背根神经节的全球转录组谱和顺铂诱导的周围神经病变的生理相关性。

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

机构信息

Sherrie Lessans, PhD RN CNL, is Assistant Professor, Department of Pain and Translational Symptom Science, and Director Clinical Nurse Leader Program, University of Maryland School of Nursing, Baltimore. Cameron B. Lassiter, MS, is Graduate Student in Molecular Medicine-Life Sciences, University of Maryland, Baltimore. Valentina Carozzi, PhD, is Assistant Professor, Experimental Neurology Unit, Milan Center for Neuroscience, School of Medicine and Surgery, University of Milan Biocca, Monza, Italy. Patrick Heindel, MS, is Research Associate, Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore. Sara Semperboni, MS, is Graduate Student, Experimental Neurology Unit, Milan Center for Neuroscience, School of Medicine and Surgery, University of Milan Biocca, Monza, Italy. Norberto Oggioni, PhD, is Research Associate and Technical Expert, Experimental Neurology Unit, Milan Center for Neuroscience, School of Medicine and Surgery, University of Milan Biocca, Monza, Italy. Alessia Chiorazzi, MS PhD, is Post-Doctoral Fellow, Experimental Neurology Unit, Milan Center for Neuroscience at the School of Medicine and Surgery, University of Milan Biocca, Monza, Italy. Carleveva Thompson, MS, is Project Manager, Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore. Monica Wagner, PhD, RN, is Graduate Student, Department of Health Behavior and Biological Sciences, University of Michigan School of Nursing, Kalamazoo. She is currently Post-Doctoral Fellow, University of Pittsburgh School of Nursing, Pennsylvania. Janean Holden, PhD RN, is Professor, Department of Health Behavior and Biological Sciences, University of Michigan School of Nursing, Kalamazoo. Elizabeth Rahn, PhD, is Post-Doctoral Fellow, Experimental Neurology Unit, Milan Center for Neuroscience, School of Medicine and Surgery, University of Milan Biocca, Monza, Italy. J. David Sweatt, PhD, is Professor and Chair, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee. Guido Cavaletti, MD, is Professor, Experimental Neurology Unit, Milan Center for Neuroscience, School of Medicine and Surgery, University of Milan Biocca, Monza, Italy. Cynthia L. Renn, PhD, RN, is Associate Professor, Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore. Susan G. Dorsey, PhD, RN, FAAN, is Professor and Chair, Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore.

出版信息

Nurs Res. 2019 Mar/Apr;68(2):145-155. doi: 10.1097/NNR.0000000000000338.

DOI:10.1097/NNR.0000000000000338

PMID:30586060

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.

摘要

背景

多种细胞信号通路参与顺铂诱导的周围神经病变的发生、发展和持续。尽管在了解特定神经毒性机制方面取得了进展，但很少有确定的预测因素可以帮助临床医生了解预防或管理症状的方法。

目的

我们研究了顺铂诱导的周围神经病的差异敏感性，并检查了两个近交系小鼠背根神经节（DRG）转录谱的贡献。

方法

顺铂（4mg/kg 腹腔内或载体对照）每周两次给药 4 周，用于成年雌性 C57BL/6J 和 A/J 小鼠- C57BL/6J 品系的小鼠表现出强烈的机械性感觉过敏，而 A/J 则表现出轻度且基本耐药的感觉过敏表型。比较了 4 周内的周围神经传导速度（NCV）、宽动态范围（WDR）神经元的电生理评估、DRG 神经元的形态学检查和脊髓组织的微阵列分析。

结果

A/J 品系对顺铂的早期、轻度伤害性反应表现为 WDR 神经元的神经元活性降低，4 周时 DRG 神经元的核横截面大小变化较小。更具伤害性敏感性的 C57BL/6J 品系在 WDR 神经元反应方面没有早期变化；然而，DRG 大小有显著变化。两种品系在 4 周治疗后 NCV 均下降，A/J 品系下降最大。转录组数据表明，神经免疫调节参与了 A/J 和 C57BL/6J 小鼠 DRG 对顺铂的差异反应。

讨论

两种品系的伤害性反应都暗示了小髓鞘和无髓鞘纤维在神经毒性顺铂反应中的参与，而 NCV 的降低反映了周围神经中大的髓鞘纤维的参与。微阵列数据分析确定了与神经病变相关的基因集，这些基因集的通路有差异激活，表明抗原呈递在不同品系对顺铂的神经毒性反应中起作用。需要进一步研究以确定这些潜在病理机制中的每一种对顺铂的神经毒性反应和靶向治疗的潜在作用的相对贡献。