Highlights
- •We studied ketamine treatment–induced miRNA alterations in blood from patients with CRPS.
- •Differential miRNA expression was observed in whole blood before and after treatment.
- •Before therapy, 33 miRNAs differed between responders and poor responders.
- •Lower pretreatment levels of miR-548d-5p may contribute to higher UDP-GT activity.
- •Circulating miRNAs can be potential biomarkers in predicting treatment response.
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.
Keywords
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Article Info
Publication History
Published online: June 10, 2015
Accepted:
May 28,
2015
Received in revised form:
May 4,
2015
Received:
March 18,
2015
Footnotes
S.R.D. and B.B.S. contributed equally to this work.
This study was supported by funds from a Rita Allen Foundation grant to S.K.A. B.B.S. is a recipient of the Fulbright Foreign Student Program Fellowship funded by the U.S. Department of State Bureau of Educational and Cultural Affairs. The authors report no disclosures. This study was not industry sponsored.
Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com.
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© 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
