Department of Biological Sciences, Beirut Arab University, Debbieh, Lebanon.
Faculty of Medicine, Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon.
PLoS One. 2021 Sep 10;16(9):e0257211. doi: 10.1371/journal.pone.0257211. eCollection 2021.
Traumatic brain injury (TBI) remains a major cause of morbidity and disability worldwide and a healthcare burden. TBI is an important risk factor for neurodegenerative diseases hallmarked by exacerbated neuroinflammation. Neuroinflammation in the cerebral cortex plays a critical role in secondary injury progression following TBI. The NOD-like receptors (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a key player in initiating the inflammatory response in various central nervous system disorders entailing TBI. This current study aims to investigate the role of NLRP3 in repetitive mild traumatic brain injury (rmTBI) and identify the potential neuroprotective effect of saffron extract in regulating the NLRP3 inflammasome. 24 hours following the final injury, rmTBI causes an upregulation in mRNA levels of NLRP3, caspase-1, the apoptosis-associated speck-like protein containing a CARD (ASC), nuclear factor kappa B (NF-κB), interleukin-1Beta (IL-1β), interleukin 18 (IL-18), nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase 1 (HMOX1). Protein levels of NLRP3, sirtuin 1 (SIRT1), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), and neuronal nuclei (Neu N) also increased after rmTBI. Administration of saffron alleviated the degree of TBI, as evidenced by reducing the neuronal damage, astrocyte, and microglial activation. Pretreatment with saffron inhibited the activation of NLRP3, caspase-1, and ASC concurrent to reduced production of the inflammatory cytokines IL-1β and IL-18. Additionally, saffron extract enhanced SIRT1 expression, NRF2, and HMOX1 upregulation. These results suggest that NLRP3 inflammasome activation and the subsequent inflammatory response in the mice cortex are involved in the process of rmTBI. Saffron blocked the inflammatory response and relieved TBI by activating detoxifying genes and inhibiting NLRP3 activation. The effect of saffron on the NLRP3 inflammasome may be SIRT1 and NF-κB dependent in the rmTBI model. Thus, brain injury biomarkers will help in identifying a potential therapeutic target in treating TBI-induced neurodegenerative diseases.
创伤性脑损伤（TBI）仍然是全球发病率和残疾的主要原因，也是医疗保健的负担。TBI 是神经退行性疾病的重要危险因素，其特征是神经炎症加剧。大脑皮层中的神经炎症在 TBI 后继发性损伤进展中起着关键作用。NOD 样受体（NLR）家族包含吡啶结构域的 3（NLRP3）炎性小体是各种中枢神经系统疾病中引发炎症反应的关键因素，这些疾病包括 TBI。本研究旨在探讨 NLRP3 在重复性轻度创伤性脑损伤（rmTBI）中的作用，并确定藏红花提取物在调节 NLRP3 炎性小体方面的潜在神经保护作用。最后一次受伤后 24 小时，rmTBI 导致 NLRP3、半胱天冬酶-1、凋亡相关斑点样蛋白含有 CARD（ASC）、核因子 kappa B（NF-κB）、白细胞介素-1β（IL-1β）、白细胞介素 18（IL-18）、核因子红细胞 2 相关因子 2（NRF2）和血红素加氧酶 1（HMOX1）的 mRNA 水平上调。rmTBI 后，NLRP3、沉默调节蛋白 1（SIRT1）、胶质纤维酸性蛋白（GFAP）、离子钙结合接头分子 1（Iba1）和神经元核（NeuN）的蛋白水平也增加。藏红花预处理可减轻 TBI 程度，这表现在减少神经元损伤、星形胶质细胞和小胶质细胞激活方面。藏红花提取物抑制 NLRP3、半胱天冬酶-1 和 ASC 的激活，同时减少炎症细胞因子 IL-1β 和 IL-18 的产生。此外，藏红花提取物增强 SIRT1 表达、NRF2 和 HMOX1 的上调。这些结果表明，NLRP3 炎性小体的激活和随后的炎症反应参与了 rmTBI 过程。藏红花通过激活解毒基因和抑制 NLRP3 激活来阻断炎症反应并缓解 TBI。藏红花对 NLRP3 炎性小体的作用可能依赖于 SIRT1 和 NF-κB 在 rmTBI 模型中的作用。因此，脑损伤生物标志物将有助于确定治疗 TBI 诱导的神经退行性疾病的潜在治疗靶点。
