School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China.
State Key Laboratory of Long-Acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai, 264003, People's Republic of China.
Arch Toxicol. 2022 Mar;96(3):845-857. doi: 10.1007/s00204-022-03226-0. Epub 2022 Jan 30.
Tyrosine kinase inhibitors (TKIs), which have been developed and approved for cancer treatment in the last few years, are involved in synaptic plasticity of learning and memory. Epigenetic modifications also play crucial roles in the process of learning and memory, but its relationship with TKI-induced learning and memory impairment has not been investigated. We hypothesized that LPM4870108, an effective anti-cancer Trk inhibitor, might affect the learning and memory via epigenetic modifications. In this study, rats were orally administered with LPM4870108 (0, 1.25, 2.5, or 5.0 mg/kg) twice daily for 28 days, after which animals were subjected to a Morris water maze test. LPM4870108 exposure caused learning and memory impairments in this test in a dose-dependent manner and reduced the spine densities. Whole-genome transcriptomic analysis revealed significant differences in the patterns of hippocampal gene expression in LPM4870108-treated rats. These transcriptomic data were combined with next-generation bisulfite sequencing analysis, after which RT-PCR and pyrosequencing were conducted, revealing epigenetic alterations associated with genes (Snx8, Fgfr1, Dusp4, Vav2, and Satb2) known to regulate learning and memory. Increased mRNA and protein expression levels of hippocampal Dnmt1 and Dnmt3a were also observed in these rats. Overall, these data suggest that gene-specific alterations in patterns of DNA methylation can potentially contribute to the incidence of learning and memory deficits associated with exposure to LPM4870108.
酪氨酸激酶抑制剂（TKIs）在过去几年中已被开发并批准用于癌症治疗，它们参与学习和记忆的突触可塑性。表观遗传修饰在学习和记忆过程中也起着至关重要的作用，但它与 TKI 诱导的学习和记忆障碍之间的关系尚未得到研究。我们假设，LPM4870108，一种有效的抗癌 Trk 抑制剂，可能通过表观遗传修饰影响学习和记忆。在这项研究中，大鼠每天口服 LPM4870108（0、1.25、2.5 或 5.0mg/kg）两次，共 28 天，之后动物进行 Morris 水迷宫测试。LPM4870108 暴露以剂量依赖的方式导致动物在该测试中出现学习和记忆障碍，并减少了棘突密度。全基因组转录组分析显示，LPM4870108 处理大鼠海马基因表达模式存在显著差异。这些转录组数据与下一代亚硫酸氢盐测序分析相结合，随后进行 RT-PCR 和焦磷酸测序，揭示了与已知调节学习和记忆的基因（Snx8、Fgfr1、Dusp4、Vav2 和 Satb2）相关的表观遗传改变。还观察到这些大鼠海马中 Dnmt1 和 Dnmt3a 的 mRNA 和蛋白质表达水平增加。总体而言，这些数据表明，DNA 甲基化模式的基因特异性改变可能导致与 LPM4870108 暴露相关的学习和记忆缺陷的发生。
