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Unilateral L4-Dorsal Root Ganglion Stimulation Evokes Pain Relief In Kinfe et al. J Transl Med (2019) 17:205 https://doi.org/10.1186/s12967-019-1952-x Journal of Translational Medicine RESEARCH Open Access Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of infammatory markers: part II whole transcriptome profling Thomas M. Kinfe1,2,3*, Maria Asif4,5,6, Krishnan V. Chakravarthy7,8, Timothy R. Deer9, Jefery M. Kramer10, Thomas L. Yearwood11, Rene Hurlemann1,2,3, Muhammad Sajid Hussain4,5,6, Susanne Motameny4, Prerana Wagle12, Peter Nürnberg4,6,12, Sascha Gravius3,13, Thomas Randau3,13, Nadine Gravius3,13, Shafqat R. Chaudhry14† and Sajjad Muhammad15† Abstract Background: In our recent clinical trial, increased peripheral concentrations of pro-infammatory molecular media- tors were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRGSTIM), signifcantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecu- lar profling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinfammatory (cytokines/chemokines) signaling pathways. Methods: Blood samples were collected from 12 CRPS patients for whole-transcriptome profling in order to assay ™ 18,845 infammation-associated genes from frozen blood at baseline and after 3 months L4-DRGSTIM using PANTHER pathway enrichment analysis tool. Results: Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of infammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of diferentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinfammatory) were signifcantly changed after L4-DRGSTIM. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. Conclusions: In our sub-group analysis of L4-DRGSTIM treated CRPS patients, we found either upregulated or down- regulated genes involved in immunoinfammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. *Correspondence: [email protected] †Shafqat R. Chaudhry and Sajjad Muhammad contributed equally to this work 1 Department of Psychiatry, Rheinische Friedrich-Wilhelms University, Sigmund-Freud Street 25, 53105 Bonn, Germany Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kinfe et al. J Transl Med (2019) 17:205 Page 2 of 13 Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https ://www.drks.de/drks_web/navig ate.do?navig ation Id trial .HTML&TRIAL _ID DRKS0 00112 67 = = Keywords: Dorsal root ganglion stimulation, Chronic neuropathic pain, Gene expression, Transcriptome Background An independent internal local ethical research board/ In line with previously reported observational cohort committee (IRB-No. 258/15) approved the study. Te and randomized-controlled trials we have most recently study was registered at the 15.11.2016 on German Reg- demonstrated that unilateral selective L4-dorsal root ister for Clinical Trials (DRKS ID 00011267). ganglion stimulation (L4-DRGSTIM) evoked pain relief https ://www.drks.de/drks_web/navig ate.do?navig ation in complex regional pain syndrome patients (CRPS) Id=trial .HTML&TRIAL _ID=DRKS0 00112 67. and improved functional capacity as well [1–4]. In addition, we observed changes of peripheral circulating RNA preparation and whole‑transcriptome profling infammatory mediators in diferent biofuids (saliva and serum). Signifcantly increased values of pro- During initiation of the sampling processes 1 sample infammatory biomarkers were observed pre- and post was lost, hence in the current study we have 11 subjects with CRPS who were fully analyzed at baseline and after L4-DRGSTIM for high-mobility group box 1 (HMGB-1), tumor-necrosis factor α (TNF-α) and interleukin (IL)-6 3 months of selective L4-DRG stimulation. and leptin. Peripheral pro-infammatory IL-1β was sig- RNA was isolated from the frozen blood and whole transcriptome analysis was performed to identify changes nifcantly elevated pre-L4 DRG STIM, but not post-L4 in gene expression pre- and post-stimulation. Blood was DRGSTIM, while anti-infammatory IL-10 also declined collected in EDTA tubes and RNA was extracted with the after 3 months of unilateral L4-DRGSTIM with oxytocin help of NucleoSpin RNA Blood Midi Kit (Cat# 740210.20, from saliva increased after 3 months L4-DRGSTIM. Members of the adipokine superfamily associated with Macherey–Nagel GmbH & Co. KG). 100 ng of RNA metabolic disorders such as ghrelin and adiponectin from each sample were subjected for gene expression ® remained unchanged [1]. analysis using Clariom-S-human array from Afymetrix ® Previous experimental studies in nerve-injury animal (Santa Clara, CA). GeneChip Hybridization Oven 645 models of chronic neuropathic pain have shown neu- were used for hybridization, GeneChip Fluidics Station rostimulation therapy reduces hyperalgesia (behavioral 450 for washing and GeneChip Scanner 7G was used testing) coincident with changes in the levels of various for scanning. After scanning, CEL-Files were gener- ® ® neuroinfammatory peptides as a result of altered genetic ated from DAT-Files by Afymetrix GeneChip Com- ® expression within tissue samples of the spinal cord and mand Console software. Data was analyzed by using ® dorsal root ganglion [5–8]. So far, the shift of pain-related Afymatrix Power Tools Programm (version 1.15.1) frst gene expression and its alteration by spinal modulation subtracting background, followed by normalization, and has not been assessed in humans treated with DRG-SCS. then summarizing expression. R-Packages Program was Hence, we extended the molecular profling of our used to obtain the diferential expression, q-values and previously published study and attempted to deter- quality check. mine gene expression changes in the whole transcrip- Te raw data was log transformed before the statisti- tome. We then attempted to quantify clinical efects cal analysis was performed. To compare two groups, we performed a Student’s t test. A p value of less than 0.05 of L4-DRGSTIM based on genomic considerations as a result of the clinically applied neurostimulation. To the was considered a signifcant diference between two best of our knowledge, this is the frst in-human study groups. Te analysis was performed using Graph Pad evaluating gene expression changes of circulating blood Prism. cells in CRPS patients treated with selective, unilateral L4-DRG stimulation. Bioinformatics Pathway enrichment of diferentially expressed genes, Methods obtained from gene expression assay, was performed by two diferent prediction tools: GOrilla ® (Gene Ontol- Te current study represents an extension of the pre- ogy enRIchment anaLysis and visuaLizAtion tool) and viously published encompassing genetic analysis of PANTHER® V. 14.0 (Protein ANalysis THrough Evolu- whole transcriptome at baseline and after 3 months of tionary Relationships; http://www.panth erdb.org). Tis L4-DRG stimulation. software was used for transcriptome profling allowing Kinfe et al. J Transl Med (2019) 17:205 Page 3 of 13 rapid analysis and standardized interpretation of large accessory protein (IL1RAP; − 1.4-fold, p = 0.02), inter- data in a fully automated workfow [9]. leukin 1 receptor antagonist (ILRN; − 1.3-fold, p = 0.04), Te PANTHER database represents a classifcation of complement component 5 (C5; − 1.3-fold, p = 0.01), peptide-coding genes (104 sequenced genome) accord- PKB (PDZ binding kinase; − 1.2-fold, p = 0.04) and ing to the evolutionary relationships of peptide func- interleukin 18 (IL18; − 1.2-fold, p = 0.05) were down- tion included in the Gene Ontology (GO) Phylogenetic regulated (Figs. 3, 4). Te remaining fourteen [14] genes Annotation Project and Biological Pathways databases. including chemokine (C-X–C motif) ligand 2 (CXCL2; Tis includes a phylogenetic tree according to the onto- 1.2-fold, p = 0.001), chemokine (C–C motif) ligand logical function, which in turns allows to identify onto- 11 (CCL11; 1.2-fold, p = 0.01), interleukin 36 gamma logically related peptide subfamilies based upon the (IL36G; 1.2-fold, p = 0.02), C-reactive protein (CRP; hidden Markov model (HMM). Te PANTHER model 1.2-fold, p = 0.02), secretoglobin, family 1A, member also enables the use of distinct analysis tools (gene
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