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DNA damage induced PARP-1 overactivation confers paclitaxel-induced neuropathic pain by regulating mitochondrial

Meng-Meng Ge1,2, Jun-Jie Hu3, Ya-Qun Zhou2

  • 1Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.

CNS Neuroscience & Therapeutics
|August 31, 2024
PubMed
Abstract

Insights

Poly (ADP-ribose) polymerase-1 (PARP-1) overactivation drives paclitaxel-induced neuropathic pain (PINP) via oxidative damage. Inhibiting PARP-1 with a novel PROTAC therapy offers a promising treatment strategy for PINP.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Poly (ADP-ribose) polymerase (PARP) inhibitors show promise in managing paclitaxel-induced neuropathic pain (PINP).
  • The precise mechanisms underlying PARP overactivation in PINP pathogenesis require further elucidation.

Purpose of the Study:

  • To investigate the role of PARP overactivation in PINP development.
  • To explore the therapeutic potential of targeting PARP-1 for PINP treatment.

Main Methods:

  • Investigated DNA oxidative damage, PARP-1 overactivation, and nicotinamide adenine dinucleotide (NAD+) depletion in PINP.
  • Developed and administered an Olaparib PROTAC via intrathecal injection in a rat model.
  • Assessed the impact of PARP-1 inhibition on mitochondrial redox metabolism and sirtuin-3 (SIRT3) activity.

Main Results:

  • PARP-1 overactivation and NAD+ depletion are key events in PINP pathogenesis.
  • Olaparib PROTAC treatment effectively inhibited PARP-1 and protected against PINP in rats.
  • PARP-1 inhibition upregulated mitochondrial redox metabolism and SIRT3 activity, linked to increased NAD+ levels.

Conclusions:

  • Findings reveal DNA oxidative damage as a mechanism in PINP.
  • PARP-1 is identified as a critical therapeutic target for managing PINP.
Keywords:
Olaparib PROTACPARP‐1Sirt‐3oxidative metabolismpaclitaxel‐induced neuropathic pain

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