The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a...

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Pharmacology

Background:

• Paclitaxel chemotherapy can cause dose-limiting peripheral neuropathy, characterized by neuronal damage.
• Mitochondrial dysfunction is a key factor in paclitaxel-induced peripheral neuropathy.
• The protein PINK1 is crucial for maintaining mitochondrial health and quality control.

Purpose of the Study:

• To investigate the therapeutic potential of niclosamide, a small-molecule PINK1 activator, for paclitaxel-induced peripheral neuropathy.
• To determine if niclosamide can ameliorate paclitaxel-induced thermal hyperalgesia and mitochondrial dysfunction in a PINK1-dependent manner.

Main Methods:

• Utilized *Drosophila* larvae models to assess paclitaxel-induced thermal hyperalgesia and C4da neuron morphology.
• Measured mitochondrial reactive oxygen species (ROS) and mitophagy levels in *Drosophila* C4da neurons and human SH-SY5Y cells.
• Evaluated the effect of niclosamide cotreatment on paclitaxel-induced mitochondrial dysfunction and hyperalgesia.

Main Results:

• Niclosamide significantly ameliorated paclitaxel-induced thermal hyperalgesia in *Drosophila* larvae, dependent on PINK1.
• Niclosamide suppressed paclitaxel-induced increases in mitochondrial ROS and aberrant mitophagy in C4da neurons.
• Niclosamide mitigated paclitaxel-induced mitochondrial dysfunction in human SH-SY5Y cells, also in a PINK1-dependent manner.

Conclusions:

• Niclosamide alleviates paclitaxel-induced thermal hyperalgesia by targeting and reducing mitochondrial dysfunction and oxidative stress.
• Niclosamide demonstrates potential as a therapeutic agent for paclitaxel-induced peripheral neuropathy with low neuronal toxicity.
• Targeting mitochondrial dysfunction represents a promising strategy for managing chemotherapy-induced peripheral neuropathy.