Abstract
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.
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Funding
This work was supported by the Natural Science Foundation of Shandong Province (No. ZR2020MH411), the “Yantai science and technology plan project” (2021XDHZ081 and 2020XFRH109), and the Key “Major New Drugs Research & Development” Project of Shandong Province (2019JZZY011122).
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SD: methodology, software, validation, formal analysis, investigation, data curation, writing—original draft, writing—review and editing, and visualization. CL and YG: conceptualization, methodology, formal analysis, investigation, writing—review and editing, data review and supervision. PM: methodology, investigation, and data curation. SJ: methodology and data curation. YX: methodology and data curation. YM: methodology and data curation. HW: formal analysis, resources, writing—review and editing, and supervision. JT: conceptualization, resources, and project administration.
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Duan, S., Li, C., Gao, Y. et al. The tyrosine kinase inhibitor LPM4870108 impairs learning and memory and induces transcriptomic and gene‑specific DNA methylation changes in rats. Arch Toxicol 96, 845–857 (2022). https://doi.org/10.1007/s00204-022-03226-0
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DOI: https://doi.org/10.1007/s00204-022-03226-0