Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment.
Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment.
复制标题
中枢神经系统中的鞘氨氨酸-1-磷酸受体1激活驱动顺铂诱导的认知障碍。
DOI：
10.1172/jci157738
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发表时间：
2022-09-01
影响因子：
15.9
通讯作者：
Salvemini, Daniela
中科院分区：
文献类型：
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作者：
Squillace, Silvia;Niehoff, Michael L.;Doyle, Timothy M.;Green, Michael;Esposito, Emanuela;Cuzzocrea, Salvatore;Arnatt, Christopher K.;Spiegel, Sarah;Farr, Susan A.;Salvemini, Daniela
癌症相关认知障碍（CRCI）是影响50%以上癌症幸存者的主要神经毒性。其基本机制大多是未知的，也没有fda批准的干预措施。对小鼠认知功能关键部位前额叶皮质和海马的鞘脂组学分析显示，顺铂增加了强效信号分子鞘鞘醇-1-磷酸（S1P）的水平，导致认知功能障碍。在生化水平上，S1P诱导线粒体功能障碍，激活NOD-、LRR-和pyrin结构域蛋白3炎性小体，并增加IL-1β的形成。这些事件可以通过全身给予功能性S1P受体1 （S1PR1）拮抗剂FTY720来减轻，FTY720也可以减轻认知障碍，而不会对运动活动产生不利影响。ozanimod（另一种fda批准的功能性S1PR1拮抗剂）也观察到类似的衰减。星形细胞特异性缺失S1pr1的小鼠失去了对FTY720的反应能力，这表明星形细胞S1pr1参与其中。值得注意的是，我们的药理学和遗传学方法，加上计算模型研究，显示顺铂通过激活TLR4来增加S1P的产生。总之，我们的研究结果确定了S1P/S1PR1轴参与CRCI的分子机制，并建立了S1PR1拮抗剂作为一种靶向CRCI的治疗方法，具有快速临床应用价值。
Cancer-related cognitive impairment (CRCI) is a major neurotoxicity affecting more than 50% of cancer survivors. The underpinning mechanisms are mostly unknown, and there are no FDA-approved interventions. Sphingolipidomic analysis of mouse prefrontal cortex and hippocampus, key sites of cognitive function, revealed that cisplatin increased levels of the potent signaling molecule sphingosine-1-phosphate (S1P) and led to cognitive impairment. At the biochemical level, S1P induced mitochondrial dysfunction, activation of NOD-, LRR-, and pyrin domain–containing protein 3 inflammasomes, and increased IL-1β formation. These events were attenuated by systemic administration of the functional S1P receptor 1 (S1PR1) antagonist FTY720, which also attenuated cognitive impairment without adversely affecting locomotor activity. Similar attenuation was observed with ozanimod, another FDA-approved functional S1PR1 antagonist. Mice with astrocyte-specific deletion of S1pr1 lost their ability to respond to FTY720, implicating involvement of astrocytic S1PR1. Remarkably, our pharmacological and genetic approaches, coupled with computational modeling studies, revealed that cisplatin increased S1P production by activating TLR4. Collectively, our results identify the molecular mechanisms engaged by the S1P/S1PR1 axis in CRCI and establish S1PR1 antagonism as an approach to target CRCI with therapeutics that have fast-track clinical application.