重复创伤性脑损伤(RTBI)被认为是一种无声的被忽视的公共卫生危机,对其病理机制信号通路的理解不完全。越来越多的证据表明凝血酶及其受体的参与,蛋白酶激活受体(PAR)1,在TBI继发性损伤的发展中;然而,PAR1调节的后果及其对铁凋亡-氧化还原信号的影响,和RTBI中的NLRP3炎性体激活,仍然不清楚。Further,PAR1作为RTBI治疗靶点的功利性功能尚未阐明.为了研究这种相声,在Wistar大鼠中通过在右额叶区域每天减重5天诱导RTBI。包括三组:正常对照组,未经处理的RTBI,和RTBI+SCH79797(一种PAR1抑制剂,创伤后给药25μg/kg/天)。PAR1拮抗作用的伴随治疗改善了行为功能的改变,皮质组织结构,和神经元细胞存活。此外,受体阻滞剂下调PAR1的mRNA表达,但上调神经保护性受体PPAR-γ的mRNA表达。SCH79797的抗炎作用由低免疫表达/NF-κBp65、TNF-α、IL-1β,IL-18因此,PAR1阻断剂阻碍了炎症小体成分NLRP3、ASC、和活化的caspase-1。最终,SCH79797治疗通过激活抗氧化剂Nrf2/HO-1轴及其随后的抗氧化机制(GPX4,SOD)来限制脂质过氧化,从而减轻了铁凋亡依赖性铁氧化还原信号,铁积累,和转铁蛋白血清增量。总的来说,SCH79797通过激活PPAR-γ/Nrf2抗氧化剂提示来阻止铁中毒和NLRP3炎性体,从而提供了针对大鼠继发性RTBI后果的推定预防机制。
Repetitive traumatic brain injury (RTBI) is acknowledged as a silent overlooked public health crisis, with an incomplete understanding of its pathomechanistic signaling pathways. Mounting evidence suggests the involvement of thrombin and its receptor, the protease-activated receptor (PAR)1, in the development of secondary injury in TBI; however, the consequences of
PAR1 modulation and its impact on ferroptosis-redox signaling, and NLRP3 inflammasome activation in RTBI, remain unclear. Further, the utilitarian function of
PAR1 as a therapeutic target in RTBI has not been elucidated. To study this crosstalk, RTBI was induced in Wistar rats by daily weight drops on the right frontal region for five days. Three groups were included: normal control, untreated RTBI, and RTBI+SCH79797 (a
PAR1 inhibitor administered post-trauma at 25 μg/kg/day). The concomitant treatment of
PAR1 antagonism improved altered behavior function, cortical histoarchitecture, and neuronal cell survival. Moreover, the receptor blockade downregulated mRNA expression of PAR1 but upregulatedthat of the neuroprotective receptor PPAR-γ. The anti-inflammatory impact of SCH79797 was signified by the low immune expression/levels of NF-κB p65,TNF-α, IL-1β, and IL-18. Consequently, the
PAR1 blocker hindered the formation of inflammasome components NLRP3, ASC, and activated caspase-1. Ultimately, SCH79797 treatment abated ferroptosis-dependent iron redox signaling through the activation of the antioxidant Nrf2/HO-1 axis and its subsequent antioxidant machinery (GPX4, SOD) to limit lipid peroxidation, iron accumulation, and transferrin serum increment. Collectively, SCH79797 offered putative preventive mechanisms against secondary RTBI consequences in rats by impeding ferroptosis and NLRP3 inflammasome through activating the PPAR-γ/Nrf2 antioxidant cue.