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.

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

“…Notably, identification of a dose-specific effect on several genes have previously been shown to be associated with neural injury and toxic-insult response. 101 , 102 , 103 To our knowledge this is the first study that has identified an effect of paracetamol on differential DNAm of KCNE3 in a neuronal differentiation model of hESCs. Differential DNAm at KCNE3 was also identified in our MoBa study in cord blood.…”

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

“…Interestingly, irrespective of the temporal differences of the two models 90 , comparing the differentially expressed and methylated genes identified in our study revealed overlap of several genes identified in cord blood with potential compelling relevance to early brain development. Notably, identification of a dose-specific effect on several genes have previously been shown to be associated with neural injury and toxic-insult response [91][92][93] . To our knowledge this is the first study that has identified an effect of paracetamol on differential DNAm of KCNE3 in a neuronal differentiation model of hESCs.…”

G Protein-Coupled Receptors and Ion Channels Involvement in Cisplatin-Induced Peripheral Neuropathy: A Review of Preclinical Studies

“…Furthermore, cisplatin reduced the current density in K2P18.1-and Kv1.4-transfected HEK 293 cells. Thus, K2P18.1, a two-pore K + channel, is another K + channel through which cisplatin may confer neuronal hyperexcitability [98]. Therefore, the regulation of these channels could be a promising alternative to reduce cisplatin-induced neuropathic pain.…”