Zhang Zhiheng, Chen Hui, Han Lin, Liu Kai, Du Shan, Gao Ruifeng
College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China.
College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China; Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China.
Free Radic Biol Med. 2024 Nov 20;225:87-97. doi: 10.1016/j.freeradbiomed.2024.09.038. Epub 2024 Sep 26.
Numerous preclinical studies have demonstrated that prolonged exposure to propofol (A general anaesthetics) can lead to hippocampus injury in immature brains and impact long-term learning and memory functions. Neuroinflammation plays a pivotal role in the impairment of brain function associated with early exposure to anesthetic drugs. Nevertheless, the involvement of hippocampal pyroptosis and neuroinflammation mediated by the NLRP3/caspase-1 signaling cascade in propofol-induced developmental neurotoxicity remains unclear.
Postnatal day (PND) 7 SD rats, PC12 cells, and HAPI cells were used to establish propofol neurotoxicity models in vivo and in vitro, respectively. We examined the potential hippocampal injury and cognitive dysfunction caused by propofol in neonatal rats through the NLRP3/caspase-1 signaling pathway using MCC950 and VX765 to inhibit the pathway. This investigation involved assessing histological changes in the hippocampus, behavioral performance in adulthood, NLRP3-related pyroptosis indicators, and neuroinflammatory cytokines.
Both in vivo and in vitro studies have demonstrated that exposure to propofol activates the NLRP3/caspase-1 signaling cascade in the hippocampus of PND7 rats, leading to pyroptosis, neuroinflammation, and subsequent hippocampal injury and behavioral changes in adulthood. However, MCC950 and VX765 inhibit the NLRP3/caspase-1 signaling cascade, reversing the developmental neurotoxicity of propofol.
Our study findings suggest that negative regulation of NLRP3/caspase-1 activation may serve as a potential therapeutic strategy for developmental neuroinflammation induced by propofol.
大量临床前研究表明，长时间暴露于丙泊酚（一种全身麻醉剂）可导致未成熟大脑的海马体损伤，并影响长期学习和记忆功能。神经炎症在与早期接触麻醉药物相关的脑功能损害中起关键作用。然而，NLRP3/半胱天冬酶-1信号级联介导的海马体焦亡和神经炎症在丙泊酚诱导的发育性神经毒性中的作用仍不清楚。
分别使用出生后第7天的SD大鼠、PC12细胞和HAPI细胞在体内和体外建立丙泊酚神经毒性模型。我们使用MCC950和VX765抑制该通路，通过NLRP3/半胱天冬酶-1信号通路研究丙泊酚对新生大鼠潜在的海马体损伤和认知功能障碍。该研究包括评估海马体的组织学变化、成年后的行为表现、NLRP3相关的焦亡指标和神经炎症细胞因子。
体内和体外研究均表明，暴露于丙泊酚会激活出生后第7天大鼠海马体中的NLRP3/半胱天冬酶-1信号级联，导致焦亡、神经炎症以及随后成年期的海马体损伤和行为变化。然而，MCC950和VX765抑制NLRP3/半胱天冬酶-1信号级联，逆转了丙泊酚的发育性神经毒性。
我们的研究结果表明，对NLRP3/半胱天冬酶-1激活的负调控可能作为丙泊酚诱导的发育性神经炎症的潜在治疗策略。
