Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling
Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling
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DOI：
10.1111/jpi.12300
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发表时间：
2016-04-01
影响因子：
10.3
通讯作者：
Liang, Guobiao
中科院分区：
文献类型：
--
作者：
Dong, Yushu;Fan, Chongxi;Liang, Guobiao
蛛网膜下腔出血（SAH）是一种毁灭性的疾病，由于缺乏有效的治疗，发病率和死亡率很高。核苷酸结合寡聚化结构域样受体家族含吡啉结构域3（NLRP 3）炎性体激活与凋亡信号通路的上调相关，其与包括出血性损伤在内的各种炎性疾病有关。据报道，褪黑激素具有显著的抗炎特性，这对SAH后的早期脑损伤（EBI）有益。然而，其分子机制尚未明确。本研究旨在探讨褪黑素对蛛网膜下腔出血（SAH）所致EBI的保护作用及其可能机制。成年小鼠进行SAH。在SAH后2小时腹膜内注射褪黑激素或载体。褪黑激素具有神经保护作用，表现为存活率增加、神经评分升高、神经元存活率增加、脑谷胱甘肽水平保持不变、脑水肿、丙二醛浓度降低、细胞凋亡率降低和血脑屏障（BBB）破坏。褪黑激素还减弱了NLRP 3、包含半胱天冬酶募集结构域（ASC）的骨化相关斑点样蛋白、裂解的半胱天冬酶-1、白细胞介素-1（IL-1）和白细胞介素-6（IL-6）的表达;这些变化还与抗凋亡因子（Bcl 2）的增加和促凋亡因子（Bim）的减少相关。总之，我们的研究结果表明，褪黑激素治疗通过抑制NLRP 3炎性小体相关的凋亡来减弱SAH后的EBI。
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-1 (IL-1), 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.