Global Transcriptomic Profile of Dorsal Root Ganglion and Physiological Correlates of Cisplatin-Induced Peripheral Neuropathy

Abstract

Background Multiple cell signaling pathways are implicated in the development, progression, and persistence of cisplatin-induced peripheral neuropathy. Although advances have been made in terms of understanding specific neurotoxic mechanisms, there are few predictive factors identified that can help inform the clinician approach to symptom prevention or management. Objective We investigate the differential sensitivity to cisplatin-induced peripheral neuropathy and examine the contribution of dorsal root ganglion (DRG) transcriptional profiles across two inbred strains of mice. Methods Cisplatin (4 mg/kg intraperitoneal or vehicle control) was administered twice a week for 4 weeks to adult female C57BL/6J and A/J mice—the C57BL/6J strain of mice characterized by a robust mechanical allodynia and the A/J with a mild largely resistant allodynia phenotype. Peripheral nerve conduction velocities (NCVs), electrophysiological evaluation of wide dynamic range (WDR) neurons, morphological examination of DRG neurons, and microarray analysis of spinal cord tissues were compared across the 4 weeks. Results The A/J strain presents with an early, mild nocifensive response to cisplatin with reduced neuronal activity in WDR neurons and small changes in cross-sectional nucleus size in DRG neurons at 4 weeks. The more nocifensive-sensitive C57BL/6J strain presents with no early changes in WDR neuron responsiveness; however, there were significant changes in DRG size. Both strains demonstrate a drop in NCV after 4 weeks of treatment, with the greatest reduction present in the A/J strain. Transcriptome data implicate neuroimmune modulation in the differential response to cisplatin in the DRGs of A/J and C57BL/6J mice. Discussion Nocifensive responses in both strains implicate involvement of small myelinated and unmyelinated fibers in neurotoxic cisplatin response, whereas reductions in NCV reflect involvement of the largest myelinated fibers in the peripheral nerves. Microarray data analysis identifies neuropathy-relevant gene sets with differential activation of pathways, suggesting a role for antigen presentation in the differential neurotoxic response to cisplatin across strains. Further research is indicated to determine the relative contributions of each of these potential pathological mechanisms to both the neurotoxic response to cisplatin and to the potential for targeted therapy.

Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

“…Collectively, this underscores the limits of the current tests to ascertain where CM-304 or AZ-66 may be acting to prevent allodynia. For instance, the dorsal root ganglion (DRG), but not dorsal horn of spinal cord, has been implicated in the development of CISN-associated allodynia, but unlike CCI, CISN is not thought to activate spinal microglia (Zheng et al, 2011; Lessans et al, 2019), and the impact of chemotherapy on S1R expression in either the dorsal horn or DRG has yet to be elucidated. Future detailed investigations using S1R-CRE mice to evaluate the role of spinal, supraspinal, and peripheral sigma receptors in neuropathic pain might clarify this matter.…”

Co‐expression gene modules involved in cisplatin‐induced peripheral neuropathy according to sensitivity, status, and severity

“…38 As previously reported, the C57BL/6J strain presented more nocifensive-sensitivity with no early changes in WDR neuron responsiveness and the A/J strain presented with an early, mild nocifensive response with reduced neuronal activity. 12 The central roles of NPY receptors and galanin receptors in nociceptive signaling in chronic pain may partly explain the differences across strains in how WDR neurons respond to noxious stimuli. [39][40][41][42][43] In summary, we constructed a WGCNA network to identify gene modules and hub genes related to CIPN status, severity, and sensitivity.…”

“…(a) Samples: forty-seven L4-L5 dorsal root ganglia samples from untreated, vehicle treated and cisplatin treated adult female C57BL/6J and A/J mice for 1 and 4 weeks. 12 (b) External traits analysed: status, severity, and sensitivity. Status refers to peripheral neuropathy induced with a biweekly treatment of 4mg/kg cisplatin or to untreated, vehicle treated samples (controls); Sensitivity refers to strains where the A/J strain presents with an early, mild nocifensive response to cisplatin with reduced neuronal activity in wide dynamic range (WDR) neurons and small changes in cross-sectional nucleus size in DRG neurons (mild-sensitivity mouse); whereas the more nocifensive-sensitive C57BL/6J strain presents with no early changes in WDR neuron responsiveness; however, there were significant changes in DRG size (high-sensitivity mouse).…”

“…11 Based on neurophysiological, behavioral, and microarray analyses, Lessans S et al found the C57BL/6J strain was more nocifensive-sensitive responsive and the A/J strain presented with an early, mild nocifensive response. 12 Using bioinformatics analysis, we explored the transcriptional spectrum of the DRG in response to cisplatin with different treatments, timepoints, and strains to broadly model the status, severity, and sensitivity responses observed in human cisplatin treatment ( Figure 1). Weighted gene co-expression network analysis (WGCNA) is a systematic biological method used to describe gene association patterns between different samples, which can be used to identify modules of highly correlated genes and further to identify alternate biomarker genes or therapeutic targets.…”

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

“…Altered NaV channel function induced by oxaliplatin has been observed and confirmed further in numerous experimental in vivo and in vitro studies. [77,78].…”