury in rats with subarachnoid haemorrhage by suppressing the inflammatory response: The TLR4/NF-κB pathway and the NLRP3 inflammasome may be involved in the mechanism.

Early brain injury (EBI) plays a pivotal role in the prognosis of patients with subarachnoid haemorrhage (SAH). Dexmedetomidine (DEX), a highly selective α2 receptor agonist, is reported to exert multiple protective effects in many neurological diseases. This study was designed to investigate whether DEX had neuroprotective functions in EBI after SAH, and to explore the possible mechanisms. The SAH model was established by an endovascular perforation in adult male Sprague-Dawley (SD) rats. DEX (25 µg/kg) or vehicle was administered intraperitoneally 2 h after SAH. Neurological deficits, brain oedema, inflammation, BBB damage, and cell apoptosis at 24 h after SAH were evaluated. Additionally, the expression of components of the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome were also assessed. We demonstrated that DEX treatment improved neurological scores, alleviated brain oedema, reduced the permeability of the blood-brain barrier (BBB), and up-regulated the expression of tight junction proteins. DEX treatment could reduce the neutrophil infiltration, microglial activation, and pro-inflammatory factor release. In addition, DEX alleviated cell apoptosis at 24 h after SAH. Notably, DEX could also suppress the activation of the TLR4/NF-κB pathway and the NLRP3 inflammasome. These findings suggested that treatment with DEX after SAH attenuated SAH-induced EBI, partially through the suppression of the TLR4/NF-κB pathway and the NLRP3 inflammasome.

Yin D ，Zhou S ，Xu X ，Gao W ，Li F ，Ma Y ，Sun D ，Wu Y ，Guo Q ，Liu H ，Han L ，Wang Z ，Wang Y ，Zhang J ... -  《-》

MCC950 Inhibits NLRP3 Inflammasome and Alleviates Axonal Injures in Early Stages of Diffuse Axonal Injury in Rats.

Zhao J ，Guo X ，Wang B ，Yang Z ，Huang T ，Guo D ，Zhang M ，Song J ... -  《-》

NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage.

The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1β production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.

Dodd WS ，Noda I ，Martinez M ，Hosaka K ，Hoh BL ... -  《Journal of Neuroinflammation》