Otilonium bromide ameliorates paclitaxel-induced peripheral neuropathy by targeting phosphatase PPM1A
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Xiaojing Liu1, Meng Zhang1, Yue Zhang1
1School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Abstract:
Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a severe side effect lacking effective treatment, largely due to its complex and poorly understood pathogenesis. Here, we observed the pathological inhibition of phosphatase PPM1A activity in the dorsal root ganglia (DRG) tissues of PIPN mice. We also found that otilonium bromide (OB), as a PPM1A activator, ameliorated the PIPN-like pathology in mice, as evidenced by the alleviation of sensory dysfunction, myelin sheath injury, intraepidermal nerve fiber loss and vascular lesions. Using PPM1A-specific knockdown mice, we demonstrated that OB suppresses pro-inflammatory M1 macrophage polarization in the DRG through the PPM1A/NF-κB/NLRP3/IL-1β pathway, thereby alleviating axonal degeneration and neuronal apoptosis. In vitro experiments revealed that PTX-damaged DRG neurons release high-mobility group box 1 (HMGB1) to promote pro-inflammatory macrophage polarization, while OB disrupts this neuron-macrophage interaction by limiting HMGB1 release and subsequent macrophage activation. Together, our findings highlight PPM1A activation as a promising therapeutic strategy for PIPN and identify OB as a potential agent for treating this clinical side effect.
Insights
Paclitaxel-induced peripheral neuropathy (PIPN) is a severe chemotherapy side effect. Otilonium bromide (OB) activates phosphatase PPM1A, reducing PIPN by inhibiting inflammation and neuronal damage.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Paclitaxel-induced peripheral neuropathy (PIPN) presents a significant clinical challenge due to its complex pathogenesis and lack of effective treatments.
- Pathological inhibition of phosphatase PPM1A activity in dorsal root ganglia (DRG) tissues is observed in PIPN models.
Purpose of the Study:
- To investigate the therapeutic potential of activating phosphatase PPM1A for PIPN.
- To elucidate the underlying mechanisms by which otilonium bromide (OB) ameliorates PIPN.
Main Methods:
- Utilized PIPN mouse models and PPM1A-specific knockdown mice.
- Assessed pathological changes including sensory dysfunction, myelin sheath integrity, nerve fiber density, and vascular lesions.
- Investigated the role of the PPM1A/NF-κB/NLRP3/IL-1β pathway and neuron-macrophage interactions involving high-mobility group box 1 (HMGB1).
Main Results:
- Otilonium bromide (OB), a PPM1A activator, significantly ameliorated PIPN-like pathologies in mice.
- OB suppressed pro-inflammatory M1 macrophage polarization in the DRG via the PPM1A/NF-κB/NLRP3/IL-1β pathway, reducing axonal degeneration and neuronal apoptosis.
- In vitro studies showed OB disrupts PTX-damaged DRG neuron-macrophage interaction by limiting HMGB1 release and subsequent macrophage activation.
Conclusions:
- PPM1A activation represents a promising therapeutic strategy for managing PIPN.
- Otilonium bromide (OB) demonstrates potential as a clinical agent for treating paclitaxel-induced peripheral neuropathy.
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