Resolution of chemotherapy-induced peripheral neuropathy by novel lipid mediator Chemotherapy-induced peripheral neuropathy (CIPN) is the dose-limiting toxicity for many commonly used classes of anti-cancer agents. CIPN can lead to dose reductions or discontinuation of cancer therapy. In particular, taxanes, such as paclitaxel, remain the most effective and commonly used drugs in human chemotherapy;however, they cause painful neuropathy in approximately 25% of cancer patients receiving standard doses, and in nearly all patients receiving high doses of chemotherapy. Currently, there are no FDA- approved interventions or prevention strategies for CIPN. CIPN results in morphological and functional insults to the peripheral nervous system, including dorsal root ganglion (DRG) abnormalities, oxidative stress, activation of glial cells, release of pro-inflammatory cytokines, and loss of epidermal innervations. Disruption of acute resolution processing may lead to uncontrolled inflammation and chronic pain. Neuroprotectin D1 (NPD1) is a newly identified endogenous lipid mediator biosynthesized from omega-3 fatty acids, and demonstrates potent anti-inflammatory and pro-resolving actions. The central hypothesis of this application is that NPD1 prevents and reverses chemotherapy-induced neuropathic pain, by resolving CIPN-induced neuroinflammation, glial activation, neuronal hyperactivity, and loss of epidermal innervations. These studies will focus on chemotherapy-induced neuropathic pain, as well as determine the mechanisms by which the endogenous lipid mediator to resolve CIPN. We believe this application will demonstrate novel molecular and cellular mechanisms of CIPN and help develop new therapy for treating chronic pain associated with CIPN.

Public Health Relevance

Disruption of acute resolving processing may lead to uncontrolled inflammation and chronic pain associated with chemotherapy-induced peripheral neuropathy (CIPN). Neuroprotectins are newly identified endogenous mediators biosynthesized from omega-3 fatty acids and potent anti-inflammatory and pro-resolving mediators. In this application, we will address whether and how neuroprotectin D1 can prevent and reserve chemotherapy-induced neuropathic pain and peripheral innervation loss. This application will demonstrate novel molecular and cellular mechanisms of CIPN and help develop new therapy for treating chronic pain associated with CIPN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082985-01
Application #
8492770
Study Section
Special Emphasis Panel (ZRG1-IFCN-Z (02))
Program Officer
Gwinn, Katrina
Project Start
2013-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$235,500
Indirect Cost
$85,500
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Park, Chul-Kyu; Xu, Zhen-Zhong; Berta, Temugin et al. (2014) Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 82:47-54
Berta, Temugin; Park, Chul-Kyu; Xu, Zhen-Zhong et al. (2014) Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-? secretion. J Clin Invest 124:1173-86
Ji, Ru-Rong; Xu, Zhen-Zhong; Gao, Yong-Jing (2014) Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov 13:533-48
Berta, T; Liu, Y-C; Xu, Z-Z et al. (2013) Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1* and ERK signaling in the spinal cord of mice. Neuroscience 247:376-85
Pagadala, Promila; Park, Chul-Kyu; Bang, Sangsu et al. (2013) Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels. J Neurosci 33:13425-30
Xu, Zhen-Zhong; Liu, Xing-Jun; Berta, Temugin et al. (2013) Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. Ann Neurol 74:490-5