# (PQ9) A NOVEL MECHANISM OF PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY AND POTENTIAL TREATMENT

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $343,846

## Abstract

Project summary
Paclitaxel-induced peripheral neuropathy (PIPN) and associated neuropathic pain is the most common and
serious adverse effect experienced by cancer patients accepted paclitaxel infusion, which adversely affects daily
activities and thereby quality of life, and sometimes forces the suspension of treatment, negatively impacting
survival. However, mechanisms underlying the pathogenesis of PIPN are uncertain, which hinders the
development of effective therapies for this comorbidity. The proposed studies attempt to identify molecular
mechanisms underlying PIPN, as well as a potential therapeutic target to prevent the development of PIPN and
neuropathic pain. Excessive neuronal excitation is a primary source of PIPN. Our preliminary data indicate
that the hyperexcitability of primary sensory neurons might result from paclitaxel-induced inhibition of
KCNQ/Kv7 channels, which are abundant in sensory neurons and axons. Retigabine, an FDA-approved
drug that opens KCNQ/Kv7 channels, could be a plausible treatment to reduce paclitaxel-induced
pathology and symptoms. We hypothesize that paclitaxel induces peripheral neuropathy and
chronic pain by inhibiting KCNQ/Kv7 channels and exciting primary sensory neurons,
activating KCNQ/Kv7 channels during chemotherapeutic agent infusion may thus prevent the
development of PIPN. In this project, we will produce PIPN in adult, tumor-free rats or mice, and utilize
techniques of immunohistochemistry, electrophysiology, electron microscopy, and behavioral testing to test
three important predictions: 1) Paclitaxel excites primary sensory neurons by inhibiting KCNQ/Kv7 channels.
Paclitaxel-induced effects on KCNQ currents in CHO cell lines in which KCNQ2/3 are overexpressed, as well as
its effects (KCNQ currents and membrane potential) on DRG neurons from naïve rats, Kcnq2fl/fl//Pax3-Cre,
Kcnq3-/-, and their littermate control mice will be assessed electrophysiologically (in vitro recording); 2)
Paclitaxel induces peripheral neuropathy and chronic pain by inhibiting KCNQ/Kv7 channels. XE-991, a
selective KCNQ/Kv7 channel blocker, will be delivered to naïve rats to see whether XE-991 can simulate PIPN
and chronic pain. The role of KCNQ/Kv7 channels in PIPN will then be evaluated by exposing of
Kcnq2fl/fl//Pax3-Cre, Kcnq3-/-, and their littermate control mice to paclitaxel. Pain-related behavior,
morphological alterations (gliosis in the spinal cord, IENF in the skin, ROS in DRG neurons, mitochondria and
microtubules in nerve sections), and neuronal excitability will be assessed; 3) Combining retigabine with
paclitaxel can prevent the development of peripheral neuropathy and neuropathic pain. Retigabine will be
given to rats during the exposure to paclitaxel. The excitability of DRG neurons, gliosis in spinal cord, IENF in
the epidermis, and pain-related behaviors will be measured. Finally, the chemosensitivity of a breast cancer
tumor to paclitaxel will be assessed in the presence of retigabine. These studies...

## Key facts

- **NIH application ID:** 9998922
- **Project number:** 5R01CA208765-05
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Qing Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,846
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998922

## Citation

> US National Institutes of Health, RePORTER application 9998922, (PQ9) A NOVEL MECHANISM OF PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY AND POTENTIAL TREATMENT (5R01CA208765-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9998922. Licensed CC0.

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