Colistin induced peripheral neurotoxicity involves mitochondrial dysfunction and oxidative stress in mice

Area of Science:

• Pharmacology
• Neuroscience
• Toxicology

Background:

• Polymyxins are vital antibiotics for multidrug-resistant Gram-negative infections.
• Neurotoxicity is a significant dose-limiting side effect of polymyxins.
• Understanding colistin's neurotoxicity mechanism is crucial for safe clinical use.

Purpose of the Study:

• To investigate the molecular mechanisms of colistin-induced peripheral neurotoxicity.
• To elucidate the role of oxidative stress, mitochondrial dysfunction, and specific signaling pathways.

Main Methods:

• A mouse model was used, with mice divided into control and colistin treatment groups (1, 3, 7 days).
• Intravenous colistin sulfate (15 mg/kg/day) was administered.
• Sciatic nerve tissues were analyzed for structural damage, oxidative stress markers, mitochondrial function, ATP levels, and gene expression (Akt, mTOR, Bax, caspase-3).

Main Results:

• Colistin treatment for 7 days caused demyelination, axonal degeneration, and mitochondrial swelling in sciatic nerves.
• It induced oxidative stress, increased mitochondrial permeability transition, decreased membrane potential, and reduced respiratory chain activity.
• Adenosine-triphosphate (ATP) levels and Na+/K+-ATPase activity were significantly decreased.
• Colistin downregulated Akt/mTOR and upregulated Bax/caspase-3 mRNA expression.

Conclusions:

• Colistin-induced sciatic nerve damage is linked to oxidative stress and mitochondrial dysfunction.
• Inhibition of the Akt/mTOR pathway and apoptosis promotion contribute to neurotoxicity.
• These findings provide insights into the molecular basis of colistin neurotoxicity.