Minocycline Protects Against NLRP3 Inflammasome-Induced Inflammation and P53-Associated Apoptosis in Early Brain Injury After Subarachnoid Hemorrhage
Minocycline Protects Against NLRP3 Inflammasome-Induced Inflammation and P53-Associated Apoptosis in Early Brain Injury After Subarachnoid Hemorrhage
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DOI：
10.1007/s12035-015-9318-8
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发表时间：
2016-05-01
影响因子：
5.1
通讯作者：
Chen, Gao
中科院分区：
文献类型：
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作者：
Li, Jianru;Chen, Jingsen;Chen, Gao
米诺环素对蛛网膜下腔出血（SAH）后早期脑损伤（EBI）有有益作用；然而，这些作用背后的分子机制尚未被清楚地确定。本研究旨在确定米诺环素对蛛网膜下腔出血后早期脑损伤的炎症和神经细胞凋亡的影响及其可能的机制。采用SAH纤维穿孔模型诱导雄性sd大鼠SAH。在SAH诱导后1小时通过腹腔注射二甲胺四环素或载体。米诺环素治疗通过抑制NLRP3炎性小体的激活，显著减轻血脑屏障（BBB）功能障碍继发的脑水肿，NLRP3炎性小体控制促炎细胞因子的成熟和释放，尤其是白细胞介素-1 β (IL-1 β)。米诺环素治疗也显著减少末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸镍端标记（TUNEL）阳性细胞的数量。为了进一步确定潜在的机制，我们证明二甲胺四环素增加了Bcl2的表达，降低了P53、Bax和cleaved caspase-3的蛋白表达。此外，二甲胺四环素降低了皮层活性氧（ROS）水平，而活性氧与NLRP3炎性体和P53表达密切相关。米诺环素在SAH后早期脑损伤中对NLRP3炎症小体诱导的炎症和p53相关的细胞凋亡具有保护作用。米诺环素的抗炎和抗凋亡作用可能与ROS的减少有关。米诺环素治疗在SAH的治疗中可能具有重要的临床潜力。
Minocycline has beneficial effects in early brain injury (EBI) following subarachnoid hemorrhage (SAH); however, the molecular mechanisms underlying these effects have not been clearly identified. This study was undertaken to determine the influence of minocycline on inflammation and neural apoptosis and the possible mechanisms of these effects in early brain injury following subarachnoid hemorrhage. SAH was induced by the filament perforation model of SAH in male Sprague-Dawley rats. Minocycline or vehicle was given via an intraperitoneal injection 1 h after SAH induction. Minocycline treatment markedly attenuated brain edema secondary to blood-brain barrier (BBB) dysfunction by inhibiting NLRP3 inflammasome activation, which controls the maturation and release of pro-inflammatory cytokines, especially interleukin-1 beta (IL-1 beta). Minocycline treatment also markedly reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells. To further identify the potential mechanisms, we demonstrated that minocycline increased Bcl2 expression and reduced the protein expression of P53, Bax, and cleaved caspase-3. In addition, minocycline reduced the cortical levels of reactive oxygen species (ROS), which are closely related to both NLRP3 inflammasome and P53 expression. Minocycline protects against NLRP3 inflammasome-induced inflammation and P53-associated apoptosis in early brain injury following SAH. Minocycline's anti-inflammatory and anti-apoptotic effect may involve the reduction of ROS. Minocycline treatment may exhibit important clinical potentials in the management of SAH.