Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons

Frontiers in Cellular Neuroscience

Jinsil Choi¹  Seojin Park¹  Ebenezer N. Yamoah¹  Yingying Chen¹  Jeong Han Lee¹  Maria Cristina Perez-Flores¹  Carrie J. Finno² 

[1] Department of Physiology and Cell Biology, School of Medicine, University of Reno, Reno, NV, United States;Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States;

关键词: cancer;    chemotherapy;    neuropathy;    sensory;    vitamin E;   

DOI  :  10.3389/fncel.2022.853035

来源: DOAJ

【 摘 要 】

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 (Kcnk18), 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.

【 授权许可】

Unknown