Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling.

Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality rates due to the lack of effective therapy. Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation associated with the upregulation of apoptotic signaling pathway has been implicated in various inflammatory diseases including hemorrhagic insults. Melatonin is reported to possess substantial anti-inflammatory properties, which is beneficial for early brain injury (EBI) after SAH. However, the molecular mechanisms have not been clearly identified. This study was designed to investigate the protective effects of melatonin against EBI induced by SAH and to elucidate the potential mechanisms. The adult mice were subjected to SAH. Melatonin or vehicle was injected intraperitoneally 2 hr after SAH. Melatonin was neuroprotective, as shown by increased survival rate, as well as elevated neurological score, greater survival of neurons, preserved brain glutathione levels, and reduced brain edema, malondialdehyde concentrations, apoptotic ratio, and blood-brain barrier (BBB) disruption. Melatonin also attenuated the expressions of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1, interleukin-1β (IL-1β), and interleukin-6 (IL-6); these changes were also associated with an increase in the anti-apoptotic factor (Bcl2) and reduction in the pro-apoptotic factor (Bim). In summary, our results demonstrate that melatonin treatment attenuates the EBI following SAH by inhibiting NLRP3 inflammasome-associated apoptosis.

Dong Y ，Fan C ，Hu W ，Jiang S ，Ma Z ，Yan X ，Deng C ，Di S ，Xin Z ，Wu G ，Yang Y ，Reiter RJ ，Liang G ... -  《-》

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 ... -  《-》

Minocycline Protects Against NLRP3 Inflammasome-Induced Inflammation and P53-Associated Apoptosis in Early Brain Injury After Subarachnoid Hemorrhage.

Li J ，Chen J ，Mo H ，Chen J ，Qian C ，Yan F ，Gu C ，Hu Q ，Wang L ，Chen G ... -  《-》

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 ... -  《-》

Dl-3-n-Butylphthalide attenuates early brain injury and delayed neurological dysfunction by regulating NLRP3 inflammasome after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe neurological event lacking of effective therapy. Early brain injury (EBI) and delayed neurological dysfunction are important cause in the poor prognosis of patients with SAH. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation has been implicated in many inflammatory lesion pathogeneses including SAH. Dl-3-n-butylphthalide (NBP) has been reported to possess substantial anti-inflammatory properties, which is beneficial for various neurodegenerative diseases. However, the effect and molecular mechanisms of NBP on SAH have not been clearly identified. We designed this study to investigate the effect of NBP against EBI and delayed neurological dysfunction after SAH and to reveal the possible underlying mechanism. The adult mice were subjected to endovascular perforation SAH model or sham operation. Mice were randomized to sham group, SAH group, or SAH+NBP group. The EBI (short-term study) was studied at 48 h post-SAH and delayed neurological dysfunction (long-term study) at 21 days post-SAH. The results suggested that NBP evidently alleviated the EBI in mice at 48 h post-SAH, as shown by elevating neurological score, reducing brain edema, blood-brain barrier disruption, neuronal loss, and astrocyte aggregation, as well as ameliorating cerebral vasospasm. Moreover, NBP was able to improve long-term neurobehavioral functions and decrease neuronal apoptosis at 21 days after SAH. Significantly, NBP treatment also inhibited the expressions of NLRP3, ASC, caspase-1, cleaved-caspase-1, IL-1β, IL-18, GSDMD and GSDMD-N in both EBI and delayed neurological dysfunction induced by SAH. Our findings suggested that NBP treatment exerts a profound neuroprotective effect against early brain injury and delayed neurological dysfunction induced by SAH, at least partially through regulating NLRP3 inflammasome signaling pathway and its related inflammation and pyroptosis.

Gao F ，Zeng S ，Chao D ，Wu L ... -  《-》