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

Finno, Carrie J. and Chen, Yingying and Park, Seojin and Lee, Jeong Han and Perez-Flores, Maria Cristina and Choi, Jinsil and Yamoah, Ebenezer N. (2022) Cisplatin Neurotoxicity Targets Specific Subpopulations and K+ Channels in Tyrosine-Hydroxylase Positive Dorsal Root Ganglia Neurons. Frontiers in Cellular Neuroscience, 16. ISSN 1662-5102

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Abstract

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.

Item Type: Article
Subjects: Article Archives > Medical Science
Depositing User: Unnamed user with email support@articlearchives.org
Date Deposited: 05 Apr 2023 05:35
Last Modified: 21 Oct 2024 04:12
URI: http://archive.paparesearch.co.in/id/eprint/948

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