Finno Carrie J, Chen Yingying, Park Seojin, Lee Jeong Han, Perez-Flores Maria Cristina, Choi Jinsil, Yamoah Ebenezer N
Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
Department of Physiology and Cell Biology, School of Medicine, University of Reno, Reno, NV, United States.
Front Cell Neurosci. 2022 May 2;16:853035. doi: 10.3389/fncel.2022.853035. eCollection 2022.
Among the features of cisplatin chemotherapy-induced peripheral neuropathy are chronic pain and innocuous mechanical hypersensitivity. The complete etiology of the latter remains unknown. Here, we show that cisplatin targets a heterogeneous population of tyrosine hydroxylase-positive (TH) primary afferent dorsal root ganglion neurons (DRGNs) in mice, determined using single-cell transcriptome and electrophysiological analyses. TH DRGNs regulate innocuous mechanical sensation through C-low threshold mechanoreceptors. A differential assessment of wild-type and vitamin E deficient TH DRGNs revealed heterogeneity and specific functional phenotypes. The TH DRGNs comprise; fast-adapting eliciting one action potential (AP; 1-AP), moderately-adapting (≥2-APs), in responses to square-pulse current injection, and spontaneously active (SA). Cisplatin increased the input resistance and AP frequency but reduced the temporal coding feature of 1-AP and ≥2-APs neurons. By contrast, cisplatin has no measurable effect on the SA neurons. Vitamin E reduced the cisplatin-mediated increased excitability but did not improve the TH neuron temporal coding properties. Cisplatin mediates its effect by targeting outward K current, likely carried through K2P18.1 ), discovered through the differential transcriptome studies and heterologous expression. Studies show a potential new cellular target for chemotherapy-induced peripheral neuropathy and implicate the possible neuroprotective effects of vitamin E in cisplatin chemotherapy.
顺铂化疗引起的周围神经病变的特征包括慢性疼痛和无害性机械超敏反应。后者的完整病因尚不清楚。在这里，我们表明，使用单细胞转录组和电生理分析确定，顺铂靶向小鼠中酪氨酸羟化酶阳性（TH）初级传入背根神经节神经元（DRGNs）的异质群体。TH DRGNs通过C类低阈值机械感受器调节无害性机械感觉。对野生型和维生素E缺乏的TH DRGNs的差异评估揭示了异质性和特定的功能表型。TH DRGNs包括：快速适应型（对方波电流注射产生一个动作电位（AP；1-AP））、中等适应型（≥2个AP）和自发活动型（SA）。顺铂增加了输入电阻和AP频率，但降低了1-AP和≥2-AP神经元的时间编码特征。相比之下，顺铂对SA神经元没有可测量的影响。维生素E降低了顺铂介导的兴奋性增加，但没有改善TH神经元的时间编码特性。顺铂通过靶向外向K电流发挥作用，该电流可能由K2P18.1携带，这是通过差异转录组研究和异源表达发现的。研究显示了化疗引起的周围神经病变的一个潜在新细胞靶点，并暗示了维生素E在顺铂化疗中可能的神经保护作用。
