Azithromycin is a widely used macrolide antibiotic with sustained and high tissue penetration and intracellular accumulation. While short-term exposure to low-dose azithromycin is usually well tolerated, prolonged treatment can lead to unwanted neurological effects like paresthesia and hearing loss. However, the mechanism causing neurodegeneration is still unknown. Here, we show that even low therapeutically relevant azithromycin concentrations like 1µg/ml decreased cell viability by 15% and induced neurite loss of 47% after 96h in differentiated PC12 cells, which are a well-established model system for neuronal cells. When higher concentrations were used, the drug-induced effects occurred earlier and were more pronounced. Thereby, azithromycin altered tropomyosin-related kinase A (TrkA) signaling and attenuated protein kinase B (Akt) activity, which subsequently induced autophagy. Simultaneously, the antibiotic impaired lysosomal functions by blocking the autophagic flux, and this concurrence reduced cell viability. In good agreement with reversible effects observed in patients, PC12 cells could completely recover if azithromycin was removed after 24h. In addition, the detrimental effects of azithromycin were limited to differentiated cells, as confirmed in the human neuronal model cell line SH-SY5Y. Thus, azithromycin alters cell surface receptor signaling and autophagy in neuronal cells, but does not automatically induce irreversible damage when used in low concentrations and for a short time.
Pubmed ID: 28479141 RIS Download
Mesh terms: Animals | Autophagy | Azithromycin | Cell Differentiation | Cell Line, Tumor | Cell Survival | Dose-Response Relationship, Drug | Humans | JNK Mitogen-Activated Protein Kinases | Mitogen-Activated Protein Kinase 1 | Mitogen-Activated Protein Kinase 3 | Nerve Growth Factor | Neurites | Neurons | PC12 Cells | Proto-Oncogene Proteins c-akt | Rats | Receptor, Nerve Growth Factor | Signal Transduction | Time Factors
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