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Neurodegenerative effects of azithromycin in differentiated PC12 cells
Vicki Waetzig1, Jeanette Riffert1, Justus Cordt1
1Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, 24105 Kiel, Germany.
Abstract:
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.
Insights
Low-dose azithromycin (macrolide antibiotic) can harm neuronal cells by disrupting signaling and autophagy. However, these neurotoxic effects are reversible in differentiated cells when exposure is brief.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Azithromycin, a macrolide antibiotic, penetrates tissues well but prolonged use may cause neurological side effects like hearing loss.
- The precise mechanism behind azithromycin-induced neurodegeneration remains unclear.
- Differentiated neuronal cells are susceptible to drug-induced toxicity.
Purpose of the Study:
- To investigate the neurotoxic effects of azithromycin at therapeutically relevant concentrations.
- To elucidate the underlying molecular mechanisms of azithromycin-induced neurotoxicity.
- To assess the reversibility of these effects in neuronal cell models.
Main Methods:
- Differentiated PC12 cells and SH-SY5Y cells were exposed to varying concentrations of azithromycin.
- Cell viability, neurite loss, tropomyosin-related kinase A (TrkA) signaling, protein kinase B (Akt) activity, and autophagy were assessed.
- Lysosomal function and autophagic flux were analyzed.
- Reversibility was tested by removing azithromycin after a 24-hour exposure.
Main Results:
- Low azithromycin concentrations (1µg/ml) reduced PC12 cell viability by 15% and neurite outgrowth by 47% after 96 hours.
- Azithromycin altered TrkA signaling, attenuated Akt activity, induced autophagy, and impaired lysosomal function, blocking autophagic flux.
- PC12 cells showed complete recovery upon azithromycin removal after 24 hours, indicating reversible effects.
- Detrimental effects were observed only in differentiated neuronal cells (PC12 and SH-SY5Y).
Conclusions:
- Azithromycin impacts cell surface receptor signaling and autophagy in differentiated neuronal cells.
- Impaired autophagic flux and lysosomal function contribute to azithromycin's neurotoxicity.
- Short-term, low-dose azithromycin exposure does not appear to cause irreversible neuronal damage.
