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

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.

SUBMITTER: Finno CJ 

PROVIDER: S-EPMC9108181 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature