title: Analgesic Response to Intravenous Ketamine Is Linked to a Circulating microRNA Signature in Female Patients With Complex Regional Pain Syndrome.
abstract: Although ketamine is beneficial in treating complex regional pain syndrome (CRPS), a subset of patients respond poorly to therapy. We investigated treatment-induced microRNA (miRNA) changes and their predictive validity in determining treatment outcome by assessing miRNA changes in whole blood from patients with CRPS. Blood samples from female patients were collected before and after 5 days of intravenous ketamine administration. Seven patients were responders and 6 were poor responders. Differential miRNA expression was observed in whole blood before and after treatment. In addition, 33 miRNAs differed between responders and poor responders before therapy, suggesting the predictive utility of miRNAs as biomarkers. Investigation of the mechanistic significance of hsa-miR-548d-5p downregulation in poor responders showed that this miRNA can downregulate UDP-glucuronosyltransferase UGT1A1 mRNA. Poor responders had a higher conjugated/unconjugated bilirubin ratio, indicating increased UGT1A1 activity. We propose that lower pretreatment levels of miR-548d-5p may result in higher UDP-GT activity, leading to higher levels of inactive glucuronide conjugates, thereby minimizing the therapeutic efficacy of ketamine in poor responders. Differences in miRNA signatures can provide molecular insights distinguishing responders from poor responders. Extending this approach to other treatment and outcome assessments might permit stratification of patients for maximal therapeutic outcome. Perspective: This study suggests the usefulness of circulating miRNAs as potential biomarkers. Assessing miRNA signatures before and after treatment demonstrated miRNA alterations from therapy; differences in miRNA signature in responders and poor responders before therapy indicate prognostic value. Mechanistic studies on altered miRNAs can provide new insights into disease.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Sabrina R
authors.initials: SR
authors.lastname: Douglas
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Botros B
authors.initials: BB
authors.lastname: Shenoda
authors.affiliation: School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Rehman A
authors.initials: RA
authors.lastname: Qureshi
authors.affiliation: School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Sacan
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Guillermo M
authors.initials: GM
authors.lastname: Alexander
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Marielle
authors.initials: M
authors.lastname: Perreault
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: James E
authors.initials: JE
authors.lastname: Barrett
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Enrique
authors.initials: E
authors.lastname: Aradillas-Lopez
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartzman
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania. Electronic address: seena.ajit@drexelmed.edu.
authors.forename: Seena K
authors.initials: SK
authors.lastname: Ajit
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000700:Analgesics / Q000627:therapeutic use*; D020918:Complex Regional Pain Syndromes / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000097:blood / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D013223:Statistics as Topic; D014162:Transfection; D000099148:UGT1A1 Enzyme
chemical_list: D000700:Analgesics; D014453:Glucuronosyltransferase; D007649:Ketamine; D035683:MicroRNAs; D012333:RNA, Messenger; D000099148:UGT1A1 Enzyme; C561887:MIRN548 microRNA, human
keywords: MicroRNA; biomarker; complex regional pain syndrome; ketamine