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PLoS One. 2019 Jan 24;14(1):e0210995. doi: 10.1371/journal.pone.0210995. eCollection 2019.

Circulating microRNA and automated motion analysis as novel methods of assessing chemotherapy-induced peripheral neuropathy in mice.

Author information

1
Drug Safety Research & Development, Pfizer Worldwide Research & Development, La Jolla, California, United States of America.
2
Vium Inc., Milpitas, California, United States of America.
3
Drug Safety Research & Development, Pfizer Worldwide Research & Development, Groton, Connecticut, United States of America.
4
Comparative Medicine, Pfizer Worldwide Research & Development, Cambridge, Massachusetts, United States of America.
5
Drug Safety Research & Development, Pfizer Worldwide Research & Development, Cambridge, Massachusetts, United States of America.

Abstract

Chemotherapy-induced peripheral neuropathy (CiPN) is a serious adverse effect in the clinic, but nonclinical assessment methods in animal studies are limited to labor intensive behavioral tests or semi-quantitative microscopic evaluation. Hence, microRNA (miRNA) biomarkers and automated in-life behavioral tracking were assessed for their utility as non-invasive methods. To address the lack of diagnostic biomarkers, we explored miR-124, miR-183 and miR-338 in a CiPN model induced by paclitaxel, a well-known neurotoxic agent. In addition, conventional and Vium's innovative Digital Vivarium technology-based in-life behavioral tests and postmortem microscopic examination of the dorsal root ganglion (DRG) and the sciatic nerve were performed. Terminal blood was collected on days 8 or 16, after 20 mg/kg paclitaxel was administered every other day for total of 4 or 7 doses, respectively, for plasma miRNA quantification by RT-qPCR. DRG and sciatic nerve samples were collected from mice sacrificed on day 16 for miRNA quantification. Among the three miRNAs analyzed, only miR-124 was statistically significantly increased (5 fold and 10 fold on day 8 and day 16, respectively). The increase in circulating miR-124 correlated with cold allodynia and axonal degeneration in both DRG and sciatic nerve. Automated home cage motion analysis revealed for the first time that nighttime motion was significantly decreased (P < 0.05) in paclitaxel-dosed animals. Although both increase in circulating miR-124 and decrease in nighttime motion are compelling, our results provide positive evidence warranting further testing using additional peripheral nerve toxicants and diverse experimental CiPN models.

Conflict of interest statement

QP, AS, IP, JF-M, AV, MB, CS, JCC and C-NL are employed by Pfizer. Pfizer paid a scientific service fee to Vium Inc. JM and LS are employed by Vium Inc. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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